Study of Pembrolizumab (MK-3475) vs. Best Supportive Care in Participants With Previously Systemically Treated Advanced Hepatocellular Carcinoma (MK-3475-240/KEYNOTE-240)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02702401
• Collaborator: (none)
• Enrollment: 413
• Arms: 2
• Actual Duration (Months): 63.9

Study Details

Study Description

Brief Summary

This is a study of pembrolizumab (MK-3475) in participants with previously systemically treated advanced hepatocellular carcinoma (HCC).

The primary objectives of this study are to determine 1) Progression-Free Survival (PFS) and 2) Overall Survival (OS) of pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC. The primary hypotheses of this study are: 1) pembrolizumab plus BSC prolongs PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed by Blinded Independent Central Review compared to placebo plus BSC, and 2) pembrolizumab plus BSC improves OS compared with placebo plus BSC.

Effective with Amendment 4: Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Biological: Pembrolizumab; Drug: Placebo; Other: Best Supportive Care	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 413 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive Care as Second-Line Therapy in Subjects With Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-240)
• Actual Study Start Date: May 26, 2016
• Actual Primary Completion Date: Jan 2, 2019
• Actual Study Completion Date: Sep 22, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab+Best Supportive Care Participants receive a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475 KEYTRUDA® ; Other: Best Supportive Care; Best supportive care will include pain management and management of other potential complications including ascites per local standards of care.
Placebo Comparator: Placebo+Best Supportive Care Participants receive a placebo IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.	Drug: Placebo; 0.90% w/v sodium chloride IV infusion; Other: Best Supportive Care; Best supportive care will include pain management and management of other potential complications including ascites per local standards of care.

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Through database cutoff date of 26-Mar-2018 (Up to approximately 21 months)]

   PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The primary analysis of PFS was performed at the time of the first interim analysis of OS (as pre-specified in the protocol), with data cutoff of 26-Mar-2018.

2. Overall Survival (OS) [Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)]

   OS was determined for all participants and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last follow-up. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The OS for all participants is presented.

Secondary Outcome Measures

1. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)]

   ORR was determined in all participants and was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Participants with missing data were considered non-responders. The ORR was analyzed using the Miettinen & Nurminen method. The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented.

2. Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)]

   DCR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions), Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), or Stable Disease (SD) per RECIST 1.1 after ≥6 weeks as assessed by Blinded Independent Central Review (BICR). The DCR was analyzed using the Miettinen & Nurminen method. The percentage of participants who experienced a CR, PR, or SD is presented.

3. Time to Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)]

   TTP was defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. If there was no documented disease progression, TTP was censored at last tumor assessment date. The TTP was analyzed using the product-limit (Kaplan-Meier) method for censored data. TTP per RECIST 1.1 is presented for all participants.

4. Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [From time of first documented evidence of CR or PR through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)]

   DOR was determined in participants who demonstrated a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. The DOR was analyzed using the product-limit (Kaplan-Meier) method for censored data.

5. Number of Participants Who Experienced At Least One Adverse Event (AE) [Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)]

   An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented. These safety results are based on a 02-Jan-2019 data cutoff date.

6. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [From Day 1 through end of treatment (Up to approximately 24 months)]

   An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented. These results are based on a 02-Jan-2019 data cutoff date.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has a HCC diagnosis confirmed by radiology, histology or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).

• Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach.

• Has a Child-Pugh Class A liver score within 7 days of first dose of study drug.

• Has a predicted life expectancy >3 months.

• Has at least one measurable lesion based on RECIST 1.1 as confirmed by the blinded central imaging vendor.

• Has a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 7 days of first dose of study drug.

• Has documented objective radiographic progression during or after treatment with sorafenib or intolerance to sorafenib.

• Participants with chronic infection by Hepatitis C Virus (HCV) who are treated (successfully or treatment failure) or untreated are allowed on study. In addition, participants with successful HCV treatment are allowed as long as there are ≥4 weeks between achieving sustained viral response (SVR12) and start of study drug.

• Has controlled infection by Hepatitis B Virus (HBV).

• Is willing to use an adequate method of contraception for the course of the study through at least 120 days or longer based on local regulation after the last dose of study drug (male and female participants of childbearing potential).

• Demonstrates adequate organ function.

Exclusion Criteria:

• Is currently participating, or has participated in a study of an investigational agent and received study drug, herbal/complementary oral or IV medicine, or used an investigational device within 4 weeks of the first dose of study drug. Participants must also have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from adverse events (AEs) due to any prior therapy.

• Has received sorafenib within 14 days of first dose of study drug.

• Has had esophageal or gastric variceal bleeding within the last 6 months.

• Has clinically apparent ascites on physical examination. Note: ascites detectable on imaging studies only ARE allowed.

• Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging.

• Has had clinically diagnosed hepatic encephalopathy in the last 6 months.

• Has had a solid organ or hematologic transplant.

• Has had prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib, prior to the start of study drug.

• Has a known severe hypersensitivity (≥Grade 3) to pembrolizumab, its active substance and/or any of its excipients.

• Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

• Has received locoregional therapy to liver (transcatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiation, radioembolization, or ablation) within 4 weeks prior to the first dose of study drug.

• Has had major surgery to liver or other site within 4 weeks prior to the first dose of study drug.

• Has had minor surgery (i.e., simple excision, tooth extraction) ≤7 days prior to the first dose of study drug (Cycle 1, Day 1).

• Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any intervention prior to starting study drug.

• Has a diagnosed additional malignancy within 3 years prior to first dose of study drug with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers.

• Has known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis.

• Has a history of non-infectious pneumonitis that required steroids or current pneumonitis.

• Has an active infection requiring systemic therapy.

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the first dose of study drug through 120 days or longer based on local regulation after the last dose of study drug.

• Has received prior immunotherapy including anti-programmed cell death-1 (anti-PD-1), anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has previously participated in Merck pembrolizumab (MK-3475) studies.

• Has a known history of human immunodeficiency virus (HIV).

• Has dual active HBV infection and HCV infection at study entry.

• Has received a live vaccine within 30 days of planned start of study drug (Cycle 1, Day 1).

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 - Dec 21, 2017

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02702401
• Other Study ID Numbers: 3475-240; 2015-004567-36; 163456; MK-3475-240; KEYNOTE-240
• First Posted: Mar 8, 2016
• Last Update Posted: Nov 4, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Merck Sharp & Dohme LLC: PD1; PD-1; PDL1; PD-L1
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Pembrolizumab

Study Results

Participant Flow

Recruitment Details	Although 278 participants were randomized to receive pembrolizumab and 135 to receive placebo, 1 participant in the placebo group received pembrolizumab in error. The efficacy population included all participants as randomized and the safety population was adjusted to account for actual treatment received (pembrolizumab = 279, placebo =134).
Pre-assignment Detail	These results are based on a database cutoff date of 26-Mar-2018 for the primary analysis of progression-free survival (PFS) and 02-Jan-2019 for all other outcomes, at which time 128 participants were ongoing in the study.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS best supportive care (BSC). Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Period Title: Overall Study
STARTED	278	135
Treated	278	135
COMPLETED	0	0
NOT COMPLETED	278	135

Baseline Characteristics

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care	Total
Arm/Group Description	Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS best supportive care (BSC). Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.	Total of all reporting groups
Overall Participants	278	135	413
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.6 (11.1)	64.4 (10.3)	65.2 (10.8)
Sex: Female, Male (Count of Participants)
Female	52 18.7%	23 17%	75 18.2%
Male	226 81.3%	112 83%	338 81.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	22 7.9%	13 9.6%	35 8.5%
Not Hispanic or Latino	233 83.8%	113 83.7%	346 83.8%
Unknown or Not Reported	23 8.3%	9 6.7%	32 7.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	5 1.8%	1 0.7%	6 1.5%
Asian	113 40.6%	52 38.5%	165 40%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	1 0.2%
Black or African American	13 4.7%	6 4.4%	19 4.6%
White	143 51.4%	70 51.9%	213 51.6%
More than one race	3 1.1%	5 3.7%	8 1.9%
Unknown or Not Reported	0 0%	1 0.7%	1 0.2%
Region of enrollment (Count of Participants)
Asia without Japan	67 24.1%	31 23%	98 23.7%
European Union	96 34.5%	43 31.9%	139 33.7%
Japan	40 14.4%	19 14.1%	59 14.3%
United States	21 7.6%	16 11.9%	37 9%
Others	54 19.4%	26 19.3%	80 19.4%
Macrovascular invasion (Count of Participants)
Yes	36 12.9%	16 11.9%	52 12.6%
No	242 87.1%	119 88.1%	361 87.4%
Alpha-fetoprotein level (Count of Participants)
<200 ng/mL	149 53.6%	77 57%	226 54.7%
≥200 ng/mL	129 46.4%	58 43%	187 45.3%

Outcome Measures

1. Primary 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) or death due to any cause, whichever occurred first, per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The primary analysis of PFS was performed at the time of the first interim analysis of OS (as pre-specified in the protocol), with data cutoff of 26-Mar-2018.
Time Frame	Through database cutoff date of 26-Mar-2018 (Up to approximately 21 months)

Outcome Measure Data

Analysis Population Description

The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	278	135
Median (95% Confidence Interval) [Months]	3.0	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + Best Supportive Care, Placebo + Best Supportive Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0186
	Comments
	Method	Log Rank
	Comments	One-sided p-value stratified by geographic region, macrovascular invasion and alfa-fetoprotein level.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.775
	Confidence Interval	(2-Sided) 95%; 0.609 to 0.987
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox regression model with Efron's method (treatment as covariate) stratified by geographic region, macrovascular invasion and alfa-fetoprotein level

2. Primary Outcome

Title	Overall Survival (OS)
Description	OS was determined for all participants and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last follow-up. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The OS for all participants is presented.
Time Frame	Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Outcome Measure Data

Analysis Population Description

The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	278	135
Median (95% Confidence Interval) [Months]	13.9	10.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + Best Supportive Care, Placebo + Best Supportive Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0238
	Comments
	Method	Log Rank
	Comments	One-sided p-value stratified by geographic region, macrovascular invasion and alfa-fetoprotein level.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.781
	Confidence Interval	(2-Sided) 95%; 0.611 to 0.998
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox regression model with Efron's method (treatment as covariate) stratified by geographic region, macrovascular invasion and alfa-fetoprotein level

3. Secondary Outcome

Title	Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	ORR was determined in all participants and was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). Participants with missing data were considered non-responders. The ORR was analyzed using the Miettinen & Nurminen method. The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented.
Time Frame	Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Outcome Measure Data

Analysis Population Description

The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	278	135
Number (95% Confidence Interval) [Percentage of participants]	18.3 6.6%	4.4 3.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + Best Supportive Care, Placebo + Best Supportive Care
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percent
	Estimated Value	13.8
	Confidence Interval	(2-Sided) 95%; 7.7 to 19.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Miettinen & Nurminen method stratified by geographic region, macrovascular invasion and alfa-fetoprotein level

4. Secondary Outcome

Title	Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	DCR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions), Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters), or Stable Disease (SD) per RECIST 1.1 after ≥6 weeks as assessed by Blinded Independent Central Review (BICR). The DCR was analyzed using the Miettinen & Nurminen method. The percentage of participants who experienced a CR, PR, or SD is presented.
Time Frame	Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Outcome Measure Data

Analysis Population Description

The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	278	135
Number (95% Confidence Interval) [Percentage of participants]	62.2 22.4%	53.3 39.5%

5. Secondary Outcome

Title	Time to Progression (TTP) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	TTP was defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. If there was no documented disease progression, TTP was censored at last tumor assessment date. The TTP was analyzed using the product-limit (Kaplan-Meier) method for censored data. TTP per RECIST 1.1 is presented for all participants.
Time Frame	Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Outcome Measure Data

Analysis Population Description

The analysis population included all randomized participants. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	278	135
Median (95% Confidence Interval) [Months]	3.8	2.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab + Best Supportive Care, Placebo + Best Supportive Care
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments	One-sided p-value stratified by geographic region, macrovascular invasion and alfa-fetoprotein level.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.688
	Confidence Interval	(2-Sided) 95%; 0.540 to 0.877
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cox regression model with Efron's method (treatment as covariate) stratified by geographic region, macrovascular invasion and alfa-fetoprotein level

6. Secondary Outcome

Title	Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Description	DOR was determined in participants who demonstrated a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Participants who had not progressed or died at the time of analysis were censored at the date of their last tumor assessment. PD was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. The appearance of ≥1 new lesion was also considered PD. The DOR was analyzed using the product-limit (Kaplan-Meier) method for censored data.
Time Frame	From time of first documented evidence of CR or PR through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Outcome Measure Data

Analysis Population Description

The analysis population included all randomized participants who demonstrated at least a partial response. Participants were included in the treatment group to which they were randomized.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	51	6
Median (95% Confidence Interval) [Months]	13.8	NA

7. Secondary Outcome

Title	Number of Participants Who Experienced At Least One Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented. These safety results are based on a 02-Jan-2019 data cutoff date.
Time Frame	Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received ≥1 dose of study treatment. Participants were grouped by actual treatment received.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	279	134
Count of Participants [Participants]	269 96.8%	121 89.6%

8. Secondary Outcome

Title	Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
Description	An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable 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 study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented. These results are based on a 02-Jan-2019 data cutoff date.
Time Frame	From Day 1 through end of treatment (Up to approximately 24 months)

Outcome Measure Data

Analysis Population Description

The analysis population included participants who received ≥1 dose of study treatment. Participants were grouped by actual treatment received.

Arm/Group Title	Pembrolizumab + Best Supportive Care	Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).	Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
Measure Participants	279	134
Count of Participants [Participants]	48 17.3%	12 8.9%

Adverse Events

Time Frame	Through database cutoff date of 02-Jan-2019 (Up to approximately 30 months)
Adverse Event Reporting Description	All participants who received at ≥1 dose of study treatment. Per protocol, progression of cancer under study was not considered an AE unless related to study drug. Therefore, MedDRA terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" not related to study drug are excluded as AEs. Due to a dosing error (a participant randomized to the placebo group received pembrolizumab), the safety population was adjusted to account for actual treatment received.
Arm/Group Title	Pembrolizumab + Best Supportive Care		Placebo + Best Supportive Care
Arm/Group Description	Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year).		Participants received placebo by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC.
All Cause Mortality
	Pembrolizumab + Best Supportive Care		Placebo + Best Supportive Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	184/279 (65.9%)		100/134 (74.6%)
Serious Adverse Events
	Pembrolizumab + Best Supportive Care		Placebo + Best Supportive Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	104/279 (37.3%)		37/134 (27.6%)
Blood and lymphatic system disorders
Anaemia	3/279 (1.1%)	3	5/134 (3.7%)	6
Immune thrombocytopenic purpura	1/279 (0.4%)	1	0/134 (0%)	0
Thrombocytopenia	0/279 (0%)	0	1/134 (0.7%)	1
Cardiac disorders
Atrial fibrillation	1/279 (0.4%)	1	2/134 (1.5%)	2
Cardiac arrest	1/279 (0.4%)	1	0/134 (0%)	0
Myocardial infarction	2/279 (0.7%)	2	0/134 (0%)	0
Myocardial ischaemia	1/279 (0.4%)	1	1/134 (0.7%)	1
Pericardial effusion	0/279 (0%)	0	1/134 (0.7%)	1
Supraventricular tachycardia	1/279 (0.4%)	1	0/134 (0%)	0
Endocrine disorders
Hypophysitis	1/279 (0.4%)	1	0/134 (0%)	0
Hypothyroidism	1/279 (0.4%)	1	0/134 (0%)	0
Eye disorders
Blindness unilateral	0/279 (0%)	0	1/134 (0.7%)	1
Macular hole	1/279 (0.4%)	1	0/134 (0%)	0
Retinal detachment	0/279 (0%)	0	1/134 (0.7%)	1
Retinal vein occlusion	0/279 (0%)	0	1/134 (0.7%)	1
Gastrointestinal disorders
Abdominal distension	1/279 (0.4%)	1	0/134 (0%)	0
Abdominal pain	1/279 (0.4%)	1	0/134 (0%)	0
Abdominal pain upper	2/279 (0.7%)	2	0/134 (0%)	0
Ascites	13/279 (4.7%)	14	5/134 (3.7%)	5
Colitis	2/279 (0.7%)	2	0/134 (0%)	0
Constipation	1/279 (0.4%)	1	0/134 (0%)	0
Diarrhoea	2/279 (0.7%)	2	1/134 (0.7%)	1
Diverticular fistula	1/279 (0.4%)	1	0/134 (0%)	0
Diverticulum intestinal haemorrhagic	1/279 (0.4%)	1	0/134 (0%)	0
Gastric ulcer	1/279 (0.4%)	1	0/134 (0%)	0
Gastritis	0/279 (0%)	0	1/134 (0.7%)	1
Gastrointestinal inflammation	1/279 (0.4%)	1	0/134 (0%)	0
Intestinal obstruction	1/279 (0.4%)	1	0/134 (0%)	0
Intestinal perforation	1/279 (0.4%)	1	0/134 (0%)	0
Intra-abdominal haemorrhage	1/279 (0.4%)	1	0/134 (0%)	0
Oesophageal varices haemorrhage	3/279 (1.1%)	4	1/134 (0.7%)	1
Small intestinal obstruction	1/279 (0.4%)	1	0/134 (0%)	0
Upper gastrointestinal haemorrhage	3/279 (1.1%)	3	0/134 (0%)	0
Varices oesophageal	2/279 (0.7%)	2	0/134 (0%)	0
Vomiting	1/279 (0.4%)	1	0/134 (0%)	0
General disorders
Chest pain	1/279 (0.4%)	1	0/134 (0%)	0
Death	1/279 (0.4%)	1	1/134 (0.7%)	1
Fatigue	1/279 (0.4%)	1	0/134 (0%)	0
General physical health deterioration	2/279 (0.7%)	2	0/134 (0%)	0
Influenza like illness	0/279 (0%)	0	1/134 (0.7%)	1
Mucosal inflammation	0/279 (0%)	0	1/134 (0.7%)	1
Pyrexia	1/279 (0.4%)	1	0/134 (0%)	0
Hepatobiliary disorders
Autoimmune hepatitis	3/279 (1.1%)	3	0/134 (0%)	0
Cholangitis	0/279 (0%)	0	1/134 (0.7%)	1
Cholestasis	2/279 (0.7%)	2	0/134 (0%)	0
Hepatic cirrhosis	2/279 (0.7%)	2	0/134 (0%)	0
Hepatic cyst	0/279 (0%)	0	1/134 (0.7%)	1
Hepatic failure	1/279 (0.4%)	1	2/134 (1.5%)	2
Hepatic haemorrhage	1/279 (0.4%)	1	0/134 (0%)	0
Hyperbilirubinaemia	2/279 (0.7%)	2	0/134 (0%)	0
Immune-mediated hepatitis	2/279 (0.7%)	2	0/134 (0%)	0
Jaundice	1/279 (0.4%)	1	0/134 (0%)	0
Jaundice cholestatic	1/279 (0.4%)	1	0/134 (0%)	0
Immune system disorders
Contrast media allergy	1/279 (0.4%)	1	0/134 (0%)	0
Infections and infestations
Bronchitis	1/279 (0.4%)	1	0/134 (0%)	0
Cellulitis	1/279 (0.4%)	1	1/134 (0.7%)	1
Gastroenteritis	1/279 (0.4%)	1	0/134 (0%)	0
Hepatitis B	0/279 (0%)	0	1/134 (0.7%)	1
Hepatitis C	1/279 (0.4%)	1	0/134 (0%)	0
Infection	2/279 (0.7%)	2	0/134 (0%)	0
Liver abscess	1/279 (0.4%)	1	1/134 (0.7%)	1
Lung infection	2/279 (0.7%)	2	1/134 (0.7%)	1
Mycobacterial infection	1/279 (0.4%)	1	0/134 (0%)	0
Peritonitis	1/279 (0.4%)	1	1/134 (0.7%)	1
Peritonitis bacterial	2/279 (0.7%)	2	0/134 (0%)	0
Pleural infection	0/279 (0%)	0	1/134 (0.7%)	1
Pneumonia	4/279 (1.4%)	4	2/134 (1.5%)	2
Pneumonia bacterial	1/279 (0.4%)	1	0/134 (0%)	0
Pneumonia mycoplasmal	0/279 (0%)	0	1/134 (0.7%)	1
Sepsis	2/279 (0.7%)	2	0/134 (0%)	0
Upper respiratory tract infection	1/279 (0.4%)	1	1/134 (0.7%)	1
Urinary tract infection	1/279 (0.4%)	1	1/134 (0.7%)	1
Injury, poisoning and procedural complications
Fall	0/279 (0%)	0	1/134 (0.7%)	1
Femoral neck fracture	1/279 (0.4%)	1	0/134 (0%)	0
Femur fracture	1/279 (0.4%)	1	0/134 (0%)	0
Hip fracture	1/279 (0.4%)	1	1/134 (0.7%)	1
Humerus fracture	1/279 (0.4%)	1	0/134 (0%)	0
Ligament sprain	1/279 (0.4%)	1	0/134 (0%)	0
Lumbar vertebral fracture	1/279 (0.4%)	1	0/134 (0%)	0
Vascular procedure complication	1/279 (0.4%)	1	0/134 (0%)	0
Investigations
Alanine aminotransferase increased	6/279 (2.2%)	6	1/134 (0.7%)	1
Aspartate aminotransferase increased	8/279 (2.9%)	8	4/134 (3%)	4
Blood bilirubin increased	8/279 (2.9%)	8	2/134 (1.5%)	3
Blood creatinine increased	1/279 (0.4%)	1	0/134 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/279 (0.4%)	1	0/134 (0%)	0
Dehydration	1/279 (0.4%)	2	0/134 (0%)	0
Diabetes mellitus	0/279 (0%)	0	1/134 (0.7%)	1
Hypercalcaemia	1/279 (0.4%)	1	0/134 (0%)	0
Hyperglycaemia	0/279 (0%)	0	1/134 (0.7%)	1
Hyperkalaemia	1/279 (0.4%)	1	0/134 (0%)	0
Hypoglycaemia	1/279 (0.4%)	1	0/134 (0%)	0
Type 1 diabetes mellitus	1/279 (0.4%)	1	1/134 (0.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/279 (0%)	0	1/134 (0.7%)	1
Back pain	0/279 (0%)	0	1/134 (0.7%)	1
Bursitis	0/279 (0%)	0	1/134 (0.7%)	1
Lumbar spinal stenosis	1/279 (0.4%)	1	0/134 (0%)	0
Neck pain	0/279 (0%)	0	1/134 (0.7%)	1
Osteochondrosis	1/279 (0.4%)	1	0/134 (0%)	0
Pathological fracture	1/279 (0.4%)	1	0/134 (0%)	0
Polymyalgia rheumatica	1/279 (0.4%)	1	0/134 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/279 (0.4%)	1	0/134 (0%)	0
Gastric cancer	1/279 (0.4%)	1	0/134 (0%)	0
Insulinoma	1/279 (0.4%)	1	0/134 (0%)	0
Malignant neoplasm progression	1/279 (0.4%)	1	0/134 (0%)	0
Oral neoplasm	1/279 (0.4%)	1	0/134 (0%)	0
Tumour haemorrhage	0/279 (0%)	0	1/134 (0.7%)	1
Tumour rupture	1/279 (0.4%)	1	0/134 (0%)	0
Nervous system disorders
Cerebral infarction	1/279 (0.4%)	1	0/134 (0%)	0
Cerebrovascular accident	1/279 (0.4%)	1	0/134 (0%)	0
Hepatic encephalopathy	1/279 (0.4%)	2	1/134 (0.7%)	1
Seizure	1/279 (0.4%)	1	0/134 (0%)	0
Syncope	0/279 (0%)	0	1/134 (0.7%)	1
Psychiatric disorders
Mental status changes	1/279 (0.4%)	1	0/134 (0%)	0
Renal and urinary disorders
Acute kidney injury	3/279 (1.1%)	3	0/134 (0%)	0
Nephrolithiasis	0/279 (0%)	0	1/134 (0.7%)	1
Renal failure	1/279 (0.4%)	1	0/134 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/279 (0.4%)	1	0/134 (0%)	0
Dyspnoea	0/279 (0%)	0	1/134 (0.7%)	1
Haemoptysis	1/279 (0.4%)	1	0/134 (0%)	0
Interstitial lung disease	3/279 (1.1%)	3	0/134 (0%)	0
Pleural effusion	2/279 (0.7%)	2	1/134 (0.7%)	1
Pleurisy	0/279 (0%)	0	1/134 (0.7%)	1
Pneumonitis	2/279 (0.7%)	2	1/134 (0.7%)	1
Pneumothorax	2/279 (0.7%)	2	0/134 (0%)	0
Skin and subcutaneous tissue disorders
Erythema multiforme	1/279 (0.4%)	1	0/134 (0%)	0
Lichenoid keratosis	1/279 (0.4%)	1	0/134 (0%)	0
Vascular disorders
Hypotension	1/279 (0.4%)	1	0/134 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab + Best Supportive Care		Placebo + Best Supportive Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	236/279 (84.6%)		109/134 (81.3%)
Blood and lymphatic system disorders
Anaemia	26/279 (9.3%)	28	11/134 (8.2%)	18
Endocrine disorders
Hypothyroidism	13/279 (4.7%)	14	7/134 (5.2%)	7
Gastrointestinal disorders
Abdominal pain	39/279 (14%)	50	9/134 (6.7%)	9
Abdominal pain upper	23/279 (8.2%)	25	10/134 (7.5%)	14
Ascites	15/279 (5.4%)	15	8/134 (6%)	8
Constipation	25/279 (9%)	29	15/134 (11.2%)	16
Diarrhoea	47/279 (16.8%)	70	20/134 (14.9%)	24
Nausea	32/279 (11.5%)	40	20/134 (14.9%)	21
Vomiting	25/279 (9%)	40	5/134 (3.7%)	9
General disorders
Asthenia	25/279 (9%)	34	15/134 (11.2%)	17
Fatigue	51/279 (18.3%)	60	31/134 (23.1%)	32
Oedema peripheral	32/279 (11.5%)	39	17/134 (12.7%)	20
Pyrexia	25/279 (9%)	27	15/134 (11.2%)	22
Investigations
Alanine aminotransferase increased	44/279 (15.8%)	47	12/134 (9%)	12
Aspartate aminotransferase increased	55/279 (19.7%)	57	18/134 (13.4%)	21
Blood alkaline phosphatase increased	20/279 (7.2%)	20	9/134 (6.7%)	9
Blood bilirubin increased	46/279 (16.5%)	58	16/134 (11.9%)	18
Gamma-glutamyltransferase increased	17/279 (6.1%)	18	7/134 (5.2%)	7
Metabolism and nutrition disorders
Decreased appetite	47/279 (16.8%)	51	21/134 (15.7%)	23
Hyperglycaemia	11/279 (3.9%)	20	7/134 (5.2%)	7
Hypoalbuminaemia	20/279 (7.2%)	24	7/134 (5.2%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	20/279 (7.2%)	23	13/134 (9.7%)	14
Back pain	27/279 (9.7%)	29	13/134 (9.7%)	14
Musculoskeletal pain	14/279 (5%)	14	5/134 (3.7%)	5
Nervous system disorders
Headache	19/279 (6.8%)	21	5/134 (3.7%)	7
Psychiatric disorders
Insomnia	12/279 (4.3%)	12	8/134 (6%)	10
Respiratory, thoracic and mediastinal disorders
Cough	24/279 (8.6%)	30	24/134 (17.9%)	27
Dyspnoea	18/279 (6.5%)	18	14/134 (10.4%)	16
Skin and subcutaneous tissue disorders
Pruritus	51/279 (18.3%)	62	16/134 (11.9%)	17
Rash	32/279 (11.5%)	37	7/134 (5.2%)	8
Vascular disorders
Hypertension	10/279 (3.6%)	10	8/134 (6%)	14

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.