Trial Outcomes & Findings for Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib (NCT NCT00474786)

Last Updated: 2013-11-21

Results Overview

Interval from date of randomization until documentation of progressive disease (PD) by an independent tumor assessment according to Response Evaluation Criteria in Solid Tumor (RECIST) or death for any reason whichever occurred first.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

512 participants

Primary outcome timeframe

Baseline up to 24 Months

Results posted on

2013-11-21

Participant Flow

Participant milestones

Participant milestones
Measure	Temsirolimus Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Overall Study STARTED	259	253
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	259	253

Reasons for withdrawal

Reasons for withdrawal
Measure	Temsirolimus Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Overall Study Not Meeting Study Criteria	0	1
Overall Study Investigator Request	2	1
Overall Study Death	189	170
Overall Study Discontinuation of Study by Sponsor	42	59
Overall Study Lost to Follow-up	4	7
Overall Study Protocol Violation	2	0
Overall Study Withdrawal by Subject	15	15
Overall Study Other	5	0

Baseline Characteristics

Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Temsirolimus n=259 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=253 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Total n=512 Participants Total of all reporting groups
Age Continuous	59.96 years STANDARD_DEVIATION 10.20 • n=5 Participants	59.74 years STANDARD_DEVIATION 10.33 • n=7 Participants	59.85 years STANDARD_DEVIATION 10.25 • n=5 Participants
Sex: Female, Male Female	66 Participants n=5 Participants	61 Participants n=7 Participants	127 Participants n=5 Participants
Sex: Female, Male Male	193 Participants n=5 Participants	192 Participants n=7 Participants	385 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to 24 Months

Population: Intent to Treat Population (ITT): all randomized participants according to their assigned treatment, regardless of whether they were received any study drug.

Outcome measures

Outcome measures
Measure	Temsirolimus n=259 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=253 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Progression-Free Survival (PFS)	4.28 months Interval 4.01 to 5.43	3.91 months Interval 2.8 to 4.21

SECONDARY outcome

Timeframe: Baseline up to 24 Months

Population: ITT population

Interval from date of randomization until documentation of PD by an investigator tumor assessment, symptomatic deterioration, or death for any reason whichever occurred first.

Outcome measures

Outcome measures
Measure	Temsirolimus n=259 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=253 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Progression Free Survival (PFS) by Investigator Assessment	5.43 months Interval 4.24 to 5.86	4.14 months Interval 3.26 to 5.36

SECONDARY outcome

Timeframe: Baseline up to 24 Months

Population: ITT population

Percentage of participants with tumor response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST and evaluated by independent central review. CR/PR persisted on repeat imaging study at least 4 weeks after initial documentation of response. PR had at least 30 percent decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Outcome measures

Outcome measures
Measure	Temsirolimus n=259 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=253 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Percentage of Participants With Tumor Response	7.7 percentage of participants Interval 4.8 to 11.7	7.9 percentage of participants Interval 4.9 to 11.9

SECONDARY outcome

Timeframe: Baseline to date of death from any cause (up to 24 months)

Population: ITT population

Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.

Outcome measures

Outcome measures
Measure	Temsirolimus n=259 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=253 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Overall Survival (OS)	12.27 months Interval 10.13 to 14.8	16.64 months Interval 13.55 to 18.72

SECONDARY outcome

Timeframe: Weeks 12, 24, and 36

Population: ITT population

PFS: Interval from date of randomization until documentation of PD by an independent tumor assessment according to RECIST or death for any reason whichever occurred first. PFS calculated as (Weeks)=(randomization date minus first dose date plus 1) divided by 7.

Outcome measures

Outcome measures
Measure	Temsirolimus n=259 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=253 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment Week 13 to Week 24	20.9 percentage of participants	20.1 percentage of participants
Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment Baseline to Week 12	31.2 percentage of participants	36.7 percentage of participants
Percentage of Participants With PFS Events at 12, 24 and 36 Weeks by Independent Assessment Week 25 to Week 36	12.3 percentage of participants	11.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to 24 Months

Population: ITT population

Duration of response as defined by the time from CR or PR (whichever status recorded first) until the date of death or PD was objectively documented. Median and its 95 percent confidence interval (95% CI) were estimated using Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Temsirolimus n=259 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=253 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Duration of Response (DR)	8.26 months Interval 6.71 to 10.36	6.96 months Interval 4.18 to 17.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 24 months

Population: Safety population: all participants who received at least 1 dose of test article.

Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to \[study drug\] was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category.

Outcome measures

Outcome measures
Measure	Temsirolimus n=249 Participants Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=252 Participants Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Serious AE	103 participants	86 participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AE	248 participants	251 participants

Adverse Events

Temsirolimus

Serious events: 104 serious events

Other events: 243 other events

Deaths: 0 deaths

Sorafenib

Serious events: 87 serious events

Other events: 249 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Temsirolimus n=249 participants at risk Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=252 participants at risk Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Surgical and medical procedures Lung operation	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Surgical and medical procedures Medical device implantation	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Anaemia	2.0% 5/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 4/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Febrile neutropenia	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Lymphopenia	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Thrombocytopenia	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Acute myocardial infarction	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Atrial fibrillation	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.2% 3/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Atrial flutter	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac arrest	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac tamponade	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardio-respiratory arrest	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiopulmonary failure	0.80% 2/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Myocardial infarction	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 4/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Myocardial ischaemia	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Palpitations	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Pericardial effusion	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Prinzmetal angina	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Endocrine disorders Hyperthyroidism	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Endocrine disorders Toxic nodular goitre	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Retinal artery occlusion	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal distension	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	2.8% 7/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Ascites	1.2% 3/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	1.2% 3/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Duodenal perforation	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dysphagia	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrointestinal obstruction	0.80% 2/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Hernial eventration	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Hiatus hernia	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Intestinal obstruction	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Intestinal ulcer perforation	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Large intestine perforation	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Obstruction gastric	0.00% 0/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.40% 1/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Oesophageal hypomotility	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Rectal haemorrhage	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Salivary hypersecretion	0.40% 1/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Other adverse events
Measure	Temsirolimus n=249 participants at risk Temsirolimus 25 milligrams (mg) once weekly by intravenous (IV) infusion administered in 6 week cycles for up to 24 months, participants were premedicated with 25-50 mg IV diphenydramine 30 minutes before temsirolimus infusion. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.	Sorafenib n=252 participants at risk Sorafenib 400 mg (two 200 mg tablets) by mouth (PO) twice daily (BID) administered in 6 week cycles for up to 24 months. In event of toxicity, dose could be modified or held according to the protocol or at the discretion of the investigator.
Investigations Blood alkaline phosphatase increased	10.4% 26/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.4% 11/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Alanine aminotransferase increased	7.2% 18/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.7% 17/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Blood lactate dehydrogenase increased	6.4% 16/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	5.2% 13/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Haemoglobin decreased	7.6% 19/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.6% 9/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Decreased appetite	30.5% 76/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	37.3% 94/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypertriglyceridaemia	21.3% 53/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.1% 18/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypercholesterolaemia	20.5% 51/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.3% 16/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperglycaemia	18.1% 45/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	5.2% 13/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypophosphataemia	11.2% 28/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	11.9% 30/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyponatraemia	5.6% 14/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	5.6% 14/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypocalcaemia	4.0% 10/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.7% 17/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperkalaemia	4.4% 11/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	5.6% 14/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypokalaemia	6.0% 15/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.6% 9/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	20.1% 50/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.3% 36/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	18.5% 46/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	11.5% 29/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Pain in extremity	12.4% 31/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	15.1% 38/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.6% 24/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.9% 20/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Muscle spasms	7.2% 18/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	8.7% 22/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Myalgia	8.0% 20/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.7% 17/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	12.9% 32/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	17.5% 44/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	8.0% 20/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.9% 20/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dysgeusia	8.8% 22/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 10/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Paraesthesia	5.6% 14/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 10/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Insomnia	6.0% 15/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.3% 16/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Anxiety	5.2% 13/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.8% 7/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Dysuria	5.2% 13/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.8% 7/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Pollakiuria	5.2% 13/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.2% 3/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	34.1% 85/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	22.6% 57/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	26.9% 67/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	15.9% 40/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	20.5% 51/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	5.2% 13/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dysphonia	2.0% 5/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	15.1% 38/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	9.2% 23/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.0% 15/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	6.0% 15/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.8% 7/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pneumonitis	7.6% 19/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Productive cough	5.6% 14/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.0% 5/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Rash	41.8% 104/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	34.5% 87/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	4.4% 11/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	52.0% 131/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Pruritus	25.3% 63/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	25.4% 64/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Alopecia	2.0% 5/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	31.0% 78/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Dry skin	16.1% 40/249 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	14.3% 36/252 • 5.3 years approximately The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.