Trial Outcomes & Findings for TAC Versus TC for Adjuvant Breast Cancer (NCT NCT00493870)

Last Updated: 2023-03-02

Results Overview

The primary objective of the study is to compare the 3-year invasive disease-free survival (IDFS) of adjuvant TC versus TAC as treatment for early stage HER2-negative breast cancer among analyzed ITT patients. ITT patients are all patients who were randomized, whether or not they followed protocol. IDFS, defined as the time from the date of randomization to local recurrence following mastectomy, invasive local recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, invasive contralateral breast cancer, second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. Patients who have not had any such event at the time of data analysis will be censored at the last date they were known to be event-free.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1961 participants

Primary outcome timeframe

3 years from randomization into study

Results posted on

2023-03-02

Participant Flow

Participant milestones

Participant milestones
Measure	TC Arm docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.
Overall Study STARTED	981	980
Overall Study COMPLETED	969	965
Overall Study NOT COMPLETED	12	15

Reasons for withdrawal

Reasons for withdrawal
Measure	TC Arm docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.
Overall Study Lost to Follow-up	12	15

Baseline Characteristics

TAC Versus TC for Adjuvant Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	TC Arm n=969 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=965 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Total n=1934 Participants Total of all reporting groups
Age, Continuous	53.4 years STANDARD_DEVIATION 9.2 • n=93 Participants	53.1 years STANDARD_DEVIATION 8.9 • n=4 Participants	53.3 years STANDARD_DEVIATION 9.1 • n=27 Participants
Sex: Female, Male Female	969 Participants n=93 Participants	965 Participants n=4 Participants	1934 Participants n=27 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race/Ethnicity, Customized Caucasian	718 Participants n=93 Participants	741 Participants n=4 Participants	1459 Participants n=27 Participants
Race/Ethnicity, Customized Hispanic	141 Participants n=93 Participants	97 Participants n=4 Participants	238 Participants n=27 Participants
Race/Ethnicity, Customized Black	94 Participants n=93 Participants	95 Participants n=4 Participants	189 Participants n=27 Participants
Race/Ethnicity, Customized Asian	11 Participants n=93 Participants	22 Participants n=4 Participants	33 Participants n=27 Participants
Race/Ethnicity, Customized Indian	1 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants
Race/Ethnicity, Customized Hawaiian	0 Participants n=93 Participants	2 Participants n=4 Participants	2 Participants n=27 Participants
Race/Ethnicity, Customized Other	2 Participants n=93 Participants	5 Participants n=4 Participants	7 Participants n=27 Participants
Race/Ethnicity, Customized Unknown	2 Participants n=93 Participants	1 Participants n=4 Participants	3 Participants n=27 Participants
Baseline Performance Status (ECOG) ECOG 0	860 Participants n=93 Participants	857 Participants n=4 Participants	1717 Participants n=27 Participants
Baseline Performance Status (ECOG) ECOG 1	109 Participants n=93 Participants	108 Participants n=4 Participants	217 Participants n=27 Participants
Stage I	136 Participants n=93 Participants	124 Participants n=4 Participants	260 Participants n=27 Participants
Stage II	705 Participants n=93 Participants	716 Participants n=4 Participants	1421 Participants n=27 Participants
Stage III	128 Participants n=93 Participants	125 Participants n=4 Participants	253 Participants n=27 Participants
Hormone Receptor Status Positive	679 Participants n=93 Participants	678 Participants n=4 Participants	1357 Participants n=27 Participants
Hormone Receptor Status Negative	290 Participants n=93 Participants	287 Participants n=4 Participants	577 Participants n=27 Participants
Histology Ductal	811 Participants n=93 Participants	789 Participants n=4 Participants	1600 Participants n=27 Participants
Histology Lobular	87 Participants n=93 Participants	100 Participants n=4 Participants	187 Participants n=27 Participants
Histology Mixed	24 Participants n=93 Participants	26 Participants n=4 Participants	50 Participants n=27 Participants
Histology Other	47 Participants n=93 Participants	48 Participants n=4 Participants	95 Participants n=27 Participants
Histology Unknown	0 Participants n=93 Participants	2 Participants n=4 Participants	2 Participants n=27 Participants
Tumor size	2.7 cm STANDARD_DEVIATION 1.5 • n=93 Participants	2.6 cm STANDARD_DEVIATION 1.5 • n=4 Participants	2.6 cm STANDARD_DEVIATION 1.5 • n=27 Participants
Positive Nodes 0 nodes	358 Participants n=93 Participants	339 Participants n=4 Participants	697 Participants n=27 Participants
Positive Nodes 1-3 nodes	455 Participants n=93 Participants	480 Participants n=4 Participants	935 Participants n=27 Participants
Positive Nodes 4-9 nodes	116 Participants n=93 Participants	111 Participants n=4 Participants	227 Participants n=27 Participants
Positive Nodes 10+ nodes	40 Participants n=93 Participants	35 Participants n=4 Participants	75 Participants n=27 Participants
Grade Well/Low	100 Participants n=93 Participants	119 Participants n=4 Participants	219 Participants n=27 Participants
Grade Moderately/Intermediate	370 Participants n=93 Participants	377 Participants n=4 Participants	747 Participants n=27 Participants
Grade Poorly/Undifferentiated	470 Participants n=93 Participants	431 Participants n=4 Participants	901 Participants n=27 Participants
Grade Unknown	29 Participants n=93 Participants	38 Participants n=4 Participants	67 Participants n=27 Participants
Menopausal Status Peri	41 Participants n=93 Participants	42 Participants n=4 Participants	83 Participants n=27 Participants
Menopausal Status Post	602 Participants n=93 Participants	579 Participants n=4 Participants	1181 Participants n=27 Participants
Menopausal Status Pre	324 Participants n=93 Participants	343 Participants n=4 Participants	667 Participants n=27 Participants
Menopausal Status Unknown	2 Participants n=93 Participants	1 Participants n=4 Participants	3 Participants n=27 Participants

PRIMARY outcome

Timeframe: 3 years from randomization into study

Population: Analyzed ITT population

Outcome measures

Outcome measures
Measure	TC Arm n=969 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=965 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Normal TOP2A normal subgroup in TC arm.
3-year Invasive Disease-free Survival (IDFS) Among Analyzed ITT Patients	91.1 percentage of participants Interval 89.1 to 92.8	93.2 percentage of participants Interval 91.3 to 94.6	—

PRIMARY outcome

Timeframe: 3 years from randomization into study

Population: Per-protocol patients

The primary objective of the study is to compare the 3-year invasive disease-free survival (IDFS) of adjuvant TC versus TAC as treatment for early stage HER2-negative breast cancer among per-protocol patients. Per-protocol only includes those patients who were randomized and received treatment as outlined in the protocol.

Outcome measures

Outcome measures
Measure	TC Arm n=950 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=934 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Normal TOP2A normal subgroup in TC arm.
3-year Invasive Disease-free Survival (IDFS) Among Per-protocol Patients	91.3 percentage of participants Interval 89.3 to 93.0	93.2 percentage of participants Interval 91.3 to 94.7	—

SECONDARY outcome

Timeframe: 3 years from randomization into study

Population: Analyzed ITT population

To compare disease-free survival-ductal carcinoma in situ (DFS-DCIS),overall survival (OS) and recurrence free interval (RFI) of TC with TAC. DFS-DCIS, defined as the time from the date of randomization to local recurrence following mastectomy, local recurrence in the ipsilateral breast following lumpectomy (invasive or non-invasive), regional recurrence, distant recurrence, contralateral breast cancer (invasive or non-invasive), second primary cancer (other than squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, colorectal carcinoma in situ, or lobular carcinoma in situ of the breast), or death from any cause prior to recurrence or second primary cancer. Patients who have not had any such event at the time of data analysis will be censored at the last date they were known to be event-free.

Outcome measures

Outcome measures
Measure	TC Arm n=969 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=965 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Normal TOP2A normal subgroup in TC arm.
3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients 3-year DFS-DCIS	90.9 percentage of participants Interval 88.8 to 92.6	93.0 percentage of participants Interval 91.1 to 94.5	—
3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients 3-year OS	96.8 percentage of participants Interval 95.4 to 97.7	96.8 percentage of participants Interval 95.5 to 97.8	—
3-year DFS-DCIS, OS and RFI Among Analyzed ITT Patients 3-year RFI	91.9 percentage of participants Interval 90.0 to 93.5	94.5 percentage of participants Interval 92.8 to 95.9	—

SECONDARY outcome

Timeframe: 3 years from randomization into study

Population: Analyzed per-protocol patients

To compare disease-free survival-ductal carcinoma in situ (DFS-DCIS),overall survival (OS) and recurrence free interval (RFI) of TC with TAC among per protocol patients.

Outcome measures

Outcome measures
Measure	TC Arm n=950 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=934 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Normal TOP2A normal subgroup in TC arm.
3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. 3-year DFS-DCIS	91.1 percentage of participants Interval 89.0 to 92.8	93.0 percentage of participants Interval 91.1 to 94.5	—
3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. 3-year OS	96.8 percentage of participants Interval 95.5 to 97.8	96.8 percentage of participants Interval 95.4 to 97.8	—
3-year DFS-DCIS, OS and RFI Among Per-protocol Patients. 3-year RFI	92.1 percentage of participants Interval 90.2 to 93.7	94.5 percentage of participants Interval 92.8 to 95.8	—

SECONDARY outcome

Timeframe: 10 years (from baseline to end of study participation)

Population: Analyzed ITT patients with TOP2A data

To evaluate the effectiveness of TC and TAC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer

Outcome measures

Outcome measures
Measure	TC Arm n=624 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=631 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Normal TOP2A normal subgroup in TC arm.
Number and Frequency of Participants by TOP2A Status by Study Treatment Amplification	14 Participants	14 Participants	—
Number and Frequency of Participants by TOP2A Status by Study Treatment Deletion	131 Participants	128 Participants	—
Number and Frequency of Participants by TOP2A Status by Study Treatment Normal	479 Participants	489 Participants	—

SECONDARY outcome

Timeframe: 3 years from randomization into study

Population: Analyzed ITT patients with TOP2A data

To evaluate DFS among TC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer.

Outcome measures

Outcome measures
Measure	TC Arm n=14 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=131 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Normal n=479 Participants TOP2A normal subgroup in TC arm.
3-year DFS Stratified by TOP2A Among TC Arm	85.1 percentage of participants Interval 52.3 to 96.1	82.8 percentage of participants Interval 75.1 to 88.3	93.8 percentage of participants Interval 91.2 to 95.6

SECONDARY outcome

Timeframe: 3 years from randomization into study

Population: Analyzed ITT patients with TOP2A data among TAC arm.

To evaluate DFS among TAC in TOP2A altered (amplified, deleted, or overexpressed at the protein level) early stage HER2-negative breast cancer.

Outcome measures

Outcome measures
Measure	TC Arm n=14 Participants docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=128 Participants doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.	Normal n=489 Participants TOP2A normal subgroup in TC arm.
3-year DFS Stratified by TOP2A Among TAC Arm	100 percentage of participants Interval 100.0 to 100.0	90.9 percentage of participants Interval 84.2 to 94.9	93.2 percentage of participants Interval 90.6 to 95.2

Adverse Events

TC Arm

Serious events: 264 serious events

Other events: 680 other events

Deaths: 110 deaths

TAC Arm

Serious events: 330 serious events

Other events: 746 other events

Deaths: 88 deaths

Serious adverse events

Other adverse events

Additional Information

Taqi Mohammad

US Oncology Research

Phone: 281-863-6439

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	TC Arm n=969 participants at risk docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 plus Cyclophosphamide 600 mg/m2 IV over 15-30 minutes on Day 1 Q 21 day cycles X 6.	TAC Arm n=965 participants at risk doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2 and docetaxel 75 mg/m2 Docetaxel: Docetaxel 75 mg/m2 IV over 1 hour on Day 1 followed by cyclophosphamide Doxorubicin: • Doxorubicin 50 mg/m2 IV push over 5-15 minutes via sidearm through a running IV line on Day 1, plus cyclophosphamide 500 mg/m2 IV over 15-30 minutes on Day 1, plus docetaxel 75 mg/m2 IV over 1 hour on Day 1, followed by pegfilgrastim 6 mg SC (or filgrastim 5 mcg/kg SC) on Day 2 Q 21 day cycles X 6.
Blood and lymphatic system disorders ANEMIA	16.9% 164/969 • Number of events 164 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	19.0% 183/965 • Number of events 183 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Blood and lymphatic system disorders LEUCOPENIA	10.3% 100/969 • Number of events 100 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	9.5% 92/965 • Number of events 92 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Blood and lymphatic system disorders NEUTROPENIA	30.3% 294/969 • Number of events 294 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	25.2% 243/965 • Number of events 243 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Blood and lymphatic system disorders THROMBOCYTOPENIA	1.9% 18/969 • Number of events 18 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	7.5% 72/965 • Number of events 72 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
General disorders FATIGUE	48.5% 470/969 • Number of events 470 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	51.6% 498/965 • Number of events 498 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Skin and subcutaneous tissue disorders ALOPECIA	56.0% 543/969 • Number of events 543 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	55.8% 538/965 • Number of events 538 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Skin and subcutaneous tissue disorders NAIL DISORDER	10.3% 100/969 • Number of events 100 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	6.0% 58/965 • Number of events 58 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Skin and subcutaneous tissue disorders RASH	17.3% 168/969 • Number of events 168 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	9.7% 94/965 • Number of events 94 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Endocrine disorders HOT FLASHES	9.8% 95/969 • Number of events 95 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	8.3% 80/965 • Number of events 80 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders ANOREXIA	7.9% 77/969 • Number of events 77 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	11.1% 107/965 • Number of events 107 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders CONSTIPATION	15.8% 153/969 • Number of events 153 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	18.1% 175/965 • Number of events 175 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders DEHYDRATION	3.4% 33/969 • Number of events 33 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	8.8% 85/965 • Number of events 85 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders DIARRHEA	25.9% 251/969 • Number of events 251 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	34.3% 331/965 • Number of events 331 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders DYSGEUSIA	10.9% 106/969 • Number of events 106 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	13.2% 127/965 • Number of events 127 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders GASTROESOPHAGEAL REFLUX	7.7% 75/969 • Number of events 75 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	10.1% 97/965 • Number of events 97 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders MUCOSITIS	8.7% 84/969 • Number of events 84 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	9.7% 94/965 • Number of events 94 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders NAUSEA	33.6% 326/969 • Number of events 326 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	42.8% 413/965 • Number of events 413 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders STOMATITIS	7.1% 69/969 • Number of events 69 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	6.5% 63/965 • Number of events 63 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Gastrointestinal disorders VOMITING	11.8% 114/969 • Number of events 114 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	17.0% 164/965 • Number of events 164 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Infections and infestations FEVER	8.0% 78/969 • Number of events 78 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	8.3% 80/965 • Number of events 80 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Infections and infestations INFECTION BACTERIAL	4.4% 43/969 • Number of events 43 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	5.2% 50/965 • Number of events 50 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Infections and infestations INFECTION FUNGAL	3.2% 31/969 • Number of events 31 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	5.3% 51/965 • Number of events 51 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Blood and lymphatic system disorders EDEMA	19.4% 188/969 • Number of events 188 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	14.7% 142/965 • Number of events 142 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Metabolism and nutrition disorders HYPERGLYCAEMIA	5.5% 53/969 • Number of events 53 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	5.8% 56/965 • Number of events 56 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Nervous system disorders ANXIETY	6.5% 63/969 • Number of events 63 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	5.8% 56/965 • Number of events 56 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Nervous system disorders DEPRESSION	6.1% 59/969 • Number of events 59 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	4.8% 46/965 • Number of events 46 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Nervous system disorders DIZZINESS	4.3% 42/969 • Number of events 42 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	5.6% 54/965 • Number of events 54 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Nervous system disorders INSOMNIA	10.5% 102/969 • Number of events 102 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	9.5% 92/965 • Number of events 92 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Nervous system disorders NEUROPATHY	20.9% 203/969 • Number of events 203 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	17.7% 171/965 • Number of events 171 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Eye disorders EPIPHORA	6.0% 58/969 • Number of events 58 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	6.3% 61/965 • Number of events 61 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Investigations ABDOMINAL PAIN	5.8% 56/969 • Number of events 56 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	7.8% 75/965 • Number of events 75 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Investigations ARTHRALGIA	13.2% 128/969 • Number of events 128 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	10.4% 100/965 • Number of events 100 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Investigations BACK PAIN	5.4% 52/969 • Number of events 52 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	5.4% 52/965 • Number of events 52 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Investigations BONE PAIN	11.7% 113/969 • Number of events 113 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	10.8% 104/965 • Number of events 104 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Investigations HEADACHE	11.6% 112/969 • Number of events 112 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	11.6% 112/965 • Number of events 112 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Investigations MYALGIA	14.9% 144/969 • Number of events 144 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	11.3% 109/965 • Number of events 109 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Investigations PAIN	19.1% 185/969 • Number of events 185 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	14.4% 139/965 • Number of events 139 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Respiratory, thoracic and mediastinal disorders BREATH SHORTNESS	6.7% 65/969 • Number of events 65 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	6.8% 66/965 • Number of events 66 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Respiratory, thoracic and mediastinal disorders COUGH	7.8% 76/969 • Number of events 76 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	9.1% 88/965 • Number of events 88 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.
Respiratory, thoracic and mediastinal disorders PHARYNGITIS	5.6% 54/969 • Number of events 54 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.	3.8% 37/965 • Number of events 37 • From Baseline to 30 days after last dose of study treatment, approximately 22 weeks. All-Cause Mortality was from baseline to end of study participation, approximately 10 years.