A Study of Pembrolizumab (MK-3475) in Combination With Etoposide/Platinum (Cisplatin or Carboplatin) for Participants With Extensive Stage Small Cell Lung Cancer (MK-3475-604/KEYNOTE-604)

A Phase 3 Randomized, Double-Blind, Placebo-controlled Trial of Pembrolizumab (MK-3475/SCH900475) in Combination With Etoposide/Platinum (Cisplatin or Carboplatin) for the First-line Treatment of Subjects With Extensive Stage Small Cell Lung Cancer (KEYNOTE-604)

The purpose of this study is to assess the safety and efficacy of pembrolizumab plus standard of care (SOC) chemotherapy (etoposide/platinum [EP]) in participants with newly diagnosed extensive stage small cell lung cancer (ES-SCLC) who have not previously received systemic therapy for this malignancy.

The primary study hypotheses are that pembrolizumab+EP prolongs Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review (BICR) and Overall Survival (OS) compared with placebo+EP in adult participants with ES-SCLC. In this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

With protocol Amendment 07 (03-Oct-2018), the outcome measure of "Change from Baseline at Weeks 12 and 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale" was replaced with a single time point analysis at Week 18.

Study Overview

• Status: Completed
• Conditions: Small Cell Lung Cancer (SCLC)
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Carboplatin; Drug: Cisplatin; Drug: Etoposide; Drug: Normal saline solution

• Study Type: Interventional
• Enrollment (Actual): 453
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Elizabeth Vale, Australia, 5112
    • Lyell McEwin Hospital ( Site 0002)
  • Fitzroy, Australia, 3065
    • St Vincents Hospital Melbourne ( Site 0005)
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital ( Site 0004)
    • Wollongong, New South Wales, Australia, 2500
      • Southern Medical Day Care Centre ( Site 0001)
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • St John of God ( Site 0006)
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • Cancer Care Manitoba ( Site 0159)
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Nova Scotia Health Authority ( Site 0157)
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • William Osler Health System (Brampton Civic Hospital) ( Site 0161)
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston Health Sciences Centre ( Site 0155)
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Research Institute ( Site 0151)
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • CISSS de la Monteregie-Centre ( Site 0152)
    • Lévis, Quebec, Canada, G6V 3Z1
      • CISSS-CA Hotel Dieu de Levis ( Site 0154)
    • Montreal, Quebec, Canada, H3T 1M5
      • CIUSSS Ouest de l'Ile - St-Mary's Hospital ( Site 0158)
    • St-Jerome, Quebec, Canada, J7Z 5T3
      • St. Jerome Medical Research Inc. ( Site 0160)
• Chile
  • Santiago, Chile, 7500006
    • Health and Care Chile ( Site 0202)
  • Santiago, Chile, 7500921
    • Fundacion Arturo Lopez Perez FALP ( Site 0203)
  • Santiago, Chile, 8330032
    • Pontificia Universidad Catolica de Chile ( Site 0206)
  • Talca, Chile, 3465584
    • Clinica Universidad Catolica del Maule ( Site 0208)
  • Region Metropolitana
    • Santiago, Region Metropolitana, Chile, 8380455
      • Instituto Nacional del Cancer ( Site 0207)
• France
  • Lille, France, 59037
    • CHRU de Lille - Hopital Albert Calmette ( Site 0353)
  • Limoges, France, 87042
    • C.H.R.U. De Limoges ( Site 0358)
  • Nantes, France, 44805
    • CHU Nantes - Hopital Laennec ( Site 0363)
  • Nice, France, 06189
    • Centre Antoine Lacassagne ( Site 0362)
  • Paris, France, 75020
    • Hopital Tenon ( Site 0360)
  • Reims, France, 51726
    • Institut de Cancerologie Jean-Godinot ( Site 0351)
  • Toulouse, France, 31059
    • CHU de Toulouse - Hopital Larrey ( Site 0354)
• Germany
  • Berlin, Germany, 13125
    • Evangelische Lungenklinik Berlin ( Site 0403)
  • Dresden, Germany, 01307
    • Medizinische Fakultaet Carl Gustav Carus der TU Dresden ( Site 0411)
  • Duesseldorf, Germany, 40489
    • Florence Nightingale Krankenhaus ( Site 0413)
  • Gera, Germany, 07548
    • SRH Waldklinikum Gera GmbH ( Site 0405)
  • Hamburg, Germany, 21075
    • Asklepios Klinikum Harburg ( Site 0412)
  • Heidelberg, Germany, 69126
    • Thoraxklinik Heidelberg gGmbH am Universitaetsklinikum Heidelberg ( Site 0401)
  • Marburg, Germany, 35032
    • Philipps-Universitat Marburg ( Site 0414)
  • Tuebingen, Germany, 72076
    • Universitaetsklinikum Tuebingen ( Site 0404)
• Hungary
  • Budapest, Hungary, 1121
    • Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0452)
  • Budapest, Hungary, 1121
    • Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0458)
  • Budapest, Hungary, 1121
    • Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0459)
  • Farkasgyepu, Hungary, 8582
    • Veszprem Megyei Tudogyogyintezet ( Site 0454)
  • Gyor, Hungary, 9023
    • Petz Aladar Megyei Oktato Korhaz ( Site 0460)
  • Szekesfehervar, Hungary, 8000
    • Fejer Megyei Szent Gyorgy Egyetemi Oktato Korhaz ( Site 0456)
  • Szolnok, Hungary, 5000
    • Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 0451)
  • Zalaegerszeg, Hungary, 8900
    • Zala Megyei Szent Rafael Korhaz ( Site 0457)
  • Pest
    • Budapest, Pest, Hungary, 1122
      • Orszagos Onkologiai Intezet ( Site 0453)
• Ireland
  • Dublin, Ireland, D04 Y8V0
    • St Vincents University Hospital ( Site 1456)
  • Dublin, Ireland, D08 K0Y5
    • St James Hospital ( Site 1452)
• Israel
  • Beer Sheva, Israel, 8489501
    • Soroka Medical Center ( Site 0505)
  • Haifa, Israel, 3525408
    • Ramban Medical Center - Dept. Hemato. & B. Marrow Transplant ( Site 0502)
  • Kfar Saba, Israel, 4428164
    • Meir Medical Center ( Site 0503)
  • Petah Tikva, Israel, 5262000
    • Rabin Medical Center ( Site 0504)
  • Ramat-Gan, Israel, 5265601
    • Chaim Sheba Medical Center. ( Site 0501)
• Japan
  • Fukuoka, Japan, 810-8563
    • National Hospital Organization Kyushu Medical Center ( Site 0617)
  • Hiroshima, Japan, 734-8551
    • Hiroshima University Hospital ( Site 0604)
  • Niigata, Japan, 951-8566
    • Niigata Cancer Center Hospital ( Site 0610)
  • Osaka, Japan, 541-8567
    • Osaka International Cancer Institute ( Site 0616)
  • Tokyo, Japan, 135-8550
    • The Cancer Institute Hospital of JFCR ( Site 0606)
  • Wakayama, Japan, 641-8509
    • Wakayama Medical University Hospital ( Site 0612)
  • Aichi
    • Nagoya, Aichi, Japan, 460-0001
      • National Hospital Organization Nagoya Medical Center ( Site 0615)
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East ( Site 0613)
  • Ehime
    • Matsuyama, Ehime, Japan, 791-0280
      • National Hospital Organization Shikoku Cancer Center ( Site 0614)
  • Fukuoka
    • Kurume, Fukuoka, Japan, 830-0011
      • Kurume University Hospital ( Site 0609)
  • Hyogo
    • Akashi, Hyogo, Japan, 673-8558
      • Hyogo Cancer Center ( Site 0611)
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 241-8515
      • Kanagawa Cancer Center ( Site 0618)
  • Miyagi
    • Sendai, Miyagi, Japan, 980-0873
      • Sendai Kousei Hospital ( Site 0602)
  • Osaka
    • Sakai, Osaka, Japan, 591-8555
      • National Hospital Organization Kinki-chuo Chest Medical Center ( Site 0608)
  • Shizuoka
    • Sunto-gun, Shizuoka, Japan, 411-8777
      • Shizuoka Cancer Center Hospital and Research Institute ( Site 0607)
  • Yamaguchi
    • Ube, Yamaguchi, Japan, 755-0241
      • National Hospital Organization Yamaguchi Ube Medical Center ( Site 0601)
• Korea, Republic of
  • Busan, Korea, Republic of, 48108
    • Inje University Haeundae Paik Hospital ( Site 0905)
  • Goyang-si, Korea, Republic of, 10408
    • National Cancer Center ( Site 0904)
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital Yonsei University Health System ( Site 0903)
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center ( Site 0901)
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center ( Site 0902)
• New Zealand
  • Christchurch, New Zealand, 8011
    • Canterbury Regional Cancer & Blood Services ( Site 0701)
• Poland
  • Konin, Poland, 62-500
    • Przychodnia Lekarska Komed ( Site 0769)
  • Krakow, Poland, 31-202
    • Krakowski Szpital Specjalistyczny im. Jana Pawla II ( Site 0768)
  • Lublin, Poland, 20-090
    • Centrum Onkologii Ziemi Lubelskiej im. sw. Jana z Dukli ( Site 0767)
  • Poznan, Poland, 60-569
    • SKPP UM im. Karola Marcinkowkiego w Poznaniu ( Site 0766)
  • Poznan, Poland, 60-569
    • Wielkopolskie Centrum Pulmonologii i Torakochirurgii ( Site 0762)
  • Torun, Poland, 87-100
    • Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu ( Site 0756)
  • Warszawa, Poland, 02-781
    • Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie ( Site 0751)
  • Wroclaw, Poland, 53-413
    • Dolnoslaskie Centrum Onkologii we Wroclawiu ( Site 0771)
  • Mazowieckie
    • Wieliszew, Mazowieckie, Poland, 05-135
      • Mazowiecki Szpital Onkologiczny ( Site 0757)
• Russian Federation
  • Belgorod, Russian Federation, 308010
    • Belgorod Regional Oncology Dispensary ( Site 0804)
  • Moscow, Russian Federation, 115478
    • N.N. Blokhin NMRCO ( Site 0801)
  • Pyatigorsk, Russian Federation, 357502
    • SBI of Stavropol region Pyatigorskiy Oncologic dispensary ( Site 0811)
  • Saint Petersburg, Russian Federation, 194291
    • SBHI Leningrad Regional Clinical Hospital ( Site 0803)
  • Saint Petersburg, Russian Federation, 198255
    • Municipal Clinical Oncology Center ( Site 0802)
• Spain
  • A Coruna, Spain, 15006
    • Complejo Hospitalario Universitario de A Coruna ( Site 0953)
  • Barcelona, Spain, 08003
    • Hospital del Mar ( Site 0956)
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d Hebron ( Site 0951)
  • Jaen, Spain, 23007
    • Hospital Ciudad de Jaen ( Site 0957)
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon ( Site 0958)
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz ( Site 0954)
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia ( Site 0955)
  • Gran Canaria
    • Las Palmas de Gran Canaria, Gran Canaria, Spain, 35016
      • Hospital Universitario Insular de Gran Canaria ( Site 0952)
• Switzerland
  • Chur, Switzerland, 7000
    • Kantonsspital Graubuenden ( Site 1403)
  • Lausanne, Switzerland, 1011
    • CHUV Centre Hospitalier Universitaire Vaudois ( Site 1405)
  • Zuerich, Switzerland, 8091
    • Universitaetsspital Zuerich ( Site 1404)
• Taiwan
  • Kaohsiung, Taiwan, 83301
    • Kaohsiung Chang Gung Memorial Hospital of the C.G.M.F. ( Site 1005)
  • Taichung, Taiwan, 40447
    • China Medical University Hospital. ( Site 1003)
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital ( Site 1007)
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital ( Site 1004)
  • Tainan, Taiwan, 736
    • Chi Mei Medical Center Liuying ( Site 1006)
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital ( Site 1001)
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital ( Site 1002)
• Turkey
  • Adana, Turkey, 01250
    • Baskent University Adana Dr. Turgut Noyan EAH ( Site 1057)
  • Ankara, Turkey, 06100
    • Ankara UTF ( Site 1055)
  • Ankara, Turkey, 06100
    • Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 1060)
  • Ankara, Turkey, 06200
    • Dr. Abdurrahman Yurtaslan Ankara Onkoloji EAH ( Site 1053)
  • Edirne, Turkey, 22030
    • Trakya Uni. Tip Fakultesi ( Site 1063)
  • Istanbul, Turkey, 34098
    • Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 1058)
  • Istanbul, Turkey, 34214
    • Medipol Hastanesi ( Site 1066)
  • Istanbul, Turkey, 34722
    • Medeniyet Uni. Goztepe Egitim ve Arast. Hast. ( Site 1064)
  • Izmir, Turkey, 35575
    • Medical Park Izmir Hospital ( Site 1051)
  • Kocaeli, Turkey, 41380
    • Kocaeli Universitesi Tip Fakultesi ( Site 1061)
  • Malatya, Turkey, 44280
    • Inonu Universitesi Tip Fakultesi ( Site 1059)
  • Bornova
    • Izmir, Bornova, Turkey, 35100
      • Ege Universitesi Tıp Fakultesi ( Site 1052)
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Birmingham Heartlands Hospital ( Site 1162)
  • Leeds, United Kingdom, LS9 7TF
    • St James s University Hospital ( Site 1161)
  • London, United Kingdom, N18 1QX
    • North Middlesex Hospital ( Site 1151)
  • Maidstone, United Kingdom, ME16 9QQ
    • Maidstone Hospital ( Site 1155)
  • Northwood, United Kingdom, HA6 2RN
    • Mount Vernon Cancer Centre ( Site 1156)
• United States
  • Florida
    • Miami, Florida, United States, 33176
      • Baptist Health Medical Group Oncology, LLC ( Site 8000)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center ( Site 1215)
    • Evanston, Illinois, United States, 60201
      • North Shore University Health System ( Site 1216)
  • Indiana
    • Munster, Indiana, United States, 46321
      • Community Hospital ( Site 1207)
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Weinberg Cancer Institute at Franklin Square ( Site 1210)
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ( Site 1203)
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center ( Site 1206)
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute [Boston] ( Site 1201)
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5936
      • University of Michigan ( Site 1217)
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System ( Site 1221)
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Minnesota Oncology Hematology, PA ( Site 8001)
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Hattiesburg Clinic ( Site 1205)
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis ( Site 1213)
  • Nevada
    • Henderson, Nevada, United States, 89074
      • Comprehensive Cancer Centers of Nevada ( Site 8004)
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan-Kettering Cancer Center At Basking Ridge ( Site 1226)
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering Cancer Center- Monmouth ( Site 1225)
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Einstein Center for Cancer Care - Main site ( Site 1204)
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center ( Site 1222)
    • Commack, New York, United States, 11725
      • Memorial Sloan-Kettering Cancer Center at Commack ( Site 1227)
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering Cancer Center ( Site 1229)
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center ( Site 1211)
    • Rockville Centre, New York, United States, 11570
      • Memorial Sloan Kettering Cancer Center - Rockville Centre ( Site 1228)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center ( Site 1214)
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Bon Secours St. Francis Health Sytem ( Site 1212)
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology, PLLC/The Sarah Cannon Research Institute ( Site 1230)
  • Texas
    • Austin, Texas, United States, 78745
      • Texas Oncology ( Site 8002)
    • Dallas, Texas, United States, 75246
      • Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 8003)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has a documented new diagnosis of SCLC by histology or cytology from brushing, washing, or needle aspiration of a defined lesion. Participants who do not have histology samples (defined as core or excisional biopsy, or resections) will need to undergo a new biopsy to provide a tissue sample.
• Has extensive-stage disease defined as Stage IV (T any, N any, M 1a/b) by the American Joint Committee on Cancer (AJCC), Seventh Edition
• Has ≥1 lesion that meets the criteria for measurable, as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology assessment
• Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Has a life expectancy of ≥3 months
• Has adequate organ function
• Female and male participants of childbearing potential must be willing to use an adequate method of contraception, starting with the first dose of study treatment through 120 days after the last dose of study treatment and up to 180 days after last dose of chemotherapeutic agents

Exclusion Criteria:

• Has received prior systemic therapy for the treatment of SCLC
• Is currently participating and receiving study treatment or has participated in a study of an investigational agent and received study treatment or used an investigational device within 4 weeks of the first dose of treatment for another health-related problem
• Is expected to require any other form of antineoplastic therapy for SCLC, including radiation therapy, while on study. (Prophylactic cranial irradiation will be possible for those participants with stable disease or better at the completion of the 4 cycles of chemotherapy with or without pembrolizumab.)
• Has known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis. Participants with brain metastases may participate only if they satisfy all of the following:
• Has completed treatment (eg, whole brain radiation treatment [WBRT], stereotactic radiosurgery, or equivalent) ≥14 days prior to the first dose of study treatment,
• Has no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging performed ≥3 weeks after pre-treatment brain imaging, and
• Is neurologically stable without the need for steroids for ≥7 days before first dose of study treatment.
• Has had major surgery within 3 weeks prior to receiving the first dose of study treatment or has not recovered adequately from toxicity and/or complications from an intervention prior to receiving the first dose of study treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has a known history of interstitial lung disease
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy.
• Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
• Has a known history of, or active, neurologic paraneoplastic syndrome
• Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, and/or abdominal carcinomatosis
• Has a history of a severe hypersensitivity reaction to treatment with another monoclonal antibody
• Is taking chronic systemic steroids (in doses exceeding 10 mg daily of prednisone equivalent) within 7 days prior to the first dose of study treatment
• Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• Has received a live vaccine within 30 days prior to the first dose of study treatment
• Has received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor (i.e., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], tumor necrosis factor receptor superfamily member 9 [TNFRSF9, OX-40, CD137]) or has previously participated in a Merck pembrolizumab (MK-3475) clinical trial
• Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of Hepatitis B or known active Hepatitis C virus infection
• Has a known history of active TB (Bacillus Tuberculosis)
• Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study starting with the screening visit through 120 days after the last dose of study treatment through and up to 180 days after last dose of chemotherapeutic agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab+EP; During each 21-day cycle, participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an area under the plasma drug concentration-time curve [AUC] 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1). Participants who stop pembrolizumab as a result of obtaining a response of stable disease (SD), partial response (PR), complete response (CR) or those who stop after receiving pembrolizumab for 24 months for reasons other than disease progression or intolerability, are eligible for up to an additional 1 year of treatment after progressive disease if they meet the criteria for retreatment.	Biological: Pembrolizumab; IV infusion on Day 1 of each cycle prior to chemotherapy; Other Names: MK-3475; KEYTRUDA®; Drug: Carboplatin; IV infusion on Day 1 of each cycle; Other Names: PARAPLATIN®; Drug: Cisplatin; IV infusion on Day 1 of each cycle; Other Names: PLATINOL®; Drug: Etoposide; IV infusion on Days 1, 2 and 3 of each cycle; Other Names: TOPOSAR™
Active Comparator: Placebo+EP; During each 21-day cycle, participants receive placebo (normal saline solution) IV on Day 1 PLUS etoposide 100 mg/m^2 IV on Days 1, 2 and 3 PLUS investigator's choice of platinum therapy (carboplatin titrated to an AUC 5 IV on Day 1 OR cisplatin 75 mg/m^2 IV on Day 1).	Drug: Carboplatin; IV infusion on Day 1 of each cycle; Other Names: PARAPLATIN®; Drug: Cisplatin; IV infusion on Day 1 of each cycle; Other Names: PLATINOL®; Drug: Etoposide; IV infusion on Days 1, 2 and 3 of each cycle; Other Names: TOPOSAR™; Drug: Normal saline solution; IV infusion on Day 1 of each cycle prior to chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)	PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD, as determined by RECIST 1.1, was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The PFS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol.	Up to approximately 30.5 months
Overall Survival (OS)	OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow up. The OS was calculated using the non-parametric Kaplan-Meier method for censored data and presented for the first course of study treatment per protocol.	Up to approximately 30.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)	ORR was defined as the percentage of participants who achieve a best objective response of complete response (CR) or partial response (PR) per RECIST 1.1. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR was calculated using the Miettinen & Nurminen method stratified by type of platinum therapy (carboplatin or cisplatin), baseline ECOG performance status (0 or 1), and baseline LDH (≤ or > upper limit of normal) and presented for the first course of study treatment per protocol.	Up to approximately 30.5 months
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)	DOR was defined as the time from first documented evidence of a Complete Response (CR) or Partial Response (PR) per RECIST 1.1 until progressive disease (PD) per RECIST 1.1 or death due to any cause, whichever occurred first. CR was defined as the disappearance of all target lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions taking as a reference the baseline sum diameters. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data and is presented for the first course of study treatment per protocol.	Up to approximately 30.5 months
Number of Participants Who Experienced an Adverse Event (AE)	An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.	Up to approximately 30.5 months
Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE)	An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have had a causal relationship with this treatment. An adverse event could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an adverse event. The number of participants who discontinued due to an AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.	Up to approximately 26 months
Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE 4.03)	The CTCAE uses Grades 1 through 5 correlating to AE severity criteria. Grade 1=mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2=moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3=severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. The number of participants who experienced any Grade 3 to 5 AE was reported for each arm according to the treatment received and is presented for the first course of study treatment per protocol.	Up to approximately 30.5 months
Change From Baseline at Week 18 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. Change from baseline scores were calculated using a constrained longitudinal data analysis (cLDA) model. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Data are presented for the first course of study treatment per protocol.	Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 18
Change From Baseline at Week 12 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment.	Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 12
Change From Baseline at Week 24 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of Life Scale	EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores were transformed to a range of 0 to 100 using a standard EORTC algorithm. Negative change from baseline values indicated deterioration in health status or functioning and positive changes indicated improvement. Per protocol, data were to be presented for the first course of study treatment.	Baseline (prior to first dose of study treatment in Cycle 1 [cycle length = 21 days]) and Week 24
Time to True Deterioration (TTD) in the Composite Endpoint of Cough, Chest Pain, and Dyspnea Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Lung Cancer Module 13 (QLQ-LC13)	TTD in patient-reported lung cancer symptoms of cough (QLQ-LC-13 Item 1), chest pain (QLQ-LC-13 Item 10), and dyspnea (QLQ-C30 Item 8) was a composite endpoint defined as the time to first onset of ≥10 point deterioration from baseline in an item confirmed by a second adjacent ≥10 point deterioration. The QLQ-LC13 consists of 13 measures of lung cancer symptoms and side effects from chemotherapy and radiation. It is scored on a 4-point scale (1=none, 2=a little, 3=quite a bit, 4=very much). Scores were transformed to a range of 0 to 100 using a standard algorithm. Higher scores represented increasing symptom severity. TTD was calculated using the product-limit Kaplan-Meier method for censored data and is presented for the first course of study treatment per protocol.	Day 1 of Cycles 1-9, Day 1 of every other cycle for Cycles 10-17 and 30 days after last dose of study treatment (Up to approximately 27 months)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csoszi T, Cheema PK, Rodriguez-Abreu D, Wollner M, Yang JC, Mazieres J, Orlandi FJ, Luft A, Gumus M, Kato T, Kalemkerian GP, Luo Y, Ebiana V, Pietanza MC, Kim HR; KEYNOTE-604 Investigators. Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. 2020 Jul 20;38(21):2369-2379. doi: 10.1200/JCO.20.00793. Epub 2020 May 29.

Helpful Links

• Merck Oncology Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2017
• Primary Completion (Actual): December 2, 2019
• Study Completion (Actual): September 21, 2021

Study Registration Dates

• First Submitted: February 23, 2017
• First Submitted That Met QC Criteria: February 23, 2017
• First Posted (Actual): February 28, 2017

Study Record Updates

• Last Update Posted (Actual): October 3, 2022
• Last Update Submitted That Met QC Criteria: September 2, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death Ligand 1 (PDL1, PD-L1); Programmed Cell Death Ligand 2 (PDL2, PD-L2); Extensive stage small cell lung cancer (ES-SCLC)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Carboplatin; Etoposide; Cisplatin; Pembrolizumab
• Other Study ID Numbers: 3475-604; 173744 (Registry Identifier: JAPIC-CTI); MK-3475-604 (Other Identifier: Merck); KEYNOTE-604 (Other Identifier: Merck); 2016-004309-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No