Study of Pembrolizumab (MK-3475) in Platinum Pre-treated Recurrent/Metastatic Nasopharyngeal Cancer (MK-3475-122/KEYNOTE-122)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02611960
• Collaborator: (none)
• Enrollment: 233
• Arms: 2
• Anticipated Duration (Months): 77.5

Study Details

Study Description

Brief Summary

This is a study of pembrolizumab (MK-3475) versus standard treatment (capecitabine, gemcitabine, or docetaxel) for the treatment of recurrent or metastatic nasopharyngeal cancer (NPC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment.

The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.

With Amendment 7 (effective 2-March-2022), upon study completion, participants will be discontinued and may be enrolled in an extension study.

Condition or Disease	Intervention/Treatment	Phase
Nasopharyngeal Neoplasms	Biological: Pembrolizumab; Drug: Capecitabine; Drug: Gemcitabine; Drug: Docetaxel	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 233 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Two-arm, Open-label, Randomized Phase III Study of Pembrolizumab (MK-3475) Monotherapy Versus Standard Chemotherapy in Platinum Pre-treated, Recurrent or Metastatic Nasopharyngeal Cancer (NPC) (Keynote-122)
• Actual Study Start Date: Apr 18, 2016
• Actual Primary Completion Date: Nov 30, 2020
• Anticipated Study Completion Date: Oct 3, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year).	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475 KEYTRUDA®
Active Comparator: Standard Treatment Participants receive capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.	Drug: Capecitabine; oral tablet; Other Names: XELODA® ; Drug: Gemcitabine; IV infusion; Other Names: GEMZAR® ; Drug: Docetaxel; IV infusion; Other Names: TAXOTERE®

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)]

   Overall Survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. OS was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

Secondary Outcome Measures

1. Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)]

   PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded independent central review (BICR), or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. PFS was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

2. Objective Response Rate (ORR) Per RECIST 1.1 [Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)]

   ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. ORR was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

3. Duration of Response (DOR) Per RECIST 1.1 [Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)]

   For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

4. Percentage of Participants Surviving (OS Rate) at 12 Months [12 months]

   OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. The percentage of participants surviving (OS rate) at 12 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

5. Percentage of Participants Surviving (OS Rate) at 24 Months [24 months]

   OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. The percentage of participants surviving (OS rate) at 24 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

6. Percentage of Participants With PFS (PFS Rate) at 6 Months [6 months]

   PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. The percentage of participants with PFS (PFS rate) at 6 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

7. Percentage of Participants With PFS (PFS Rate) at 12 Months [12 months]

   PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. The percentage of participants with PFS (PFS rate) at 12 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.

8. Percentage of Participants Who Experience One or More Adverse Events (AEs) [Up to approximately 52 months]

   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm.

9. Percentage of Participants Who Discontinue Study Treatment Due to an AE [Up to approximately 51 months]

   An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The percentage of participants that discontinued study treatment due to an AE was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed non-keratinizing differentiated NPC or undifferentiated NPC

• Metastatic disease or incurable locally recurrent disease

• Treatment with prior platinum therapy

• Tumor tissue available for programmed cell death ligand 1 (PD-L1) testing

• Measurable disease based on RECIST 1.1

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Adequate organ function

• Male or female participants of childbearing potential must be willing to use an adequate method of contraception starting with the first dose of study drug through 180 days after the last dose of study drug

• Life expectancy of at least 3 months

Exclusion Criteria:

• Disease is suitable for local therapy administered with curative intent

• Participants previously treated in the recurrent/metastatic setting with any 1 of the 3 standard therapies in this study (i.e., docetaxel, capecitabine, or gemcitabine) may not receive the same therapy if randomized to the Standard Treatment arm. Additionally, participants previously treated in the recurrent/metastatic setting with all 3 standard therapies are excluded from this study

• Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of study drug

• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug

• Not recovered from adverse events due to therapy more than 4 weeks earlier

• Prior anti-cancer monoclonal antibody (mAb) therapy within 4 weeks prior to Study Day 1, or not recovered from adverse events

• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1

• Diagnosed and/or treated additional malignancy within 5 years of randomization, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin, and/or curatively-resected in situ cervical and/or breast carcinoma

• Active autoimmune disease that has required systemic therapy in the past 2 years with modifying agents, corticosteroids, or immunosuppressive agents

• Active central nervous system metastases and/or carcinomatous meningitis

• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

• Active infection requiring systemic therapy

• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment for the chemotherapy arm or 120 days after the last dose of trial treatment for the pembrolizumab arm

• Prior therapy with an anti-PD-1 or anti-PD1-L1 or -L2 therapy or previously participated in a Merck pembrolizumab (MK-3475) study

• Human immunodeficiency virus (HIV) positive

• Hepatitis B or C positive

• Live vaccine within 30 days of planned start of study drug

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 19, 2021

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02611960
• Other Study ID Numbers: 3475-122; MK-3475-122; KEYNOTE-122
• First Posted: Nov 23, 2015
• Last Update Posted: Jun 15, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Merck Sharp & Dohme LLC: Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)
• Additional relevant MeSH terms: Nasopharyngeal Neoplasms; Nasopharyngeal Carcinoma; Gemcitabine; Capecitabine; Docetaxel; Pembrolizumab

Study Results

Participant Flow

Pre-assignment Detail

Five participants randomized to the Pembrolizumab arm received a second course of pembrolizumab at the investigator's discretion as specified by the protocol. Per protocol, response/progression or adverse events (AEs) that occurred during a non-randomized second course of pembrolizumab were not counted towards efficacy or safety outcome measures, respectively. These results are for randomized treatment only.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Period Title: Overall Study
STARTED	117	116
Treated	116	112
COMPLETED	0	0
NOT COMPLETED	117	116

Baseline Characteristics

Arm/Group Title	Pembrolizumab	Standard Treatment	Total
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.	Total of all reporting groups
Overall Participants	117	116	233
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.6 (12.7)	53.1 (11.2)	51.9 (12.0)
Sex: Female, Male (Count of Participants)
Female	19 16.2%	21 18.1%	40 17.2%
Male	98 83.8%	95 81.9%	193 82.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 0.9%	3 2.6%	4 1.7%
Not Hispanic or Latino	116 99.1%	113 97.4%	229 98.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	110 94%	112 96.6%	222 95.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 0.9%	1 0.4%
White	7 6%	3 2.6%	10 4.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Presence of Baseline Liver Metastasis (Count of Participants)
Liver Metastasis Present	57 48.7%	56 48.3%	113 48.5%
Liver Metastasis Absent	60 51.3%	60 51.7%	120 51.5%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	Overall Survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. OS was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)

Outcome Measure Data

Analysis Population Description

All randomized participants (Intent-to-Treat [ITT]) were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	117	116
Median (95% Confidence Interval) [Months]	17.2	15.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Standard Treatment
	Comments	Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by presence of liver metastasis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2262
	Comments	One-sided p-value based on log-rank test stratified by presence of liver metastasis.
	Method	Stratified Log-Rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded independent central review (BICR), or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. PFS was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT) were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	117	116
Median (95% Confidence Interval) [Months]	4.1	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Standard Treatment
	Comments	Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by presence of liver metastasis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9419
	Comments	One-sided p-value based on log-rank test stratified by presence of liver metastasis.
	Method	Stratified Log-Rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Objective Response Rate (ORR) Per RECIST 1.1
Description	ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. ORR was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT) were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	117	116
Number (95% Confidence Interval) [Percentage of Participants]	21.4 18.3%	23.3 20.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Standard Treatment
	Comments	Comparison based on Miettinen & Nurminen method stratified by presence of liver metastasis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63479
	Comments	One-sided p-value for testing. H0: difference in percentage = 0 versus H1: difference in percentage > 0.
	Method	Stratified Miettinen and Nurminen Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -12.7 to 8.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Duration of Response (DOR) Per RECIST 1.1
Description	For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020)

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT population) who demonstrated a confirmed CR or PR were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	25	27
Median (95% Confidence Interval) [Months]	12.0	13.1

5. Secondary Outcome

Title	Percentage of Participants Surviving (OS Rate) at 12 Months
Description	OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. The percentage of participants surviving (OS rate) at 12 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT) were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	117	116
Number (95% Confidence Interval) [Percentage of Participants]	58.1 49.7%	57.4 49.5%

6. Secondary Outcome

Title	Percentage of Participants Surviving (OS Rate) at 24 Months
Description	OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. The percentage of participants surviving (OS rate) at 24 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT) were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	117	116
Number (95% Confidence Interval) [Percentage of Participants]	40.2 34.4%	32.2 27.8%

7. Secondary Outcome

Title	Percentage of Participants With PFS (PFS Rate) at 6 Months
Description	PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. The percentage of participants with PFS (PFS rate) at 6 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT) were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	117	116
Number (95% Confidence Interval) [Percentage of Participants]	36.3 31%	43.9 37.8%

8. Secondary Outcome

Title	Percentage of Participants With PFS (PFS Rate) at 12 Months
Description	PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. The percentage of participants with PFS (PFS rate) at 12 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All randomized participants (ITT) were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	117	116
Number (95% Confidence Interval) [Percentage of Participants]	18.7 16%	30.8 26.6%

9. Secondary Outcome

Title	Percentage of Participants Who Experience One or More Adverse Events (AEs)
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm.
Time Frame	Up to approximately 52 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study treatment were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	116	112
Number [Percentage of Participants]	97.4 83.2%	97.3 83.9%

10. Secondary Outcome

Title	Percentage of Participants Who Discontinue Study Treatment Due to an AE
Description	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The percentage of participants that discontinued study treatment due to an AE was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm.
Time Frame	Up to approximately 51 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study treatment were analyzed.

Arm/Group Title	Pembrolizumab	Standard Treatment
Arm/Group Description	Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.	Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Measure Participants	116	112
Number [Percentage of Participants]	8.6 7.4%	15.2 13.1%

Adverse Events

Time Frame	All-Cause Mortality and Adverse Events (including first and second courses): Up to approximately 53 months (through Primary Analysis cut-off date of 30-Nov-2020)
Adverse Event Reporting Description	All-Cause Mortality table includes all randomized participants. Serious and Other AEs include all treated participants according to treatment received. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug were excluded as AEs. Five participants randomized to Pembrolizumab arm received a second course of pembrolizumab per protocol and were monitored for AEs and All-Cause Mortality separately.
Arm/Group Title	Pembrolizumab (First Course)		Standard Treatment		Pembrolizumab (Second Course)
Arm/Group Description	Participants received pembrolizumab 200 mg IV Q3W until PD or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years).		Participants received capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.		Eligible participants randomized to the pembrolizumab arm who stopped pembrolizumab with SD or better but progressed after discontinuation initiated a second course of pembrolizumab at the investigator's discretion at the same dose and schedule (200 mg Q3W) for up to 17 cycles (up to approximately 1 additional year).
All Cause Mortality
	Pembrolizumab (First Course)		Standard Treatment		Pembrolizumab (Second Course)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/117 (81.2%)		97/116 (83.6%)		0/5 (0%)
Serious Adverse Events
	Pembrolizumab (First Course)		Standard Treatment		Pembrolizumab (Second Course)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/116 (33.6%)		41/112 (36.6%)		3/5 (60%)
Blood and lymphatic system disorders
Anaemia	0/116 (0%)	0	3/112 (2.7%)	3	0/5 (0%)	0
Febrile neutropenia	0/116 (0%)	0	3/112 (2.7%)	3	0/5 (0%)	0
Cardiac disorders
Acute coronary syndrome	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Sinus tachycardia	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Endocrine disorders
Adrenal insufficiency	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Constipation	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Diarrhoea	0/116 (0%)	0	4/112 (3.6%)	4	0/5 (0%)	0
Enteritis	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Gastrointestinal toxicity	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Vomiting	2/116 (1.7%)	2	0/112 (0%)	0	0/5 (0%)	0
General disorders
Chest pain	1/116 (0.9%)	1	1/112 (0.9%)	1	0/5 (0%)	0
Death	1/116 (0.9%)	1	1/112 (0.9%)	1	0/5 (0%)	0
Pyrexia	3/116 (2.6%)	4	1/112 (0.9%)	1	0/5 (0%)	0
Hepatobiliary disorders
Hepatic failure	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Immune-mediated hepatitis	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Infections and infestations
Abdominal wall abscess	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Abscess jaw	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Abscess neck	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Acute sinusitis	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Appendicitis	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Bronchitis	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Cellulitis	0/116 (0%)	0	1/112 (0.9%)	2	0/5 (0%)	0
Chest wall abscess	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Herpes zoster	1/116 (0.9%)	1	1/112 (0.9%)	1	0/5 (0%)	0
Influenza	1/116 (0.9%)	1	1/112 (0.9%)	1	0/5 (0%)	0
Lower respiratory tract infection	1/116 (0.9%)	1	1/112 (0.9%)	1	0/5 (0%)	0
Meningitis	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Muscle abscess	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Pharyngeal abscess	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Pharyngitis	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Pneumonia	9/116 (7.8%)	10	8/112 (7.1%)	8	0/5 (0%)	0
Pulmonary sepsis	0/116 (0%)	0	2/112 (1.8%)	2	0/5 (0%)	0
Pulmonary tuberculosis	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Respiratory syncytial virus infection	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Sepsis	2/116 (1.7%)	3	0/112 (0%)	0	0/5 (0%)	0
Sinusitis	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Upper respiratory tract infection	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Urinary tract infection	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Injury, poisoning and procedural complications
Muscle strain	0/116 (0%)	0	0/112 (0%)	0	1/5 (20%)	1
Road traffic accident	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Wound dehiscence	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Investigations
Blood bilirubin increased	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Blood creatinine increased	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Neutrophil count decreased	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Platelet count decreased	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Metabolism and nutrition disorders
Hypercalcaemia	1/116 (0.9%)	1	1/112 (0.9%)	1	0/5 (0%)	0
Hyperkalaemia	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Hypoglycaemia	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Hyponatraemia	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Muscular weakness	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Osteonecrosis	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Pain in jaw	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Temporomandibular joint syndrome	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of the tongue	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Tumour associated fever	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Tumour haemorrhage	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Nervous system disorders
Cauda equina syndrome	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Dizziness	1/116 (0.9%)	1	0/112 (0%)	0	1/5 (20%)	1
Facial neuralgia	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Haemorrhage intracranial	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Syncope	2/116 (1.7%)	2	0/112 (0%)	0	0/5 (0%)	0
Psychiatric disorders
Delirium	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/116 (0%)	0	1/112 (0.9%)	1	0/5 (0%)	0
Autoimmune nephritis	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Asthma	1/116 (0.9%)	4	0/112 (0%)	0	1/5 (20%)	1
Cough	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Epistaxis	1/116 (0.9%)	2	4/112 (3.6%)	6	0/5 (0%)	0
Pneumonia aspiration	4/116 (3.4%)	7	0/112 (0%)	0	1/5 (20%)	1
Pneumonitis	3/116 (2.6%)	3	0/112 (0%)	0	0/5 (0%)	0
Pneumothorax	0/116 (0%)	0	2/112 (1.8%)	2	0/5 (0%)	0
Skin and subcutaneous tissue disorders
Lichenoid keratosis	1/116 (0.9%)	1	0/112 (0%)	0	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab (First Course)		Standard Treatment		Pembrolizumab (Second Course)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	100/116 (86.2%)		103/112 (92%)		3/5 (60%)
Blood and lymphatic system disorders
Anaemia	13/116 (11.2%)	15	33/112 (29.5%)	47	0/5 (0%)	0
Endocrine disorders
Hypothyroidism	20/116 (17.2%)	20	11/112 (9.8%)	12	0/5 (0%)	0
Eye disorders
Vision blurred	6/116 (5.2%)	6	2/112 (1.8%)	2	0/5 (0%)	0
Gastrointestinal disorders
Abdominal pain	6/116 (5.2%)	8	3/112 (2.7%)	3	0/5 (0%)	0
Constipation	13/116 (11.2%)	15	17/112 (15.2%)	20	0/5 (0%)	0
Diarrhoea	12/116 (10.3%)	17	19/112 (17%)	27	0/5 (0%)	0
Dry mouth	6/116 (5.2%)	7	4/112 (3.6%)	7	0/5 (0%)	0
Dysphagia	7/116 (6%)	7	8/112 (7.1%)	10	0/5 (0%)	0
Nausea	11/116 (9.5%)	12	18/112 (16.1%)	30	0/5 (0%)	0
Stomatitis	3/116 (2.6%)	3	16/112 (14.3%)	19	0/5 (0%)	0
Vomiting	13/116 (11.2%)	21	17/112 (15.2%)	20	0/5 (0%)	0
General disorders
Chest pain	10/116 (8.6%)	12	2/112 (1.8%)	2	0/5 (0%)	0
Chills	5/116 (4.3%)	11	6/112 (5.4%)	8	0/5 (0%)	0
Fatigue	24/116 (20.7%)	29	28/112 (25%)	36	0/5 (0%)	0
Malaise	7/116 (6%)	9	6/112 (5.4%)	7	0/5 (0%)	0
Mucosal inflammation	3/116 (2.6%)	4	10/112 (8.9%)	13	0/5 (0%)	0
Oedema peripheral	6/116 (5.2%)	7	7/112 (6.3%)	8	0/5 (0%)	0
Pyrexia	18/116 (15.5%)	29	28/112 (25%)	51	0/5 (0%)	0
Infections and infestations
Nasopharyngitis	5/116 (4.3%)	8	8/112 (7.1%)	13	0/5 (0%)	0
Upper respiratory tract infection	13/116 (11.2%)	17	16/112 (14.3%)	24	0/5 (0%)	0
Investigations
Alanine aminotransferase increased	8/116 (6.9%)	9	5/112 (4.5%)	13	0/5 (0%)	0
Aspartate aminotransferase increased	10/116 (8.6%)	10	5/112 (4.5%)	7	0/5 (0%)	0
Blood alkaline phosphatase increased	9/116 (7.8%)	10	1/112 (0.9%)	2	0/5 (0%)	0
Blood creatinine increased	5/116 (4.3%)	6	11/112 (9.8%)	14	0/5 (0%)	0
Neutrophil count decreased	2/116 (1.7%)	3	38/112 (33.9%)	107	0/5 (0%)	0
Platelet count decreased	1/116 (0.9%)	1	10/112 (8.9%)	59	0/5 (0%)	0
Weight decreased	8/116 (6.9%)	9	7/112 (6.3%)	7	0/5 (0%)	0
White blood cell count decreased	0/116 (0%)	0	19/112 (17%)	52	0/5 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	23/116 (19.8%)	24	14/112 (12.5%)	18	0/5 (0%)	0
Hypokalaemia	10/116 (8.6%)	17	8/112 (7.1%)	16	0/5 (0%)	0
Hyponatraemia	11/116 (9.5%)	13	7/112 (6.3%)	11	0/5 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	16/116 (13.8%)	23	4/112 (3.6%)	6	0/5 (0%)	0
Back pain	14/116 (12.1%)	16	13/112 (11.6%)	15	0/5 (0%)	0
Musculoskeletal stiffness	1/116 (0.9%)	2	0/112 (0%)	0	1/5 (20%)	1
Myalgia	9/116 (7.8%)	9	9/112 (8%)	10	0/5 (0%)	0
Pain in extremity	11/116 (9.5%)	12	5/112 (4.5%)	7	0/5 (0%)	0
Nervous system disorders
Dizziness	16/116 (13.8%)	21	20/112 (17.9%)	22	0/5 (0%)	0
Headache	16/116 (13.8%)	19	11/112 (9.8%)	22	0/5 (0%)	0
Hypoaesthesia	6/116 (5.2%)	6	4/112 (3.6%)	4	0/5 (0%)	0
Neuropathy peripheral	2/116 (1.7%)	2	8/112 (7.1%)	9	0/5 (0%)	0
Psychiatric disorders
Insomnia	13/116 (11.2%)	14	11/112 (9.8%)	13	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/116 (0.9%)	1	0/112 (0%)	0	1/5 (20%)	1
Cough	34/116 (29.3%)	51	19/112 (17%)	32	1/5 (20%)	1
Dyspnoea	11/116 (9.5%)	14	6/112 (5.4%)	6	0/5 (0%)	0
Epistaxis	7/116 (6%)	11	13/112 (11.6%)	20	0/5 (0%)	0
Oropharyngeal pain	4/116 (3.4%)	7	11/112 (9.8%)	14	0/5 (0%)	0
Productive cough	10/116 (8.6%)	10	8/112 (7.1%)	11	1/5 (20%)	1
Rhinorrhoea	6/116 (5.2%)	9	11/112 (9.8%)	14	0/5 (0%)	0
Throat tightness	0/116 (0%)	0	0/112 (0%)	0	1/5 (20%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/116 (0.9%)	1	16/112 (14.3%)	17	0/5 (0%)	0
Dry skin	5/116 (4.3%)	6	8/112 (7.1%)	8	0/5 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	0/116 (0%)	0	22/112 (19.6%)	28	0/5 (0%)	0
Pruritus	15/116 (12.9%)	22	13/112 (11.6%)	16	0/5 (0%)	0
Rash	20/116 (17.2%)	32	20/112 (17.9%)	30	1/5 (20%)	1
Vascular disorders
Hypertension	3/116 (2.6%)	3	12/112 (10.7%)	13	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.