Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03553836
• Collaborator: (none)
• Enrollment: 976
• Locations: 159
• Arms: 2
• Anticipated Duration (Months): 181
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This 2-part study will evaluate the safety and efficacy of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma. Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design every 3 weeks (Q3W) for up to 17 cycles/~1 year (each cycle = 21 days). Participants who complete the initial treatment of 17 cycles of pembrolizumab in Part 1 and experience disease recurrence may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2 in an open label design. Participants who complete the initial treatment of placebo and experience disease recurrence may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2 in an open label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo.

Per protocol, response/ progression or adverse events (AEs) during re-challenge/switch-over in Part 2 will not be counted towards the RFS outcome measure or safety outcome measures respectively.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Biological: Pembrolizumab; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 976 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: Participants and Investigators will be blinded in Part 1 and unblinded in Part 2, if done.
• Primary Purpose: Treatment
• Official Title: Adjuvant Therapy With Pembrolizumab Versus Placebo in Resected High-risk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE-716)
• Actual Study Start Date: Sep 12, 2018
• Actual Primary Completion Date: Jun 21, 2021
• Anticipated Study Completion Date: Oct 12, 2033

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Participants receive 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who complete the initial treatment of 17 cycles of pembrolizumab and experience disease recurrence may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.	Biological: Pembrolizumab; Administered as an intravenous (IV) infusion every 3 weeks (Q3W); Other Names: KEYTRUDA® MK-3475
Placebo Comparator: Placebo Participants receive saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who complete the initial treatment of 17 cycles of placebo and experience disease recurrence may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.	Biological: Pembrolizumab; Administered as an intravenous (IV) infusion every 3 weeks (Q3W); Other Names: KEYTRUDA® MK-3475 ; Other: Placebo; Administered as an IV infusion every 3 weeks (Q3W)

Outcome Measures

Primary Outcome Measures

1. Recurrence-free Survival (RFS) [Up to ~32.7 months]

   RFS was defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first. Per protocol, final analysis for this primary outcome measure was performed using the initial pembrolizumab or placebo treatment with a protocol-specified analysis data cut-off date of June-21-2021.

Secondary Outcome Measures

1. Distant Metastasis-free Survival (DMFS) [Up to ~9 years]

   DMFS will be defined as the time from randomization to the first diagnosis of a distant metastasis per RECIST 1.1. Distant metastasis will refer to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes. DMFS will be reported for randomized participants.

2. Overall Survival (OS) [Up to ~15 years]

   OS will be defined as the time from randomization to death due to any cause. OS will be reported for randomized participants.

3. Number of Participants Who Experienced at Least One Adverse Event (AE) [Up to ~19.3 months]

   An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.

4. Number of Participants Who Discontinued Study Treatment Due to an AE [Up to ~19.3 months]

   An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion:

• Has surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer (AJCC) 8th edition guidelines

• Has not been previously treated for melanoma beyond complete surgical resection

• Has ≤12 weeks between final surgical resection and randomization

• Has no evidence of metastatic disease on imaging as determined by investigator

• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale or Lansky Play-Performance Scale (LPS) score ≥50 for participants ≤16 years old, or a Karnofsky Performance Scale (KPS) score ≥50 for participants >16 and <18 years old

• Has recovered adequately from toxicity and/or complications from surgery prior to study start

• Female participants must not be pregnant or breastfeeding, and must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment if they are a woman of childbearing potential (WOCBP)

Exclusion:

• Has a known additional malignancy that is progressing or has required active antineoplastic therapy (including hormonal) within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy

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

• WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1), anti-Programmed Cell Death Receptor Ligand 1 (PD-L1) or anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137)

• Has received prior systemic anti-cancer therapy for melanoma including investigational agents

• Has received a live vaccine within 30 days prior to the first dose of study treatment

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment

• Has severe hypersensitivity (≥Grade 3) to any excipients of pembrolizumab

• Has an active autoimmune disease that has required systemic treatment in the past 2 years

• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis

• Has an active infection requiring systemic therapy

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

• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) or known active Hepatitis C virus (defined as Hepatitis C virus ribonucleic acid [RNA] [qualitative] is detected) infection

• Has a history of active tuberculosis (Bacillus tuberculosis)

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator

• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

• Has had an allogeneic tissue/solid organ transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center ( Site 0121)	Tucson	Arizona	United States	85719
2	UCSD Moores Cancer Center ( Site 0133)	La Jolla	California	United States	92037
3	The Angeles Clinic and Research Institute ( Site 0029)	Los Angeles	California	United States	90025
4	UCLA Hematology & Oncology ( Site 0130)	Los Angeles	California	United States	90095
5	John Wayne Cancer Institute ( Site 0026)	Santa Monica	California	United States	90404
6	University of Colorado Cancer Center ( Site 0027)	Aurora	Colorado	United States	80045
7	Yale University ( Site 0035)	New Haven	Connecticut	United States	06511
8	Mayo Clinic Florida ( Site 0024)	Jacksonville	Florida	United States	32224
9	Moffitt McKinley Outpatient Center ( Site 0131)	Tampa	Florida	United States	33612
10	Winship Cancer Institute of Emory University ( Site 0046)	Atlanta	Georgia	United States	30322-1013
11	Northside Hospital ( Site 0115)	Atlanta	Georgia	United States	30341
12	Northwestern Medical Group ( Site 0135)	Chicago	Illinois	United States	60611
13	The University of Chicago Medical Center ( Site 0007)	Chicago	Illinois	United States	60637
14	Advocate Medical Group-Park Ridge ( Site 0025)	Park Ridge	Illinois	United States	60068
15	University of Iowa Hospital and Clinics ( Site 0001)	Iowa City	Iowa	United States	52242
16	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 0047)	Baltimore	Maryland	United States	21287
17	Massachusetts General Hospital ( Site 0126)	Boston	Massachusetts	United States	02114
18	Beth Israel Deaconess Medical Center ( Site 0141)	Boston	Massachusetts	United States	02215
19	Dana Farber Cancer Institute ( Site 0124)	Boston	Massachusetts	United States	02215
20	Karmanos Cancer Institute ( Site 0111)	Detroit	Michigan	United States	48201
21	Mayo Clinic [Rochester, MN] ( Site 0016)	Rochester	Minnesota	United States	55905
22	Siteman Cancer Center ( Site 0143)	Saint Louis	Missouri	United States	63110
23	Memorial Sloan Kettering ( Site 0006)	Harrison	New York	United States	10604
24	Laura and Isaac Perlmutter Cancer Center ( Site 0137)	New York	New York	United States	10016
25	Memorial Sloan Kettering Cancer Center ( Site 0142)	New York	New York	United States	10022
26	Mount Sinai Medical Center ( Site 0038)	New York	New York	United States	10029
27	University of Rochester ( Site 0019)	Rochester	New York	United States	14642
28	The Lindner Center for Research and Education at The Christ Hospital ( Site 0004)	Cincinnati	Ohio	United States	45219
29	Stephenson Cancer Center ( Site 0042)	Oklahoma City	Oklahoma	United States	73104
30	Oregon Health & Science University ( Site 0032)	Portland	Oregon	United States	97239
31	Children's Hospital of Pittsburgh UPMC ( Site 0144)	Pittsburgh	Pennsylvania	United States	15224
32	UPMC Hillman Cancer Centers ( Site 0043)	Pittsburgh	Pennsylvania	United States	15232
33	West Cancer Center - East Campus ( Site 0022)	Germantown	Tennessee	United States	38138
34	University of Tennessee Medical Center Knoxville ( Site 0116)	Knoxville	Tennessee	United States	37920
35	University of Texas-MD Anderson Cancer Center ( Site 0134)	Houston	Texas	United States	77030
36	Inova Schar Cancer Institute ( Site 0014)	Fairfax	Virginia	United States	22031
37	VCU Massey Cancer Center ( Site 0008)	Richmond	Virginia	United States	23298
38	Seattle Cancer Care Alliance ( Site 0044)	Seattle	Washington	United States	98109
39	University of Wisconsin Hospital and Clinics ( Site 0030)	Madison	Wisconsin	United States	53792
40	Melanoma Institute Australia ( Site 0856)	North Sydney	New South Wales	Australia	2065
41	Westmead Hospital ( Site 0853)	Westmead	New South Wales	Australia	2145
42	Cairns Base Hospital ( Site 0859)	Cairns	Queensland	Australia	4870
43	Tasman Oncology Research Pty Ltd ( Site 0858)	Southport	Queensland	Australia	4215
44	Princess Alexandra Hospital ( Site 0857)	Woolloongabba	Queensland	Australia	4102
45	Royal Adelaide Hospital ( Site 0861)	Adelaide	South Australia	Australia	5000
46	Ashford Cancer Centre Research ( Site 0860)	Kurralta Park	South Australia	Australia	5037
47	The Alfred Hospital ( Site 0852)	Melbourne	Victoria	Australia	3004
48	Fiona Stanley Hospital ( Site 0851)	Murdoch	Western Australia	Australia	6150
49	GZA Sint Augustinus ( Site 0259)	Wilrijk - Antwerpen	Antwerpen	Belgium	2610
50	Cliniques Universitaires Saint-Luc ( Site 0251)	Brussels	Bruxelles-Capitale, Region De	Belgium	1200
51	Institut Jules Bordet ( Site 0254)	Bruxelles	Bruxelles-Capitale, Region De	Belgium	1000
52	Jessa Ziekenhuis Campus Virga Jesse ( Site 0256)	Hasselt	Limburg	Belgium	3500
53	UZ Gent ( Site 0255)	Gent	Oost-Vlaanderen	Belgium	9000
54	UZ Leuven ( Site 0252)	Leuven	Vlaams-Brabant	Belgium	3000
55	Hospital Erasto Gaertner ( Site 0159)	Curitiba	Parana	Brazil	81520-060
56	Hospital de Caridade de Ijui ( Site 0156)	Ijui	Rio Grande Do Sul	Brazil	98700 000
57	Hospital Sao Vicente de Paulo ( Site 0158)	Passo Fundo	Rio Grande Do Sul	Brazil	99010-080
58	Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da Pucrs ( Site 0154)	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
59	Fundacao Pio XII - Hospital de Cancer de Barretos ( Site 0155)	Barretos	Sao Paulo	Brazil	14784-400
60	Hospital de Clinicas de Rio Preto ( Site 0162)	Sao Jose Do Rio Preto - SP	Sao Paulo	Brazil	15090-000
61	Instituto Nacional do Cancer II ( Site 0160)	Rio de Janeiro		Brazil	20220-410
62	Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 0151)	Sao Paulo		Brazil	01246-000
63	Real e Benemerita Associacao Portuguesa de Beneficencia ( Site 0161)	Sao Paulo		Brazil	01321-001
64	A.C. Camargo Cancer Center ( Site 0164)	Sao Paulo		Brazil	01508-010
65	Cross Cancer Institute ( Site 0057)	Edmonton	Alberta	Canada	T6G 1Z2
66	CancerCare Manitoba ( Site 0053)	Winnipeg	Manitoba	Canada	R3E 0V9
67	Moncton Hospital - Horizon Health Network ( Site 0055)	Moncton	New Brunswick	Canada	E1C 6Z8
68	The Ottawa Hospital ( Site 0058)	Ottawa	Ontario	Canada	K1H 8L6
69	Sunnybrook Research Institute ( Site 0060)	Toronto	Ontario	Canada	M4N 3M5
70	Princess Margaret Cancer Centre ( Site 0059)	Toronto	Ontario	Canada	M5G 2M9
71	Hopital Maisonneuve Rosemont ( Site 0056)	Montreal	Quebec	Canada	H1T 2M4
72	Jewish General Hospital ( Site 0054)	Montreal	Quebec	Canada	H3T 1E2
73	McGill University Health Centre ( Site 0062)	Montreal	Quebec	Canada	H4A 3J1
74	CHU de Quebec - Hotel-Dieu de Quebec ( Site 0061)	Quebec		Canada	G1R 2J6
75	Instituto Clinico Oncologico del Sur ( Site 0203)	Temuco	Araucania	Chile	4810469
76	Fundacion Arturo Lopez Perez FALP ( Site 0200)	Santiago	Region M. De Santiago	Chile	7500921
77	Pontificia Universidad Catolica de Chile ( Site 0201)	Santiago	Region M. De Santiago	Chile	8330032
78	Sociedad Medica Aren y Bachero Limitada ( Site 0207)	Santiago	Region M. De Santiago	Chile	8420383
79	Oncocentro ( Site 0204)	Vina del Mar	Valparaiso	Chile	2520598
80	Centro Oncologico Antofagasta ( Site 0206)	Antofagasta		Chile	1240000
81	Hopital La Timone ( Site 0302)	Marseille	Bouches-du-Rhone	France	13385
82	CHU Dijon Bourgogne ( Site 0320)	Dijon	Cote-d Or	France	21000
83	CHU de Bordeaux- Hopital Saint Andre ( Site 0304)	Bordeaux	Gironde	France	33075
84	Institut Claudius Regaud IUCT Oncopole ( Site 0306)	Toulouse	Haute-Garonne	France	31059
85	Hopital Ambroise Pare Boulogne ( Site 0316)	Boulogne-Billancourt	Hauts-de-Seine	France	92100
86	CHU Montpellier. ( Site 0312)	Montpellier	Herault	France	34295
87	Centre Eugene Marquis ( Site 0305)	Rennes	Ille-et-Vilaine	France	35042
88	CHU Angers ( Site 0321)	Angers	Maine-et-Loire	France	49933
89	CHU de Reims ( Site 0307)	Reims	Marne	France	51100
90	CHRU Lille - Hopital Claude Huriez ( Site 0301)	Lille	Nord	France	59037
91	C.H.U. Lyon Sud ( Site 0303)	Pierre Benite	Rhone	France	69495
92	CHU Amiens Picardie Hopital Nord ( Site 0317)	Amiens	Somme	France	80054
93	Institut Gustave Roussy ( Site 0300)	Villejuif	Val-de-Marne	France	94805
94	Hopital Saint Louis ( Site 0322)	Paris		France	75475
95	Universitaetsklinikum in Mannheim ( Site 0351)	Mannheim	Baden-Wurttemberg	Germany	68135
96	Universitaetsklinikum Tuebingen ( Site 0353)	Tuebingen	Baden-Wurttemberg	Germany	72076
97	Klinikum der Ludwig-Maximilians-Universitaet Muenchen ( Site 0357)	Muenchen	Bayern	Germany	80337
98	Klinikum Nuernberg Nord ( Site 0355)	Nuernberg	Bayern	Germany	90419
99	Klinikum der Universitaet in Wuerzburg ( Site 0356)	Wuerzburg	Bayern	Germany	97080
100	Elbe Klinikum Buxtehude ( Site 0354)	Buxtehude	Niedersachsen	Germany	21614
101	Medizinische Hochschule Hannover ( Site 0358)	Hannover	Niedersachsen	Germany	30625
102	Klinik und Poliklinik fuer Dermatologie Venerologie und Allergologie ( Site 0361)	Essen	Nordrhein-Westfalen	Germany	45147
103	Universitaetsklinikum Schleswig-Holstein Campus Kiel ( Site 0359)	Kiel	Schleswig-Holstein	Germany	24105
104	SRH Wald-Klinikum Gera GmbH ( Site 0360)	Gera	Thuringen	Germany	07548
105	Universitaetsklinikum Hamburg Eppendorf (UKE) ( Site 0352)	Hamburg		Germany	20246
106	Soroka Medical Center ( Site 0653)	Beer Sheva	Southern	Israel	8457108
107	Sourasky Medical Center ( Site 0656)	Tel Aviv	Tell Abib	Israel	6423906
108	HaEmek Medical Center ( Site 0655)	Afula		Israel	1834111
109	Rambam Medical Center ( Site 0654)	Haifa		Israel	3109601
110	Hadassah Ein Kerem Medical Center ( Site 0651)	Jerusalem		Israel	9112001
111	Chaim Sheba Medical Center. ( Site 0652)	Ramat Gan		Israel	5262000
112	Shamir Medical Center-Assaf Harofeh ( Site 0657)	Zerifin		Israel	70300
113	Istituto Scientifico Romagnolo per Studio e Cura Tumori IRST ( Site 0403)	Meldola	Forli-Cesena	Italy	47014
114	IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 0406)	Bari		Italy	70124
115	ASST Papa Giovanni XXIII ( Site 0402)	Bergamo		Italy	24127
116	IRCCS A.O.U. San Martino - IST ( Site 0404)	Genova		Italy	16132
117	Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 0408)	Milano		Italy	20133
118	Istituto Nazionale Tumori Fondazione Pascale ( Site 0400)	Napoli		Italy	80131
119	IRCCS Istituto Oncologico Veneto ( Site 0407)	Padova		Italy	35128
120	IDI - Istituto Dermopatico dell'Immacolata ( Site 0405)	Roma		Italy	00167
121	Azienda Ospedaliero Universitaria Senese ( Site 0401)	Siena		Italy	53100
122	National Cancer Center Hospital ( Site 0910)	Tokyo		Japan	104-0045
123	Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 0769)	Bydgoszcz	Kujawsko-pomorskie	Poland	85-796
124	Pratia MCM Krakow ( Site 0773)	Krakow	Malopolskie	Poland	30-510
125	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie ( Site 0751)	Warszawa	Mazowieckie	Poland	02-781
126	Instytut Pomnik Centrum Zdrowia Dziecka ( Site 0759)	Warszawa	Mazowieckie	Poland	04-730
127	Kliniczny Szpital Wojewodzki Nr 1 ( Site 0758)	Rzeszow	Podkarpackie	Poland	35-055
128	Uniwersyteckie Centrum Kliniczne ( Site 0770)	Gdansk	Pomorskie	Poland	80-402
129	Beskidzkie Centrum Onkologii im. Jana Pawla II ( Site 0754)	Bielsko-Biala	Slaskie	Poland	43-300
130	Uniwersyteckie Centrum Kliniczne Slaskiego Uniwersytetu Medycznego ( Site 0757)	Katowice	Slaskie	Poland	40-514
131	LIFTMED ( Site 0765)	Rybnik	Slaskie	Poland	44-200
132	Szpital Kliniczny im. Heliodora Swiecickiego Uniwers Medyczn ( Site 0753)	Poznan	Wielkopolskie	Poland	60-780
133	Cancer Care Langenhoven Drive Oncology Centre ( Site 0812)	Port Elizabeth	Eastern Cape	South Africa	6045
134	Sandton Oncology Medical Group PTY LTD ( Site 0801)	Johannesburg	Gauteng	South Africa	2196
135	Charlotte Maxeke Johannesburg Academic Hospital ( Site 0811)	Parktown	Gauteng	South Africa	2196
136	Wilgers Oncology Centre ( Site 0806)	Pretoria	Gauteng	South Africa	0081
137	MPOC ( Site 0803)	Pretoria	Gauteng	South Africa	0181
138	Cancercare ( Site 0810)	Cape Town	Limpopo	South Africa	7700
139	Cape Town Oncology Trials Pty Ltd ( Site 0807)	Kraaifontein	Western Cape	South Africa	7570
140	Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0457)	San Sebastian	Gipuzkoa	Spain	20014
141	Hospital General Universitario de Valencia ( Site 0451)	Valencia	Valenciana, Comunitat	Spain	46014
142	Hospital General Universitari Vall d Hebron ( Site 0456)	Barcelona		Spain	08035
143	Hospital Clinic de Barcelona ( Site 0452)	Barcelona		Spain	08036
144	Hospital General Universitario Gregorio Maranon ( Site 0454)	Madrid		Spain	28009
145	Hospital Universitario Virgen Macarena ( Site 0455)	Sevilla		Spain	41009
146	Universitaetsspital Basel ( Site 0554)	Basel	Basel-Stadt	Switzerland	4031
147	Universitaetsspital Bern ( Site 0552)	Bern	Berne	Switzerland	3010
148	Hopitaux Universitaires de Geneve HUG ( Site 0556)	Geneva	Geneve	Switzerland	1211
149	Kantonsspital Graubuenden ( Site 0555)	Chur	Grisons	Switzerland	7000
150	Kantonsspital St. Gallen ( Site 0559)	St. Gallen	Sankt Gallen	Switzerland	9007
151	Oncological Institute of Southern Switzerland ( Site 0557)	Bellinzona	Ticino	Switzerland	6500
152	Centre Hospitalier Universitaire Vaudois ( Site 0553)	Lausanne	Vaud	Switzerland	1011
153	Hopital du Valais ( Site 0558)	Sion	Wallis	Switzerland	1951
154	Universitaetsspital Zuerich ( Site 0551)	Zuerich	Zurich	Switzerland	8091
155	Addenbrooke's Hospital in Cambridge ( Site 0600)	Cambridge	Cambridgeshire	United Kingdom	CB2 0QQ
156	Guy s & St Thomas NHS Foundation Trust ( Site 0601)	London	London, City Of	United Kingdom	SE1 9RT
157	Royal Marsden Hospital - Fulham Road London ( Site 0613)	London	London, City Of	United Kingdom	SW3 6JJ
158	The Royal Marsden NHS Foundation Trust. ( Site 0612)	Sutton	Surrey	United Kingdom	SM2 5PT
159	Christie NHS Foundation Trust ( Site 0604)	Manchester		United Kingdom	M20 4GJ

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

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

Study Documents (Full-Text)

• Study Protocol - May 11, 2021
• Statistical Analysis Plan - Jan 19, 2021

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03553836
• Other Study ID Numbers: 3475-716; MK-3475-716; KEYNOTE-716; 205203; 2018-000669-35
• First Posted: Jun 12, 2018
• Last Update Posted: Jun 24, 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 Cell Death 1 Ligand 1(PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
• Additional relevant MeSH terms: Melanoma; Pembrolizumab

Study Results

Participant Flow

Pre-assignment Detail	Per protocol, response/progression or adverse events (AEs) during re-challenge/switch-over in Part 2 were not counted towards the recurrence-free survival (RFS) outcome measure or safety outcome measures respectively.

Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description	Participants received 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of pembrolizumab and experienced disease recurrence may have been eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.	Participants received saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of placebo and experienced disease recurrence may have been eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.
Period Title: Overall Study
STARTED	487	489
Treated	483	486
Re-challenged or Switched-over to Pembrolizumab	1	45
COMPLETED	0	0
NOT COMPLETED	487	489

Baseline Characteristics

Arm/Group Title	Pembrolizumab	Placebo	Total
Arm/Group Description	Participants received 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of pembrolizumab and experienced disease recurrence may have been eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.	Participants received saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of placebo and experienced disease recurrence may have been eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.	Total of all reporting groups
Overall Participants	487	489	976
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.0 (12.6)	59.6 (13.3)	59.3 (12.9)
Sex: Female, Male (Count of Participants)
Female	187 38.4%	200 40.9%	387 39.7%
Male	300 61.6%	289 59.1%	589 60.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	49 10.1%	30 6.1%	79 8.1%
Not Hispanic or Latino	390 80.1%	409 83.6%	799 81.9%
Unknown or Not Reported	48 9.9%	50 10.2%	98 10%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.2%	0 0%	1 0.1%
Asian	4 0.8%	1 0.2%	5 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 0.8%	4 0.8%	8 0.8%
White	435 89.3%	439 89.8%	874 89.5%
More than one race	1 0.2%	0 0%	1 0.1%
Unknown or Not Reported	42 8.6%	45 9.2%	87 8.9%
Melanoma Primary Tumor (T) Stage (Count of Participants)
T3a	2 0.4%	0 0%	2 0.2%
T3b	200 41.1%	201 41.1%	401 41.1%
T4a	113 23.2%	116 23.7%	229 23.5%
T4b	172 35.3%	172 35.2%	344 35.2%

Outcome Measures

1. Primary Outcome

Title	Recurrence-free Survival (RFS)
Description	RFS was defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first. Per protocol, final analysis for this primary outcome measure was performed using the initial pembrolizumab or placebo treatment with a protocol-specified analysis data cut-off date of June-21-2021.
Time Frame	Up to ~32.7 months

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description	Participants received 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1.	Participants received saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1.
Measure Participants	487	489
Median (95% Confidence Interval) [Months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.00046
	Comments	One-sided p-value based on log-rank test stratified by melanoma T Stage (T3b, T4a, T4b).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by melanoma T Stage (T3b, T4a, T4b).

2. Secondary Outcome

Title	Distant Metastasis-free Survival (DMFS)
Description	DMFS will be defined as the time from randomization to the first diagnosis of a distant metastasis per RECIST 1.1. Distant metastasis will refer to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes. DMFS will be reported for randomized participants.
Time Frame	Up to ~9 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS will be defined as the time from randomization to death due to any cause. OS will be reported for randomized participants.
Time Frame	Up to ~15 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. 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 clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.
Time Frame	Up to ~19.3 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study treatment.

Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description	Participants received 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1.	Participants received saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1.
Measure Participants	483	486
Count of Participants [Participants]	461 94.7%	444 90.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentage based on Miettinen & Nurminen method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Percentage
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; 1.0 to 7.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants Who Discontinued Study Treatment Due to an AE
Description	An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.
Time Frame	Up to ~19.3 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study treatment.

Arm/Group Title	Pembrolizumab	Placebo
Arm/Group Description	Participants received 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1.	Participants received saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1.
Measure Participants	483	486
Count of Participants [Participants]	84 17.2%	22 4.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	Difference in percentage based on Miettinen & Nurminen method.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	12.9
	Confidence Interval	(2-Sided) 95%; 9.1 to 16.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	All-cause mortality (ACM) : Up to ~32.7 months and safety: Up to ~30.2 months
Adverse Event Reporting Description	ACM was analyzed in all randomized participants. Safety was analyzed in all participants who received ≥1 dose of study drug. Per protocol disease progression of cancer was not considered an AE unless related to study drug. Thus MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression", "Disease progression" unrelated to study drug are excluded as AEs. ACM and Safety were analyzed separately in participants who switched over from placebo to pembrolizumab.
Arm/Group Title	Pembrolizumab		Placebo		Placebo Switched Over to Pembrolizumab
Arm/Group Description	Participants received 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of pembrolizumab and experienced disease recurrence may have been eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.		Participants received saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of placebo and experienced disease recurrence may have been eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.		Participants who received the initial treatment of saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to ~1 year) in Part 1 and experienced disease recurrence may have been eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2.
All Cause Mortality
	Pembrolizumab		Placebo		Placebo Switched Over to Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/487 (3.5%)		18/489 (3.7%)		3/45 (6.7%)
Serious Adverse Events
	Pembrolizumab		Placebo		Placebo Switched Over to Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	101/483 (20.9%)		91/486 (18.7%)		6/45 (13.3%)
Blood and lymphatic system disorders
Lymphadenopathy	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/483 (0%)	0	2/486 (0.4%)	2	0/45 (0%)	0
Atrial fibrillation	4/483 (0.8%)	5	1/486 (0.2%)	1	0/45 (0%)	0
Autoimmune myocarditis	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Cardiac failure	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Cardiomyopathy	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Coronary artery disease	0/483 (0%)	0	2/486 (0.4%)	2	0/45 (0%)	0
Mitral valve incompetence	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Ear and labyrinth disorders
Vertigo	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Endocrine disorders
Adrenal insufficiency	4/483 (0.8%)	4	0/486 (0%)	0	0/45 (0%)	0
Endocrine disorder	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Hypophysitis	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Hypopituitarism	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Eye disorders
Glaucoma	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Macular detachment	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Gastrointestinal disorders
Anal fistula	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Autoimmune colitis	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Colitis	4/483 (0.8%)	4	0/486 (0%)	0	0/45 (0%)	0
Diarrhoea	2/483 (0.4%)	2	1/486 (0.2%)	1	0/45 (0%)	0
Haematemesis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Immune-mediated enterocolitis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Inguinal hernia	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Pancreatitis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
General disorders
Chest pain	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Cyst	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Infusion site urticaria	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Pyrexia	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Hepatobiliary disorders
Autoimmune hepatitis	3/483 (0.6%)	3	1/486 (0.2%)	1	0/45 (0%)	0
Hepatotoxicity	0/483 (0%)	0	0/486 (0%)	0	1/45 (2.2%)	1
Immune system disorders
Sarcoidosis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Infections and infestations
Abdominal wall abscess	0/483 (0%)	0	1/486 (0.2%)	2	0/45 (0%)	0
Abscess soft tissue	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Anorectal infection	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Appendicitis	0/483 (0%)	0	0/486 (0%)	0	1/45 (2.2%)	1
COVID-19 pneumonia	2/483 (0.4%)	2	3/486 (0.6%)	3	0/45 (0%)	0
Cellulitis	3/483 (0.6%)	3	1/486 (0.2%)	1	0/45 (0%)	0
Cellulitis streptococcal	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Cystitis	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Enterocolitis infectious	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Infected seroma	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Lower respiratory tract infection	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Pneumonia	2/483 (0.4%)	2	1/486 (0.2%)	1	1/45 (2.2%)	1
Pyelonephritis	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Sepsis	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Urinary tract infection	0/483 (0%)	0	1/486 (0.2%)	2	1/45 (2.2%)	1
Viral infection	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Injury, poisoning and procedural complications
Anastomotic leak	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Ankle fracture	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Foot fracture	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Foreign body	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Humerus fracture	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Infusion related reaction	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Lower limb fracture	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Procedural pain	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Rib fracture	0/483 (0%)	0	0/486 (0%)	0	1/45 (2.2%)	1
Seroma	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Soft tissue injury	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Vascular pseudoaneurysm	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Wound dehiscence	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Wrist fracture	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Investigations
Aspartate aminotransferase increased	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Blood creatine phosphokinase increased	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Lipase increased	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Ultrasound bladder abnormal	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/483 (0.2%)	2	0/486 (0%)	0	0/45 (0%)	0
Type 1 diabetes mellitus	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Type 2 diabetes mellitus	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Arthritis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Compartment syndrome	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Intervertebral disc protrusion	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Muscular weakness	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Myopathy	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Myositis	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Pseudarthrosis	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	17/483 (3.5%)	23	24/486 (4.9%)	53	1/45 (2.2%)	1
Bladder cancer	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Bowen's disease	1/483 (0.2%)	1	1/486 (0.2%)	1	0/45 (0%)	0
Breast cancer	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Lentigo maligna	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Lung adenocarcinoma	0/483 (0%)	0	0/486 (0%)	0	1/45 (2.2%)	1
Lung neoplasm malignant	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Lymphoma	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Malignant melanoma	4/483 (0.8%)	5	5/486 (1%)	6	0/45 (0%)	0
Malignant melanoma in situ	5/483 (1%)	5	6/486 (1.2%)	6	0/45 (0%)	0
Meningioma	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Mucinous adenocarcinoma of appendix	0/483 (0%)	0	0/486 (0%)	0	1/45 (2.2%)	1
Prostate cancer	2/483 (0.4%)	2	1/486 (0.2%)	1	0/45 (0%)	0
Recurrent cancer	1/483 (0.2%)	1	2/486 (0.4%)	2	0/45 (0%)	0
Renal cell carcinoma	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Seborrhoeic keratosis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Second primary malignancy	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Seminoma	0/483 (0%)	0	0/486 (0%)	0	1/45 (2.2%)	1
Squamous cell carcinoma of skin	7/483 (1.4%)	11	14/486 (2.9%)	18	0/45 (0%)	0
Transitional cell carcinoma	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Transitional cell carcinoma recurrent	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Nervous system disorders
Carpal tunnel syndrome	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Facial paralysis	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Lumbar radiculopathy	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Myasthenia gravis	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Myelitis transverse	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Neuralgic amyotrophy	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Paraesthesia	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Peripheral sensory neuropathy	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Seizure	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Psychiatric disorders
Completed suicide	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Depression	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Mania	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Suicidal ideation	0/483 (0%)	0	2/486 (0.4%)	2	0/45 (0%)	0
Renal and urinary disorders
Acute kidney injury	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Autoimmune nephritis	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Haematuria	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Nephritis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Nephrolithiasis	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Renal failure	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Tubulointerstitial nephritis	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Endometrial hyperplasia	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Ovarian cyst torsion	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Asthma	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Chronic obstructive pulmonary disease	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Cough	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Immune-mediated lung disease	2/483 (0.4%)	2	0/486 (0%)	0	0/45 (0%)	0
Lung disorder	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Pleural effusion	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Pneumonitis	1/483 (0.2%)	1	0/486 (0%)	0	1/45 (2.2%)	1
Pulmonary embolism	1/483 (0.2%)	1	2/486 (0.4%)	2	0/45 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis bullous	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Rash	0/483 (0%)	0	1/486 (0.2%)	1	0/45 (0%)	0
Skin ulcer	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Vascular disorders
Haematoma	1/483 (0.2%)	1	1/486 (0.2%)	1	0/45 (0%)	0
Hypertension	1/483 (0.2%)	1	0/486 (0%)	0	0/45 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab		Placebo		Placebo Switched Over to Pembrolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	417/483 (86.3%)		364/486 (74.9%)		26/45 (57.8%)
Endocrine disorders
Hyperthyroidism	50/483 (10.4%)	50	3/486 (0.6%)	4	4/45 (8.9%)	4
Hypothyroidism	82/483 (17%)	82	16/486 (3.3%)	16	3/45 (6.7%)	3
Gastrointestinal disorders
Abdominal pain	30/483 (6.2%)	37	24/486 (4.9%)	29	2/45 (4.4%)	3
Constipation	40/483 (8.3%)	46	40/486 (8.2%)	45	1/45 (2.2%)	1
Diarrhoea	134/483 (27.7%)	222	96/486 (19.8%)	176	4/45 (8.9%)	5
Dry mouth	31/483 (6.4%)	33	9/486 (1.9%)	10	3/45 (6.7%)	3
Nausea	66/483 (13.7%)	100	56/486 (11.5%)	90	0/45 (0%)	0
Vomiting	31/483 (6.4%)	40	15/486 (3.1%)	17	1/45 (2.2%)	1
General disorders
Asthenia	54/483 (11.2%)	75	53/486 (10.9%)	80	3/45 (6.7%)	3
Fatigue	140/483 (29%)	161	122/486 (25.1%)	137	2/45 (4.4%)	2
Oedema peripheral	28/483 (5.8%)	35	22/486 (4.5%)	23	0/45 (0%)	0
Pyrexia	31/483 (6.4%)	32	26/486 (5.3%)	26	3/45 (6.7%)	3
Infections and infestations
Nasopharyngitis	22/483 (4.6%)	27	29/486 (6%)	35	2/45 (4.4%)	2
Investigations
Alanine aminotransferase increased	55/483 (11.4%)	63	29/486 (6%)	38	1/45 (2.2%)	2
Aspartate aminotransferase increased	36/483 (7.5%)	42	19/486 (3.9%)	22	1/45 (2.2%)	1
Metabolism and nutrition disorders
Decreased appetite	26/483 (5.4%)	31	12/486 (2.5%)	15	1/45 (2.2%)	1
Hyperglycaemia	13/483 (2.7%)	16	28/486 (5.8%)	36	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	113/483 (23.4%)	155	83/486 (17.1%)	107	2/45 (4.4%)	2
Back pain	40/483 (8.3%)	44	37/486 (7.6%)	38	1/45 (2.2%)	1
Myalgia	50/483 (10.4%)	56	28/486 (5.8%)	29	1/45 (2.2%)	1
Pain in extremity	26/483 (5.4%)	29	28/486 (5.8%)	31	1/45 (2.2%)	2
Nervous system disorders
Dizziness	32/483 (6.6%)	38	27/486 (5.6%)	29	3/45 (6.7%)	3
Headache	81/483 (16.8%)	102	55/486 (11.3%)	70	3/45 (6.7%)	3
Respiratory, thoracic and mediastinal disorders
Cough	56/483 (11.6%)	65	57/486 (11.7%)	65	1/45 (2.2%)	1
Dyspnoea	22/483 (4.6%)	22	25/486 (5.1%)	32	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
Pruritus	131/483 (27.1%)	177	61/486 (12.6%)	78	4/45 (8.9%)	4
Rash	89/483 (18.4%)	116	41/486 (8.4%)	52	2/45 (4.4%)	4
Rash maculo-papular	40/483 (8.3%)	52	9/486 (1.9%)	13	0/45 (0%)	0
Vascular disorders
Hypertension	40/483 (8.3%)	49	43/486 (8.8%)	61	0/45 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

If publication activity is not directed by the Sponsor, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect proprietary information and to provide comments.