Trial Outcomes & Findings for Study In Women And Men With Metastatic Breast Cancer That Have Overexpression Of ErbB2 (NCT NCT00281658)

NCT ID: NCT00281658

Last Updated: 2023-02-10

Results Overview

Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 444 participants
• Primary outcome timeframe: From date of randomization until date of death from any cause, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
• Results posted on: 2023-02-10

Participant Flow

This study was conducted in 43 centers in eight participating countries: Brazil (7), China (20), Hong Kong (3), Pakistan (3), Peru (1), Russian Federation (6), Thailand (2) and Ukraine (1).

Participant milestones

Measure	Lapatinib 1500 mg + Paclitaxel Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks	Open Label - Monotherapy Open Label - Monotherapy (Lapatinib)	Open Label - Combination Therapy Open Label - Combination Therapy (Lapatinib and Paclitaxel)
Randomized Phase STARTED	222	222	0	0
Randomized Phase Safety Population	222	221	0	0
Randomized Phase COMPLETED	133	149	0	0
Randomized Phase NOT COMPLETED	89	73	0	0
Open Label Phase STARTED	0	0	149	4
Open Label Phase COMPLETED	0	0	104	0
Open Label Phase NOT COMPLETED	0	0	45	4

Reasons for withdrawal

Measure	Lapatinib 1500 mg + Paclitaxel Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks	Open Label - Monotherapy Open Label - Monotherapy (Lapatinib)	Open Label - Combination Therapy Open Label - Combination Therapy (Lapatinib and Paclitaxel)
Randomized Phase Adverse Event	0	2	0	0
Randomized Phase Lost to Follow-up	34	27	0	0
Randomized Phase Withdrawal by Subject	8	7	0	0
Randomized Phase Study closed/terminated	1	1	0	0
Randomized Phase Disease progression	36	27	0	0
Randomized Phase Physician Decision	1	1	0	0
Randomized Phase Other reasons as defined per protocol	4	3	0	0
Randomized Phase Reason for withdrawal unspecified	4	5	0	0
Randomized Phase Treatment ongoing	1	0	0	0
Open Label Phase Adverse Event	0	0	1	0
Open Label Phase Lost to Follow-up	0	0	16	2
Open Label Phase Withdrawal by Subject	0	0	3	2
Open Label Phase Disease progression	0	0	18	0
Open Label Phase Physician Decision	0	0	1	0
Open Label Phase Relocation of patient	0	0	1	0
Open Label Phase Reason for withdrawal unspecified	0	0	5	0

Baseline Characteristics

Study In Women And Men With Metastatic Breast Cancer That Have Overexpression Of ErbB2

Baseline characteristics by cohort

Measure	Lapatinib 1500 mg + Paclitaxel n=222 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=222 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks	Total n=444 Participants Total of all reporting groups
Age, Continuous	49.1 Years STANDARD_DEVIATION 10.74 • n=5 Participants	49.3 Years STANDARD_DEVIATION 9.75 • n=7 Participants	49.2 Years STANDARD_DEVIATION 10.25 • n=5 Participants
Sex: Female, Male Female	222 Participants n=5 Participants	217 Participants n=7 Participants	439 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	5 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized White	9 Participants n=5 Participants	13 Participants n=7 Participants	22 Participants n=5 Participants
Race/Ethnicity, Customized Asian	192 Participants n=5 Participants	192 Participants n=7 Participants	384 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	21 Participants n=5 Participants	16 Participants n=7 Participants	37 Participants n=5 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Number of participants with any visceral metastatic disease and with only non-visceral disease Visceral	187 Participants n=5 Participants	186 Participants n=7 Participants	373 Participants n=5 Participants
Number of participants with any visceral metastatic disease and with only non-visceral disease Non-visceral	35 Participants n=5 Participants	36 Participants n=7 Participants	71 Participants n=5 Participants
Number of Participants with the Indicated Hormone Receptor Status ER+ and/or PgR+ or Unknown	111 Participants n=5 Participants	113 Participants n=7 Participants	224 Participants n=5 Participants
Number of Participants with the Indicated Hormone Receptor Status ER- and PgR-	111 Participants n=5 Participants	109 Participants n=7 Participants	220 Participants n=5 Participants
Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Stage I to II	107 Participants n=5 Participants	119 Participants n=7 Participants	226 Participants n=5 Participants
Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Stage III	75 Participants n=5 Participants	68 Participants n=7 Participants	143 Participants n=5 Participants
Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Stage IV	30 Participants n=5 Participants	24 Participants n=7 Participants	54 Participants n=5 Participants
Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Unknown	10 Participants n=5 Participants	11 Participants n=7 Participants	21 Participants n=5 Participants
Number of Participants with the Indicated Eastern Cooperative Oncology Group Performance Status 0, Fully Active	103 Participants n=5 Participants	113 Participants n=7 Participants	216 Participants n=5 Participants
Number of Participants with the Indicated Eastern Cooperative Oncology Group Performance Status 1, Ambulatory, Restricted Strenuous Activity	119 Participants n=5 Participants	109 Participants n=7 Participants	228 Participants n=5 Participants
Number of Participants with the Indicated Number of Metastatic Sites Greater than or equal to 3	131 Participants n=5 Participants	115 Participants n=7 Participants	246 Participants n=5 Participants
Number of Participants with the Indicated Number of Metastatic Sites Less than 3	91 Participants n=5 Participants	107 Participants n=7 Participants	198 Participants n=5 Participants
Mean Time of Disease-Free Interval	27.51 months STANDARD_DEVIATION 27.481 • n=5 Participants	29.04 months STANDARD_DEVIATION 34.522 • n=7 Participants	28.27 months STANDARD_DEVIATION 31.174 • n=5 Participants

PRIMARY outcome

Timeframe: From date of randomization until date of death from any cause, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)

Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.

Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=222 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=222 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Overall Survival (OS) at 53 Months	27.8 months Interval 23.2 to 32.2	20.5 months Interval 17.9 to 24.3

SECONDARY outcome

Timeframe: From date of randomization until date of death from any cause, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021)

Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.

Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=222 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=222 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Overall Survival (OS) at 190 Months	27.6 months Interval 23.7 to 31.5	20.3 months Interval 17.9 to 24.3

SECONDARY outcome

Timeframe: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)

Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.

Progression-free survival (PFS) during the randomized phase was defined as the interval of time (in months) between the date of randomization and the earlier of date of disease progression (radiological or clinical assessment of symptomatic progression), or date of death due to any cause.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=222 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=222 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Progression-free Survival (PFS) by Investigator Assessment	9.7 months Interval 9.2 to 11.1	6.5 months Interval 5.5 to 7.3

SECONDARY outcome

Timeframe: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)

Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.

Overall response rate (ORR) during the randomized phase was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and defined as the percentage of subjects achieving either a Complete Response (CR) or a Partial Response (PR). Participants with unknown or missing responses were treated as non-responders.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=222 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=222 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Overall Response Rate (ORR) by Investigator Assessment	69 Percentage of Participants Interval 62.9 to 75.4	50 Percentage of Participants Interval 42.8 to 56.3

SECONDARY outcome

Timeframe: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary analysis cut-off date = 18-Jun-2010)

Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.

Clinical benefit rate (CBR) was defined as the percentage of subjects with evidence of CR or PR or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesions], taking as reference the smallest sum LD since treatment start) of >=24 weeks, based on confirmed responses from the investigator assessment of best overall response during the randomized phase.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=222 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=222 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Clinical Benefit Rate (CBR)	75 Percentage of Participants Interval 68.5 to 80.3	56 Percentage of Participants Interval 49.1 to 62.5

SECONDARY outcome

Timeframe: From date of confirmed CR or PR until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)

Population: Subset of participants in the Intent-to-Treat (ITT) Population with a confirmed CR or PR

For subjects who show CR or PR, duration of response (DOR) was defined to be the time from first documented evidence of PR or CR until the first documented sign of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause, if sooner during the randomized phase.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=154 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=110 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Duration of Response (DOR)	9.3 months Interval 7.7 to 10.7	5.8 months Interval 5.6 to 7.4

SECONDARY outcome

Timeframe: Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72

Population: Participants in the Intent-to-Treat (ITT) Population with a confirmed CR or PR

The original outcome measure to be analyzed was Time to response (TTR) during the randomized phase defined as the time from randomization until first documented evidence of PR or CR (whichever status was recorded first); however, data were presented as the number of participants with a response at each nominal visit. Responses were based on the investigator's assessment, and only participants with a confirmed CR or PR were included in this analysis.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=154 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=110 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 8	94 Participants	61 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 12	40 Participants	28 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 16	6 Participants	11 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 24	7 Participants	8 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 32	3 Participants	2 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 40	0 Participants	0 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 48	1 Participants	0 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 56	1 Participants	0 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 64	1 Participants	0 Participants
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 Week 72	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline

Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations

Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=104 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=106 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Number of Tumors Evaluable for PIK3CA Mutations PIK3CA mutation	29 Participants	36 Participants
Number of Tumors Evaluable for PIK3CA Mutations PIK3CA wild-type	58 Participants	48 Participants
Number of Tumors Evaluable for PIK3CA Mutations PIK3CA indeterminate	17 Participants	22 Participants

SECONDARY outcome

Timeframe: Baseline

Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PTEN

Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=180 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=175 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Number of Participants With Tumors Evaluable for PTEN PTEN IHC 0	28 Participants	21 Participants
Number of Participants With Tumors Evaluable for PTEN PTEN IHC 1+	76 Participants	80 Participants
Number of Participants With Tumors Evaluable for PTEN PTEN IHC 2+/3+	76 Participants	74 Participants

SECONDARY outcome

Timeframe: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)

Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations (PIK3CA mutation and PIK3CA wild type)

ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=87 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=84 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) PIK3CA mutation	62 percentage of participants	50 percentage of participants
Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) PIK3CA wild-type	80 percentage of participants	59 percentage of participants

SECONDARY outcome

Timeframe: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)

Population: Participants in the Intent-to-Treat (ITT) Population with PTEN low and without PTEN low

ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=180 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=175 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Predictive Effect of PTEN Low on Overall Response Rate (ORR) PTEN low	73 percentage of participants	53 percentage of participants
Predictive Effect of PTEN Low on Overall Response Rate (ORR) Without PTEN low	76 percentage of participants	58 percentage of participants

SECONDARY outcome

Timeframe: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)

Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations (PIK3CA mutation and PIK3CA wild type)

CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=87 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=84 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) PIK3CA mutation	69 percentage of participants	56 percentage of participants
Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) PIK3CA wild-type	84 percentage of participants	65 percentage of participants

SECONDARY outcome

Timeframe: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)

Population: Participants in the Intent-to-Treat (ITT) Population with PTEN low and without PTEN low

CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low.

Outcome measures

Measure	Lapatinib 1500 mg + Paclitaxel n=180 Participants Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=175 Participants Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks
Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) PTEN low	82 percentage of participants	59 percentage of participants
Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) Without PTEN low	80 percentage of participants	61 percentage of participants

Adverse Events

Lapatinib 1500 mg + Paclitaxel

Serious events: 67 serious events

Other events: 219 other events

Deaths: 10 deaths

Placebo + Paclitaxel

Serious events: 30 serious events

Other events: 206 other events

Deaths: 15 deaths

Open Label - Monotherapy

Serious events: 8 serious events

Other events: 86 other events

Deaths: 2 deaths

Open Label - Combination Therapy

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	Lapatinib 1500 mg + Paclitaxel n=222 participants at risk Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=221 participants at risk Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks	Open Label - Monotherapy n=149 participants at risk Open Label - Monotherapy (Lapatinib)	Open Label - Combination Therapy n=4 participants at risk Open Label - Combination Therapy (Lapatinib and Paclitaxel)
General disorders Non-cardiac chest pain	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Pyrexia	1.4% 3/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Hepatobiliary disorders Cholecystitis	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Hepatobiliary disorders Hepatobiliary disease	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Hepatobiliary disorders Hepatotoxicity	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Immune system disorders Anaphylactic reaction	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Cellulitis	0.90% 2/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Escherichia bacteraemia	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Pharyngitis	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Pneumonia	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Pyelonephritis acute	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Septic shock	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Urinary tract infection	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Viral infection	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.90% 2/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Ejection fraction decreased	5.9% 13/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.4% 3/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Haemoglobin decreased	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Neutrophil count decreased	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Metabolism and nutrition disorders Hyperglycaemia	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Metabolism and nutrition disorders Hypokalaemia	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Spinal stenosis	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast neoplasm	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Nervous system disorders Intracranial pressure increased	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Nervous system disorders Presyncope	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Psychiatric disorders Completed suicide	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.90% 2/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Laryngeal oedema	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Vascular disorders Deep vein thrombosis	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Blood and lymphatic system disorders Febrile neutropenia	2.7% 6/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Blood and lymphatic system disorders Granulocytopenia	1.8% 4/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Blood and lymphatic system disorders Leukopenia	3.2% 7/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Blood and lymphatic system disorders Neutropenia	16.2% 36/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	4.5% 10/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Cardiac disorders Cardiac failure chronic	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Cardiac disorders Left ventricular dysfunction	1.4% 3/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Abdominal pain	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Diarrhoea	4.5% 10/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Pancreatitis acute	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Stomatitis	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Vomiting	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Fatigue	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Lithiasis	0.45% 1/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Multiple organ dysfunction syndrome	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.

Other adverse events

Measure	Lapatinib 1500 mg + Paclitaxel n=222 participants at risk Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks	Placebo + Paclitaxel n=221 participants at risk Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks	Open Label - Monotherapy n=149 participants at risk Open Label - Monotherapy (Lapatinib)	Open Label - Combination Therapy n=4 participants at risk Open Label - Combination Therapy (Lapatinib and Paclitaxel)
Blood and lymphatic system disorders Anaemia	22.5% 50/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	10.0% 22/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.0% 3/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Blood and lymphatic system disorders Granulocytopenia	7.7% 17/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	6.8% 15/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Blood and lymphatic system disorders Leukopenia	50.9% 113/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	33.5% 74/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	4.0% 6/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Blood and lymphatic system disorders Neutropenia	75.7% 168/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	46.6% 103/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	3.4% 5/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Abdominal distension	5.4% 12/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.4% 3/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Abdominal pain	7.7% 17/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	4.5% 10/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	3.4% 5/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Abdominal pain upper	5.9% 13/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.4% 3/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Constipation	3.6% 8/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	8.1% 18/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Diarrhoea	77.5% 172/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	29.0% 64/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	28.2% 42/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Mouth ulceration	7.2% 16/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Nausea	29.7% 66/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	19.9% 44/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.7% 4/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Gastrointestinal disorders Vomiting	21.6% 48/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	11.8% 26/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.7% 4/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Asthenia	6.8% 15/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	3.2% 7/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Fatigue	21.2% 47/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	15.8% 35/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Mucosal erosion	0.00% 0/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	25.0% 1/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Mucosal inflammation	8.1% 18/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.4% 3/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Oedema peripheral	4.1% 9/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.4% 12/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
General disorders Pyrexia	13.5% 30/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	15.4% 34/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	3.4% 5/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Hepatobiliary disorders Hepatic function abnormal	7.7% 17/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	4.1% 9/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Hepatobiliary disorders Hyperbilirubinaemia	5.4% 12/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.90% 2/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Paronychia	7.7% 17/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	4.0% 6/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Infections and infestations Upper respiratory tract infection	9.0% 20/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.4% 12/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Alanine aminotransferase increased	11.3% 25/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	7.7% 17/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.0% 3/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Aspartate aminotransferase increased	9.0% 20/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	7.2% 16/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.7% 4/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Blood bilirubin increased	3.2% 7/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.3% 5/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	25.0% 1/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Haemoglobin decreased	10.4% 23/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.8% 4/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Neutrophil count decreased	1.4% 3/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	25.0% 1/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations Red blood cell count decreased	2.7% 6/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.45% 1/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	25.0% 1/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Investigations White blood cell count decreased	5.0% 11/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.0% 11/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	25.0% 1/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Metabolism and nutrition disorders Decreased appetite	31.5% 70/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	18.6% 41/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.0% 3/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Metabolism and nutrition disorders Hyperglycaemia	2.3% 5/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.7% 6/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	25.0% 1/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Arthralgia	11.7% 26/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	9.0% 20/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Myalgia	13.5% 30/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	11.8% 26/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Nervous system disorders Dizziness	8.6% 19/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.0% 11/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Nervous system disorders Headache	9.0% 20/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	9.0% 20/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.7% 4/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Nervous system disorders Hypoaesthesia	8.1% 18/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	11.3% 25/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.0% 3/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Nervous system disorders Neuropathy peripheral	14.0% 31/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	13.6% 30/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.67% 1/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Nervous system disorders Peripheral sensory neuropathy	5.4% 12/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.9% 13/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Psychiatric disorders Insomnia	5.9% 13/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	8.1% 18/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Cough	9.9% 22/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	10.0% 22/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.9% 13/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.4% 12/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Acne	7.2% 16/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.3% 5/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	2.7% 4/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Alopecia	46.8% 104/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	53.8% 119/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.3% 2/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Dry skin	7.2% 16/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.4% 3/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.4% 8/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	50.0% 2/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Nail disorder	11.7% 26/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	1.4% 3/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	5.4% 8/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Pruritus	10.4% 23/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	4.1% 9/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	6.7% 10/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
Skin and subcutaneous tissue disorders Rash	49.1% 109/222 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	21.3% 47/221 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	34.9% 52/149 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.	0.00% 0/4 • From study treatment start date till 30 days safety follow-up, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: Novartis.email@novartis.com

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
• Publication restrictions are in place

Restriction type: OTHER