Trial Outcomes & Findings for A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery (NCT NCT01864746)

Last Updated: 2023-12-12

Results Overview

Invasive disease-free survival (iDFS) is defined according to Hudis (J Clin Oncol 2007) as the time period between randomization and first event (ipsi- or contralateral invasive in-breast or loco-regional recurrence, distant recurrence, death from breast cancer, death from non-breast cancer cause, death from unknown cause, invasive contralateral breast cancer, second primary invasive cancer (non-breast)) assessed until the end of study.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1250 participants

Primary outcome timeframe

From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

Results posted on

2023-12-12

Participant Flow

Approximately 4 years (Q-I 2014 -Q-IV 2017) in 221 sites worldwide (11 countries). 1708 patients were screened, 1250 patients were randomized (Palbociclib 631; Placebo 619).

Female patients \>=18 years with residual invasive disease after NACT (in breast or lymph nodes), centrally assessed ER+ and/or PgR+ and HER2- tumors and centrally assessed Ki-67 status and a CPS-EG score of \>=3 or 2 with ypN1 (after amendment 3, February 9, 2015) were eligible. \>=16weeks NACT (incl. 6 weeks taxane), surgery and radiation received.

Participant milestones

Participant milestones
Measure	Palbociclib Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Overall Study STARTED	631	619
Overall Study Started Treatment	628	616
Overall Study Safety Population	633	611
Overall Study COMPLETED	508	523
Overall Study NOT COMPLETED	123	96

Reasons for withdrawal

Reasons for withdrawal
Measure	Palbociclib Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Overall Study Disease recurrence	25	40
Overall Study Second primary invasive nonbreast	2	3
Overall Study Death	2	1
Overall Study Adverse Event	33	5
Overall Study Withdrawal by Subject	56	41
Overall Study Physician Decision	5	6

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Palbociclib n=631 Participants Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo n=619 Participants Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles	Total n=1250 Participants Total of all reporting groups
Age, Continuous	49 years n=631 Participants	48 years n=619 Participants	49 years n=1250 Participants
Sex: Female, Male Female	631 Participants n=631 Participants	619 Participants n=619 Participants	1250 Participants n=1250 Participants
Sex: Female, Male Male	0 Participants n=631 Participants	0 Participants n=619 Participants	0 Participants n=1250 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
ECOG performance status ECOG 0	537 Participants n=631 Participants	527 Participants n=619 Participants	1064 Participants n=1250 Participants
ECOG performance status ECOG 1	94 Participants n=631 Participants	92 Participants n=619 Participants	186 Participants n=1250 Participants
Menopausal status Premenopausal	300 Participants n=631 Participants	316 Participants n=619 Participants	616 Participants n=1250 Participants
Menopausal status Postmenopausal	331 Participants n=631 Participants	303 Participants n=619 Participants	634 Participants n=1250 Participants

PRIMARY outcome

Timeframe: From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

Population: Intention-to-treat population

Outcome measures

Outcome measures
Measure	Palbociclib n=631 Participants Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo n=619 Participants Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Invasive Disease Free Survival (iDFS) for Palbociclib vs. Placebo in Patients With High CPS-EG Score After Neoadjuvant Chemotherapy Receiving Standard Adjuvant Endocrine Therapy for HR-positive/HER2-normal Primary Breast Cancer. 3-year iDFS	81.2 % of patients without invasive disease Interval 77.8 to 84.1	77.7 % of patients without invasive disease Interval 74.1 to 80.9
Invasive Disease Free Survival (iDFS) for Palbociclib vs. Placebo in Patients With High CPS-EG Score After Neoadjuvant Chemotherapy Receiving Standard Adjuvant Endocrine Therapy for HR-positive/HER2-normal Primary Breast Cancer. 5-year iDFS	63.6 % of patients without invasive disease Interval 56.4 to 69.9	67.9 % of patients without invasive disease Interval 61.6 to 73.3

SECONDARY outcome

Timeframe: From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

Population: Intention-to-treat population

Invasive disease-free survival (iDFS) is defined according to Hudis (J Clin Oncol 2007) as the time period between randomization and first event assessed until the end of study.

Outcome measures

Outcome measures
Measure	Palbociclib n=631 Participants Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo n=619 Participants Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
iDFS Excluding Second Non-breast Cancers 3-year iDFS	82 % of patients free of event Interval 78.6 to 84.9	78.5 % of patients free of event Interval 75.0 to 81.7
iDFS Excluding Second Non-breast Cancers 5-year iDFS	64 % of patients free of event Interval 56.6 to 70.4	68.6 % of patients free of event Interval 62.4 to 74.1

SECONDARY outcome

Timeframe: From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

Population: Intention-to-treat population

Distant disease free survival (DDFS) is defined as the time period between randomization and diagnosis of first distant breast cancer recurrences assessed until the end of study.

Outcome measures

Outcome measures
Measure	Palbociclib n=631 Participants Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo n=619 Participants Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Distant Disease Free Survival (DDFS) 3-year DDFS	82.4 % of patients free of event Interval 79.1 to 85.3	80 % of patients free of event Interval 76.6 to 83.1
Distant Disease Free Survival (DDFS) 5-year DDFS	65.8 % of patients free of event Interval 58.5 to 72.1	69.9 % of patients free of event Interval 63.8 to 75.2

SECONDARY outcome

Timeframe: From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

Population: Intention-to-treat analysis

Overall survival (OS) is defined as the time period between randomization and death of any cause assessed until the end of study.

Outcome measures

Outcome measures
Measure	Palbociclib n=631 Participants Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo n=619 Participants Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Overall Survival (OS) 3-year OS	93.6 % of patients free of event Interval 91.3 to 95.3	90.5 % of patients free of event Interval 87.8 to 92.6
Overall Survival (OS) 5-year OS	79.6 % of patients free of event Interval 72.1 to 85.3	84.6 % of patients free of event Interval 78.9 to 88.9

Adverse Events

Palbociclib

Serious events: 64 serious events

Other events: 632 other events

Deaths: 63 deaths

Placebo

Serious events: 65 serious events

Other events: 610 other events

Deaths: 67 deaths

Serious adverse events

Other adverse events

Additional Information

Prof. Dr. Sibylle Loibl

German Breast Group (GBG) Forschungs GmbH

Phone: +49 6102 7480

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Only after the sponsor's publication of the overall study results of the primary endpoint do participating sites have the right to publish publications related to study data collected by participating sites, and any results of add-on research conducted by participating sites, subject to compliance with the study publications and presentations policy.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Palbociclib n=633 participants at risk Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo n=611 participants at risk Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Infections and infestations Infections and infestations	3.0% 19/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	4.1% 25/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Cellulitis	0.63% 4/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.82% 5/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Erysipelas	0.47% 3/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Influenza	0.47% 3/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Postoperative wound infection	0.00% 0/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.49% 3/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Wound infection	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.33% 2/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Infection	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Neutropenic sepsis	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Infections and infestations Pharyngitis	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	1.7% 11/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	1.6% 10/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Injury, poisoning and procedural complications Overdose	1.1% 7/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.49% 3/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Injury, poisoning and procedural complications Fracture	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.33% 2/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Injury, poisoning and procedural complications Seroma	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Vascular disorders Vascular disorders	0.95% 6/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.65% 4/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Vascular disorders Pulmonary embolism	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Vascular disorders Thrombosis	0.00% 0/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.33% 2/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
General disorders General disorders and administration site conditions	0.47% 3/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.65% 4/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
General disorders Impaired healing	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Nervous system disorders Nervous system disorders	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.82% 5/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Nervous system disorders Headache	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Blood and the lymphatic system disorders	0.79% 5/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Febrile neutropenia	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Neutropenia	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Musculoskeletal and connective tissue disorders Musculoskeletal, connective tissue and bone disorders	0.47% 3/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.33% 2/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign and malignant (including cysts and polyps)	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.65% 4/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Gastrointestinal disorders	0.47% 3/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Reproductive system and breast disorders Reproductive system and breast disorders	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.33% 2/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.33% 2/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Hepatobiliary disorders Hepato-biliary disorders	0.00% 0/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.49% 3/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Psychiatric disorders Psychiatric disorders	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.33% 2/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Renal and urinary disorders Renal and urinary disorders	0.47% 3/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Cardiac disorders Cardiac disorders	0.32% 2/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Eye disorders Eye disorders	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Ear and labyrinth disorders Ear and labyrinth disorders	0.16% 1/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.00% 0/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Surgical and medical procedures Surgical and medical procedures	0.00% 0/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.

Other adverse events
Measure	Palbociclib n=633 participants at risk Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991: palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle	Placebo n=611 participants at risk Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo: Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Vascular disorders Hot flush	43.8% 277/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	50.9% 311/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Vascular disorders Hypertension	8.5% 54/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	9.8% 60/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Vascular disorders Embolism	2.1% 13/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	1.1% 7/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
General disorders Fatigue	66.4% 420/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	51.1% 312/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
General disorders Peripheral edema	19.9% 126/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	16.2% 99/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
General disorders Pyrexia	11.2% 71/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	8.0% 49/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Reproductive system and breast disorders Vaginal dryness	8.2% 52/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	9.0% 55/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Reproductive system and breast disorders Vaginal hemorrhage	1.9% 12/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	2.5% 15/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Investigations Alanine aminotransferase increased	21.8% 138/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	23.1% 141/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Investigations Aspartate aminotransferase increased	20.7% 131/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	16.7% 102/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Investigations Blood alkaline phosphatase increased	16.7% 106/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	19.6% 120/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Investigations Blood creatinine increased	12.3% 78/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	11.0% 67/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Investigations Blood albumin decreased	10.0% 63/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	7.5% 46/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Investigations Blood bilirubin increased	6.6% 42/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	7.2% 44/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Leukopenia	99.2% 628/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	69.9% 427/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Neutropenia	95.7% 606/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	23.4% 143/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Anemia	73.9% 468/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	30.3% 185/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Thrombocytopenia	56.6% 358/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	16.2% 99/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Blood and lymphatic system disorders Febrile neutropenia	2.5% 16/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	0.16% 1/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Respiratory, thoracic and mediastinal disorders Cough	20.9% 132/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	16.2% 99/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Respiratory, thoracic and mediastinal disorders Dyspnea	11.5% 73/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	7.0% 43/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Respiratory, thoracic and mediastinal disorders Epistaxis	6.0% 38/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	1.3% 8/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Nervous system disorders Dysgeusia	6.5% 41/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	5.2% 32/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Nervous system disorders Headache	23.2% 147/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	23.1% 141/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Nervous system disorders Other nervous system disorders	21.0% 133/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	22.6% 138/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Eye disorders Cataract	0.95% 6/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	1.1% 7/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Ear and labyrinth disorders Vertigo	7.3% 46/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	7.0% 43/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Nausea	23.7% 150/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	20.6% 126/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Stomatitis	27.5% 174/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	8.7% 53/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Constipation	22.1% 140/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	13.7% 84/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Diarrhea	18.3% 116/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	15.7% 96/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Vomiting	10.4% 66/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	9.3% 57/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Abdominal distension	2.7% 17/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	3.4% 21/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Gastrointestinal disorders Other gastrointestinal disorders	23.2% 147/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	17.5% 107/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Skin and subcutaneous tissue disorders Other skin and subcutaneous tissue disorders	27.6% 175/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	23.7% 145/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Musculoskeletal and connective tissue disorders Arthralgia	41.2% 261/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	46.8% 286/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Musculoskeletal and connective tissue disorders Myalgia	20.2% 128/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	18.5% 113/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Musculoskeletal and connective tissue disorders Bone pain	17.2% 109/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	19.1% 117/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Musculoskeletal and connective tissue disorders Other nusculoskeletal, connective tissue and bone disorders	19.3% 122/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	21.8% 133/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.
Metabolism and nutrition disorders Hypocalcemia	35.2% 223/633 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.	24.4% 149/611 • For AEs and SAEs, the reporting period is from the time the patient took the first dose of the investigational product until (and including) 30 calendar days after the last administration of the investigational product (i.e., from first dose to 30 days after last dose). Serious and Other (Not Including Serious) Adverse Events were assessed for up to 14 months, and all-cause mortality was assessed up to 6 years and 6 months. All recorded events meeting the definitions of All-Cause Mortality, Serious Adverse Events, and Other (Not Including Serious) Adverse Events are currently reported.