Trial Outcomes & Findings for BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation (NCT NCT00949650)

Last Updated: 2018-04-06

Results Overview

PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

345 participants

Primary outcome timeframe

Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Results posted on

2018-04-06

Participant Flow

Two-arm, randomised (2:1 ratio), open-label, active-controlled, parallel-group comparison. 345 patients were randomised, 5 patients were not treated: 4 patients were not eligible for treatment and 1 patient in the chemotherapy arm refused to take study medication.

Participant milestones

Participant milestones
Measure	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Study STARTED	230	115
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	230	115

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Overall Study Progressive disease	188	19
Overall Study Completed 6 courses of chemotherapy	0	60
Overall Study Other Adverse Event (AE)	28	17
Overall Study Protocol Violation	1	4
Overall Study Refusal to continue medication	7	11
Overall Study Not treated	1	4
Overall Study Other not specified above	5	0

Baseline Characteristics

BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Total n=345 Participants Total of all reporting groups
Age, Continuous	60.5 Years STANDARD_DEVIATION 10.1 • n=93 Participants	59.9 Years STANDARD_DEVIATION 10.0 • n=4 Participants	60.3 Years STANDARD_DEVIATION 10.1 • n=27 Participants
Sex: Female, Male Female	147 Participants n=93 Participants	77 Participants n=4 Participants	224 Participants n=27 Participants
Sex: Female, Male Male	83 Participants n=93 Participants	38 Participants n=4 Participants	121 Participants n=27 Participants
Race/Ethnicity, Customized Asian	166 Participants n=93 Participants	83 Participants n=4 Participants	249 Participants n=27 Participants
Race/Ethnicity, Customized Non-Asian	64 Participants n=93 Participants	32 Participants n=4 Participants	96 Participants n=27 Participants
Epidermal Growth Factor Receptor (EGFR) mutation group EGFR mutation category: L858R	91 Participants n=93 Participants	47 Participants n=4 Participants	138 Participants n=27 Participants
Epidermal Growth Factor Receptor (EGFR) mutation group EGFR mutation category: Deletion Exon 19	112 Participants n=93 Participants	57 Participants n=4 Participants	169 Participants n=27 Participants
Epidermal Growth Factor Receptor (EGFR) mutation group EGFR mutation category: Other	27 Participants n=93 Participants	11 Participants n=4 Participants	38 Participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 0 (baseline)	92 Participants n=93 Participants	41 Participants n=4 Participants	133 Participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 1 (baseline)	138 Participants n=93 Participants	73 Participants n=4 Participants	211 Participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 2 (baseline)	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants

PRIMARY outcome

Timeframe: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Population: Randomised set (RS)

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Progression-Free Survival (PFS) Time	11.17 Months. Interval 9.63 to 13.7	6.90 Months. Interval 5.39 to 8.25	—	—

SECONDARY outcome

Timeframe: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Population: RS.

OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Percentage of Patients With Objective Response (OR)	56.5 Percentage of patients with OR. Interval 49.8 to 63.0	22.6 Percentage of patients with OR. Interval 15.3 to 31.3	—	—

SECONDARY outcome

Timeframe: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Population: RS.

DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Percentage of Participants With Disease Control (DC)	90.4 Percentage of participants with DC. Interval 85.9 to 93.9	80.9 Percentage of participants with DC. Interval 72.5 to 87.6	—	—

SECONDARY outcome

Timeframe: From randomisation to cut-off date (17MAR2017).

Population: RS.

OS was defined as time from randomisation to death.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Overall Survival (OS) Time	28.16 Months. Interval 24.64 to 33.58	28.22 Months. Interval 20.73 to 33.22	—	—

SECONDARY outcome

Timeframe: Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression

Population: RS. There were only 203 patients in the Afatinib 40 mg arm and 101 patients in the Pemetrexed/Cisplatin Chemotherapy with tumour measurements.

Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=203 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=101 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Tumour Shrinkage	33.19 mm. Standard Error 1.12	43.00 mm. Standard Error 1.59	—	—

SECONDARY outcome

Timeframe: Baseline and throughout the trial until progression (every 3 weeks), up to 28 months.

Population: RS. Only patients with baseline and at least one post-baseline assessment were included.

Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=224 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=109 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Change From Baseline in Body Weight Change from baseline at lowest value	-3.95 Kg. Standard Deviation 3.91	-2.68 Kg. Standard Deviation 2.90	—	—
Change From Baseline in Body Weight Change from baseline at last value	-1.19 Kg. Standard Deviation 5.36	-0.29 Kg. Standard Deviation 4.02	—	—

SECONDARY outcome

Timeframe: Throughout the trial until progression (every 3 weeks), up to 28 months.

Population: RS. Only patients with baseline and at least one post-baseline assessment were included.

ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. 1. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. 2. Ambulatory (\>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. 3. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. 4. Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 5. Dead.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=228 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=111 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 0 (last value)	92 Participants	41 Participants	—	—
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 1 (last value)	138 Participants	73 Participants	—	—
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ECOG PS 2 (last value)	0 Participants	1 Participants	—	—

SECONDARY outcome

Timeframe: Throughout the trial until progression (every 3 weeks).

Population: RS.

HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing	26.97 Months. Interval 19.22 to As only 82 patients (35.7 percent) in the Afatinib 40 mg deteriorated, the upper limit of Confidence Interval (CI) was not estimable.	8.02 Months. Interval 4.44 to As only 44 patients (38.3 percent) in the Pemetrexed/Cisplatin Chemotherapy deteriorated, the upper limit of the CI was not estimable.	—	—

SECONDARY outcome

Timeframe: Throughout the trial until progression (every 3 weeks).

Population: RS.

HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
HRQOL: Time to Deterioration in Dyspnoea	10.41 Months. Interval 5.59 to 15.93	2.86 Months. Interval 2.17 to 4.9	—	—

SECONDARY outcome

Timeframe: Throughout the trial until progression (every 3 weeks).

Population: RS.

HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=230 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=115 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
HRQOL: Time to Deterioration in Pain	4.17 Months. Interval 2.79 to 5.59	3.09 Months. Interval 2.17 to 3.98	—	—

SECONDARY outcome

Timeframe: Day 22.

Population: Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=11 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg n=165 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg n=3 Participants Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Trough Plasma Concentrations of Afatinib at Day 22	—	21.8 ng/mL. Geometric Coefficient of Variation 36.6	28.0 ng/mL. Geometric Coefficient of Variation 85.0	29.9 ng/mL. Geometric Coefficient of Variation 46.1

SECONDARY outcome

Timeframe: Day 29.

Population: Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=25 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg n=143 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg n=16 Participants Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Trough Plasma Concentrations of Afatinib at Day 29	—	28.0 ng/mL. Geometric Coefficient of Variation 82.4	25.8 ng/mL. Geometric Coefficient of Variation 69.5	29.6 ng/mL. Geometric Coefficient of Variation 79.2

SECONDARY outcome

Timeframe: Day 43.

Population: Patients from the treated set with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.

Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg.

Outcome measures

Outcome measures
Measure	Afatinib 40 mg n=2 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=39 Participants Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.	Afatinib 40 mg n=126 Participants Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Afatinib 50 mg n=14 Participants Patients received Afatinib monotherapy 50 mg film-coated tablets orally once daily after a dose escalation.
Trough Plasma Concentrations of Afatinib at Day 43	24.4 ng/mL. Geometric Coefficient of Variation 260	24.7 ng/mL. Geometric Coefficient of Variation 63.9	23.5 ng/mL. Geometric Coefficient of Variation 66.2	27.5 ng/mL. Geometric Coefficient of Variation 64.4

Adverse Events

Afatinib 40 mg

Serious events: 72 serious events

Other events: 229 other events

Deaths: 0 deaths

Pemetrexed/Cisplatin Chemotherapy

Serious events: 25 serious events

Other events: 108 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Afatinib 40 mg n=229 participants at risk Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.	Pemetrexed/Cisplatin Chemotherapy n=111 participants at risk Patients received Pemetrexed 500 mg/m\^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m\^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
Blood and lymphatic system disorders Anaemia	8.3% 19/229 • First administration of trial medication until 28 days after last administration of trial medication.	26.1% 29/111 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Leukopenia	2.6% 6/229 • First administration of trial medication until 28 days after last administration of trial medication.	18.9% 21/111 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Neutropenia	1.7% 4/229 • First administration of trial medication until 28 days after last administration of trial medication.	31.5% 35/111 • First administration of trial medication until 28 days after last administration of trial medication.
Blood and lymphatic system disorders Thrombocytopenia	0.44% 1/229 • First administration of trial medication until 28 days after last administration of trial medication.	7.2% 8/111 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Dry eye	6.1% 14/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Eye disorders Vision blurred	5.2% 12/229 • First administration of trial medication until 28 days after last administration of trial medication.	1.8% 2/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Abdominal pain	5.7% 13/229 • First administration of trial medication until 28 days after last administration of trial medication.	4.5% 5/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Abdominal pain upper	6.6% 15/229 • First administration of trial medication until 28 days after last administration of trial medication.	7.2% 8/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Cheilitis	9.6% 22/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Constipation	16.2% 37/229 • First administration of trial medication until 28 days after last administration of trial medication.	35.1% 39/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Diarrhoea	94.3% 216/229 • First administration of trial medication until 28 days after last administration of trial medication.	22.5% 25/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Dyspepsia	9.2% 21/229 • First administration of trial medication until 28 days after last administration of trial medication.	6.3% 7/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Mouth ulceration	10.5% 24/229 • First administration of trial medication until 28 days after last administration of trial medication.	2.7% 3/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Nausea	28.4% 65/229 • First administration of trial medication until 28 days after last administration of trial medication.	67.6% 75/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Stomatitis	38.4% 88/229 • First administration of trial medication until 28 days after last administration of trial medication.	9.0% 10/111 • First administration of trial medication until 28 days after last administration of trial medication.
Gastrointestinal disorders Vomiting	23.1% 53/229 • First administration of trial medication until 28 days after last administration of trial medication.	45.0% 50/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Asthenia	7.0% 16/229 • First administration of trial medication until 28 days after last administration of trial medication.	12.6% 14/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Chest pain	7.0% 16/229 • First administration of trial medication until 28 days after last administration of trial medication.	12.6% 14/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Fatigue	19.7% 45/229 • First administration of trial medication until 28 days after last administration of trial medication.	35.1% 39/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Malaise	3.1% 7/229 • First administration of trial medication until 28 days after last administration of trial medication.	5.4% 6/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Mucosal inflammation	29.3% 67/229 • First administration of trial medication until 28 days after last administration of trial medication.	4.5% 5/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Oedema	3.1% 7/229 • First administration of trial medication until 28 days after last administration of trial medication.	11.7% 13/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Oedema peripheral	7.4% 17/229 • First administration of trial medication until 28 days after last administration of trial medication.	7.2% 8/111 • First administration of trial medication until 28 days after last administration of trial medication.
General disorders Pyrexia	12.2% 28/229 • First administration of trial medication until 28 days after last administration of trial medication.	5.4% 6/111 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Conjunctivitis	12.2% 28/229 • First administration of trial medication until 28 days after last administration of trial medication.	2.7% 3/111 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Cystitis	6.6% 15/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.90% 1/111 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Folliculitis	5.2% 12/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Nasopharyngitis	17.0% 39/229 • First administration of trial medication until 28 days after last administration of trial medication.	8.1% 9/111 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Paronychia	57.6% 132/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Upper respiratory tract infection	12.7% 29/229 • First administration of trial medication until 28 days after last administration of trial medication.	3.6% 4/111 • First administration of trial medication until 28 days after last administration of trial medication.
Infections and infestations Urinary tract infection	8.3% 19/229 • First administration of trial medication until 28 days after last administration of trial medication.	4.5% 5/111 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Alanine aminotransferase increased	11.8% 27/229 • First administration of trial medication until 28 days after last administration of trial medication.	2.7% 3/111 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Aspartate aminotransferase increased	9.6% 22/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.90% 1/111 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Blood creatinine increased	2.2% 5/229 • First administration of trial medication until 28 days after last administration of trial medication.	9.0% 10/111 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Haemoglobin decreased	1.3% 3/229 • First administration of trial medication until 28 days after last administration of trial medication.	11.7% 13/111 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Neutrophil count decreased	0.44% 1/229 • First administration of trial medication until 28 days after last administration of trial medication.	7.2% 8/111 • First administration of trial medication until 28 days after last administration of trial medication.
Investigations Weight decreased	19.2% 44/229 • First administration of trial medication until 28 days after last administration of trial medication.	14.4% 16/111 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Decreased appetite	30.6% 70/229 • First administration of trial medication until 28 days after last administration of trial medication.	55.0% 61/111 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hypokalaemia	9.2% 21/229 • First administration of trial medication until 28 days after last administration of trial medication.	3.6% 4/111 • First administration of trial medication until 28 days after last administration of trial medication.
Metabolism and nutrition disorders Hyponatraemia	1.7% 4/229 • First administration of trial medication until 28 days after last administration of trial medication.	5.4% 6/111 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Arthralgia	9.2% 21/229 • First administration of trial medication until 28 days after last administration of trial medication.	5.4% 6/111 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Back pain	16.2% 37/229 • First administration of trial medication until 28 days after last administration of trial medication.	11.7% 13/111 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Muscle spasms	8.7% 20/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.2% 21/229 • First administration of trial medication until 28 days after last administration of trial medication.	1.8% 2/111 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Myalgia	5.2% 12/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.90% 1/111 • First administration of trial medication until 28 days after last administration of trial medication.
Musculoskeletal and connective tissue disorders Pain in extremity	8.7% 20/229 • First administration of trial medication until 28 days after last administration of trial medication.	3.6% 4/111 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Dizziness	12.2% 28/229 • First administration of trial medication until 28 days after last administration of trial medication.	10.8% 12/111 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Dysgeusia	7.9% 18/229 • First administration of trial medication until 28 days after last administration of trial medication.	8.1% 9/111 • First administration of trial medication until 28 days after last administration of trial medication.
Nervous system disorders Headache	16.2% 37/229 • First administration of trial medication until 28 days after last administration of trial medication.	17.1% 19/111 • First administration of trial medication until 28 days after last administration of trial medication.
Psychiatric disorders Insomnia	16.2% 37/229 • First administration of trial medication until 28 days after last administration of trial medication.	9.0% 10/111 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Cough	17.0% 39/229 • First administration of trial medication until 28 days after last administration of trial medication.	18.9% 21/111 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.9% 18/229 • First administration of trial medication until 28 days after last administration of trial medication.	10.8% 12/111 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Epistaxis	17.9% 41/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.90% 1/111 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Hiccups	2.2% 5/229 • First administration of trial medication until 28 days after last administration of trial medication.	9.0% 10/111 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Nasal inflammation	6.6% 15/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.7% 13/229 • First administration of trial medication until 28 days after last administration of trial medication.	2.7% 3/111 • First administration of trial medication until 28 days after last administration of trial medication.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	7.0% 16/229 • First administration of trial medication until 28 days after last administration of trial medication.	6.3% 7/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Acne	22.7% 52/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Alopecia	13.1% 30/229 • First administration of trial medication until 28 days after last administration of trial medication.	18.0% 20/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Dermatitis acneiform	14.0% 32/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Dry skin	31.4% 72/229 • First administration of trial medication until 28 days after last administration of trial medication.	1.8% 2/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Nail disorder	6.1% 14/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	8.3% 19/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Pruritus	21.8% 50/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.90% 1/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Rash	63.3% 145/229 • First administration of trial medication until 28 days after last administration of trial medication.	9.9% 11/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Skin exfoliation	5.7% 13/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Skin and subcutaneous tissue disorders Skin fissures	7.0% 16/229 • First administration of trial medication until 28 days after last administration of trial medication.	0.00% 0/111 • First administration of trial medication until 28 days after last administration of trial medication.
Vascular disorders Hypertension	6.1% 14/229 • First administration of trial medication until 28 days after last administration of trial medication.	12.6% 14/111 • First administration of trial medication until 28 days after last administration of trial medication.