Trial Outcomes & Findings for (VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST (NCT NCT03465722)

Last Updated: 2022-10-06

Results Overview

To demonstrate the efficacy of avapritinib based on progression-free survival (PFS) determined by central radiological assessment per modified Response Evaluation Criteria in Solid Tumors (mRECIST), version 1.1 in patients with advanced GIST following 2 or 3 regimens of prior treatment with a tyrosine kinase inhibitor (TKI), including imatinib, compared to patients treated with regorafenib. A progressively growing tumor must meet the following criteria: a) the target lesions must be greater or equal to 2cm in size and be a new GIST active lesion or b) the target lesions must be expanding on at least 2 sequential imaging studies.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

476 participants

Primary outcome timeframe

24 Months

Results posted on

2022-10-06

Participant Flow

Participant milestones

Participant milestones
Measure	Avapritinib 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Overall Study STARTED	240	236
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	240	236

Reasons for withdrawal

Reasons for withdrawal
Measure	Avapritinib 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Overall Study Withdrawal by Subject	21	14
Overall Study Death	89	87
Overall Study Lost to Follow-up	5	3
Overall Study Administrative/Other	33	32
Overall Study Not treated	1	2
Overall Study Sponsor decision	91	98

Baseline Characteristics

Both height and weight measurements are needed for body mass index calculation. Some patients had missing height and/or weight measurements. Only patients with both a height and a weight measurement are included in the body mass index calculation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Avapritinib n=240 Participants 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib n=236 Participants 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).	Total n=476 Participants Total of all reporting groups
Age, Continuous	61.1 years STANDARD_DEVIATION 10.96 • n=240 Participants	61.0 years STANDARD_DEVIATION 10.74 • n=236 Participants	61.1 years STANDARD_DEVIATION 10.84 • n=476 Participants
Sex: Female, Male Female	78 Participants n=240 Participants	80 Participants n=236 Participants	158 Participants n=476 Participants
Sex: Female, Male Male	162 Participants n=240 Participants	156 Participants n=236 Participants	318 Participants n=476 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=240 Participants	0 Participants n=236 Participants	0 Participants n=476 Participants
Race (NIH/OMB) Asian	64 Participants n=240 Participants	64 Participants n=236 Participants	128 Participants n=476 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=240 Participants	1 Participants n=236 Participants	2 Participants n=476 Participants
Race (NIH/OMB) Black or African American	9 Participants n=240 Participants	5 Participants n=236 Participants	14 Participants n=476 Participants
Race (NIH/OMB) White	139 Participants n=240 Participants	143 Participants n=236 Participants	282 Participants n=476 Participants
Race (NIH/OMB) More than one race	0 Participants n=240 Participants	0 Participants n=236 Participants	0 Participants n=476 Participants
Race (NIH/OMB) Unknown or Not Reported	27 Participants n=240 Participants	23 Participants n=236 Participants	50 Participants n=476 Participants
Region of Enrollment Singapore	2 participants n=240 Participants	2 participants n=236 Participants	4 participants n=476 Participants
Region of Enrollment Hungary	2 participants n=240 Participants	1 participants n=236 Participants	3 participants n=476 Participants
Region of Enrollment United States	71 participants n=240 Participants	62 participants n=236 Participants	133 participants n=476 Participants
Region of Enrollment Czechia	3 participants n=240 Participants	1 participants n=236 Participants	4 participants n=476 Participants
Region of Enrollment United Kingdom	12 participants n=240 Participants	12 participants n=236 Participants	24 participants n=476 Participants
Region of Enrollment Spain	14 participants n=240 Participants	11 participants n=236 Participants	25 participants n=476 Participants
Region of Enrollment Canada	2 participants n=240 Participants	6 participants n=236 Participants	8 participants n=476 Participants
Region of Enrollment Austria	0 participants n=240 Participants	1 participants n=236 Participants	1 participants n=476 Participants
Region of Enrollment Netherlands	2 participants n=240 Participants	6 participants n=236 Participants	8 participants n=476 Participants
Region of Enrollment South Korea	23 participants n=240 Participants	20 participants n=236 Participants	43 participants n=476 Participants
Region of Enrollment Sweden	6 participants n=240 Participants	7 participants n=236 Participants	13 participants n=476 Participants
Region of Enrollment Belgium	1 participants n=240 Participants	1 participants n=236 Participants	2 participants n=476 Participants
Region of Enrollment China	35 participants n=240 Participants	39 participants n=236 Participants	74 participants n=476 Participants
Region of Enrollment Poland	10 participants n=240 Participants	9 participants n=236 Participants	19 participants n=476 Participants
Region of Enrollment Italy	13 participants n=240 Participants	15 participants n=236 Participants	28 participants n=476 Participants
Region of Enrollment Australia	5 participants n=240 Participants	5 participants n=236 Participants	10 participants n=476 Participants
Region of Enrollment France	22 participants n=240 Participants	20 participants n=236 Participants	42 participants n=476 Participants
Region of Enrollment Germany	17 participants n=240 Participants	18 participants n=236 Participants	35 participants n=476 Participants
Body Mass Index (BMI)	25.50 kilogram per meter square STANDARD_DEVIATION 5.563 • n=230 Participants • Both height and weight measurements are needed for body mass index calculation. Some patients had missing height and/or weight measurements. Only patients with both a height and a weight measurement are included in the body mass index calculation	24.69 kilogram per meter square STANDARD_DEVIATION 5.163 • n=225 Participants • Both height and weight measurements are needed for body mass index calculation. Some patients had missing height and/or weight measurements. Only patients with both a height and a weight measurement are included in the body mass index calculation	25.10 kilogram per meter square STANDARD_DEVIATION 5.378 • n=455 Participants • Both height and weight measurements are needed for body mass index calculation. Some patients had missing height and/or weight measurements. Only patients with both a height and a weight measurement are included in the body mass index calculation

PRIMARY outcome

Timeframe: 24 Months

Population: Intent-to-Treat Population that included all patients randomized to study.

Outcome measures

Outcome measures
Measure	Avapritinib n=240 Participants 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib n=236 Participants 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Efficacy of Avapritinib Based on Progression-free Survival (PFS) Determined by Central Radiological Assessment Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST), Version 1.1	4.2 months Interval 3.7 to 5.6	5.6 months Interval 3.8 to 7.2

SECONDARY outcome

Timeframe: 24 Months

Population: Intent-to-Treat Population that included all patients randomized to study.

To evaluate objective response rate (ORR) determined by central radiology assessment per mRECIST, version 1.1 in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib. A complete response (CR) per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response (PR) is defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Overall Response (OR) = CR + PR

Outcome measures

Outcome measures
Measure	Avapritinib n=240 Participants 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib n=236 Participants 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 Responder	41 Participants	17 Participants
Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 Non-Responder	199 Participants	219 Participants

SECONDARY outcome

Timeframe: 24 Months

To evaluate overall survival (OS) in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib

Outcome measures

Outcome measures
Measure	Avapritinib n=240 Participants 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib n=236 Participants 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Overall Survival (OS) in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib	19.2 months Interval 19.2 to Since the primary endpoint of statistically significant improvement in PFS was not met patients are not being followed for OS. The upper bound of the confidence interval is not estimable by the Kaplan-Meier analysis due to the short follow-up time.	17.4 months Interval 15.8 to Since the primary endpoint of statistically significant improvement in PFS was not met patients are not being followed for OS. The upper bound of the confidence interval is not estimable by the Kaplan-Meier analysis due to the short follow-up time.

SECONDARY outcome

Timeframe: Difference between baseline and week 12 of treatment

Population: Intent-to-Treat Population with both a baseline and a Week 12 measurements.

The Global Health Status Score is derived from question 29 and 30 on the EORTC-QLQ-C30 tool. The change in score was assessed between baseline and week 12 in patients treated with advanced GIST treated with avapritinib compared to patients treated with regorafenib. The Global Health Status Score score range is 0 to 100 with a higher score indicating better global health status. A positive change indicates improvement in global health status.

Outcome measures

Outcome measures
Measure	Avapritinib n=123 Participants 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib n=138 Participants 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30). Change in Individual Scores in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib	-5.7 scores on a scale Standard Deviation 24.29	-4.4 scores on a scale Standard Deviation 20.74

Adverse Events

Avapritinib

Serious events: 106 serious events

Other events: 218 other events

Deaths: 89 deaths

Regorafinib

Serious events: 91 serious events

Other events: 224 other events

Deaths: 87 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Information Call Center

Blueprint Medicines

Phone: 1-888-258-7768

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Avapritinib n=239 participants at risk 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib n=234 participants at risk 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Blood and lymphatic system disorders Anaemia	11.3% 27/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	3.0% 7/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Blood and lymphatic system disorders Febrile neutropenia	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Blood and lymphatic system disorders Haemolytic uraemic syndrome	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Cardiac failure congestive	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Myocarditis	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Pericardial effusion	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Acute coronary syndrome	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Atrial fibrillation	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Cardiac failure	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Myocardial infarction	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Cardiac disorders Ventricular arrhythmia	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Eye disorders Retinal vein occlusion	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Abdominal pain	5.4% 13/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	4.7% 11/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Ascites	2.1% 5/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.85% 2/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Gastrointestinal haemorrhage	2.5% 6/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	2.1% 5/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Vomiting	2.1% 5/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.85% 2/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Diarrhoea	1.7% 4/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	2.1% 5/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Gastric haemorrhage	1.7% 4/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Abdominal distension	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Intra-abdominal haemorrhage	1.3% 3/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Abdominal pain upper	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	1.3% 3/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Nausea	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Rectal haemorrhage	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Constipation	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Diverticular perforation	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Duodenitis	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Gastritis	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.85% 2/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Gastrointestinal fistula	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Intestinal obstruction	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	1.3% 3/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Intestinal perforation	0.84% 2/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Oesophagitis	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.42% 1/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Anal fistula	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Colitis	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Gastric ulcer	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Gastrointestinal toxicity	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Inguinal hernia strangulated	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Large intestinal obstruction	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Peritoneal haemorrhage	0.00% 0/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.43% 1/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.

Other adverse events
Measure	Avapritinib n=239 participants at risk 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.	Regorafinib n=234 participants at risk 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Eye disorders Periorbital oedema	28.5% 68/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Eye disorders Lacrimation increased	18.8% 45/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Eye disorders Eyelid oedema	14.6% 35/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Dyspepsia	8.8% 21/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	6.8% 16/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Gastrooesophageal reflux disease	6.7% 16/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	3.0% 7/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Dry mouth	2.9% 7/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	6.4% 15/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Gastrointestinal disorders Stomatitis	2.9% 7/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	17.1% 40/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
General disorders Oedema peripheral	23.0% 55/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	5.6% 13/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
General disorders Mucosal inflammation	1.3% 3/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	12.0% 28/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Infections and infestations Conjunctivitis	5.0% 12/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.00% 0/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Investigations White blood cell count decreased	17.6% 42/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	3.0% 7/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Investigations Aspartate aminotransferase increased	13.8% 33/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	14.1% 33/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Investigations Weight decreased	10.0% 24/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	22.6% 53/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Investigations Blood creatinine increased	8.8% 21/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	5.1% 12/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Investigations Weight increased	7.5% 18/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	1.7% 4/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Investigations Alanine aminotransferase increased	6.3% 15/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	12.4% 29/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Investigations Blood alkaline phosphatase increased	2.5% 6/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	5.6% 13/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Metabolism and nutrition disorders Hypocalcaemia	6.3% 15/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	4.7% 11/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Metabolism and nutrition disorders Hypoalbuminaemia	5.0% 12/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	6.8% 16/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Metabolism and nutrition disorders Hypomagnesaemia	4.6% 11/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	5.1% 12/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Musculoskeletal and connective tissue disorders Arthralgia	3.8% 9/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	6.8% 16/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Musculoskeletal and connective tissue disorders Muscle spasms	2.5% 6/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	10.7% 25/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Musculoskeletal and connective tissue disorders Myalgia	2.9% 7/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	9.4% 22/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Nervous system disorders Dizziness	13.4% 32/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	8.1% 19/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Nervous system disorders Memory impairment	13.0% 31/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	2.1% 5/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Nervous system disorders Headache	12.1% 29/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	18.4% 43/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Nervous system disorders Dysgeusia	8.4% 20/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	4.7% 11/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Respiratory, thoracic and mediastinal disorders Dysphonia	3.3% 8/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	30.3% 71/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Skin and subcutaneous tissue disorders Hair colour changes	13.8% 33/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	0.85% 2/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Skin and subcutaneous tissue disorders Alopecia	10.0% 24/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	16.2% 38/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Skin and subcutaneous tissue disorders Pruritus	4.6% 11/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	6.4% 15/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Skin and subcutaneous tissue disorders Dry skin	4.2% 10/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	7.7% 18/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Skin and subcutaneous tissue disorders Rash maculo-papular	2.9% 7/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	6.0% 14/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	1.7% 4/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	61.1% 143/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Respiratory, thoracic and mediastinal disorders Cough	7.1% 17/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	5.6% 13/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.
Psychiatric disorders Anxiety	5.0% 12/239 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.	1.3% 3/234 • From the date of first study drug administration to 30 days after last study drug administration, approximately 6 months The total number of at risk patients includes patients that were randomized to treatment and received at least one dose of treatment. Patients that were randomized by did not receive treatment were excluded from the safety analysis.