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)

Small Cell Lung Cancer (SCLC) Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03066778
• Other study ID #: 3475-604
• Secondary ID: 173744MK-3475-60
• Status: Completed
• Phase: Phase 3
• Start date: May 2, 2017
• Est. completion date: September 21, 2021

Study information

• Verified date: August 2022
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 453
• Est. completion date: September 21, 2021
• Est. primary completion date: December 2, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Lung Neoplasms
• Small Cell Lung Cancer (SCLC)
• Small Cell Lung Carcinoma

Intervention

Biological:
• Pembrolizumab
IV infusion on Day 1 of each cycle prior to chemotherapy

Drug:
• Normal saline solution
IV infusion on Day 1 of each cycle prior to chemotherapy
• Carboplatin
IV infusion on Day 1 of each cycle
• Cisplatin
IV infusion on Day 1 of each cycle
• Etoposide
IV infusion on Days 1, 2 and 3 of each cycle

Locations

Country	Name	City	State
Australia	Blacktown Hospital ( Site 0004)	Blacktown	New South Wales
Australia	Lyell McEwin Hospital ( Site 0002)	Elizabeth Vale
Australia	St Vincents Hospital Melbourne ( Site 0005)	Fitzroy
Australia	St John of God ( Site 0006)	Murdoch	Western Australia
Australia	Southern Medical Day Care Centre ( Site 0001)	Wollongong	New South Wales
Canada	William Osler Health System (Brampton Civic Hospital) ( Site 0161)	Brampton	Ontario
Canada	CISSS de la Monteregie-Centre ( Site 0152)	Greenfield Park	Quebec
Canada	Nova Scotia Health Authority ( Site 0157)	Halifax	Nova Scotia
Canada	Kingston Health Sciences Centre ( Site 0155)	Kingston	Ontario
Canada	CISSS-CA Hotel Dieu de Levis ( Site 0154)	Lévis	Quebec
Canada	CIUSSS Ouest de l'Ile - St-Mary's Hospital ( Site 0158)	Montreal	Quebec
Canada	St. Jerome Medical Research Inc. ( Site 0160)	St-Jerome	Quebec
Canada	Sunnybrook Research Institute ( Site 0151)	Toronto	Ontario
Canada	Cancer Care Manitoba ( Site 0159)	Winnipeg	Manitoba
Chile	Fundacion Arturo Lopez Perez FALP ( Site 0203)	Santiago
Chile	Health and Care Chile ( Site 0202)	Santiago
Chile	Instituto Nacional del Cancer ( Site 0207)	Santiago	Region Metropolitana
Chile	Pontificia Universidad Catolica de Chile ( Site 0206)	Santiago
Chile	Clinica Universidad Catolica del Maule ( Site 0208)	Talca
France	CHRU de Lille - Hopital Albert Calmette ( Site 0353)	Lille
France	C.H.R.U. De Limoges ( Site 0358)	Limoges
France	CHU Nantes - Hopital Laennec ( Site 0363)	Nantes
France	Centre Antoine Lacassagne ( Site 0362)	Nice
France	Hopital Tenon ( Site 0360)	Paris
France	Institut de Cancerologie Jean-Godinot ( Site 0351)	Reims
France	CHU de Toulouse - Hopital Larrey ( Site 0354)	Toulouse
Germany	Evangelische Lungenklinik Berlin ( Site 0403)	Berlin
Germany	Medizinische Fakultaet Carl Gustav Carus der TU Dresden ( Site 0411)	Dresden
Germany	Florence Nightingale Krankenhaus ( Site 0413)	Duesseldorf
Germany	SRH Waldklinikum Gera GmbH ( Site 0405)	Gera
Germany	Asklepios Klinikum Harburg ( Site 0412)	Hamburg
Germany	Thoraxklinik Heidelberg gGmbH am Universitaetsklinikum Heidelberg ( Site 0401)	Heidelberg
Germany	Philipps-Universitat Marburg ( Site 0414)	Marburg
Germany	Universitaetsklinikum Tuebingen ( Site 0404)	Tuebingen
Hungary	Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0452)	Budapest
Hungary	Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0458)	Budapest
Hungary	Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0459)	Budapest
Hungary	Orszagos Onkologiai Intezet ( Site 0453)	Budapest	Pest
Hungary	Veszprem Megyei Tudogyogyintezet ( Site 0454)	Farkasgyepu
Hungary	Petz Aladar Megyei Oktato Korhaz ( Site 0460)	Gyor
Hungary	Fejer Megyei Szent Gyorgy Egyetemi Oktato Korhaz ( Site 0456)	Szekesfehervar
Hungary	Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 0451)	Szolnok
Hungary	Zala Megyei Szent Rafael Korhaz ( Site 0457)	Zalaegerszeg
Ireland	St James Hospital ( Site 1452)	Dublin
Ireland	St Vincents University Hospital ( Site 1456)	Dublin
Israel	Soroka Medical Center ( Site 0505)	Beer Sheva
Israel	Ramban Medical Center - Dept. Hemato. & B. Marrow Transplant ( Site 0502)	Haifa
Israel	Meir Medical Center ( Site 0503)	Kfar Saba
Israel	Rabin Medical Center ( Site 0504)	Petah Tikva
Israel	Chaim Sheba Medical Center. ( Site 0501)	Ramat-Gan
Japan	Hyogo Cancer Center ( Site 0611)	Akashi	Hyogo
Japan	National Hospital Organization Kyushu Medical Center ( Site 0617)	Fukuoka
Japan	Hiroshima University Hospital ( Site 0604)	Hiroshima
Japan	National Cancer Center Hospital East ( Site 0613)	Kashiwa	Chiba
Japan	Kurume University Hospital ( Site 0609)	Kurume	Fukuoka
Japan	National Hospital Organization Shikoku Cancer Center ( Site 0614)	Matsuyama	Ehime
Japan	National Hospital Organization Nagoya Medical Center ( Site 0615)	Nagoya	Aichi
Japan	Niigata Cancer Center Hospital ( Site 0610)	Niigata
Japan	Osaka International Cancer Institute ( Site 0616)	Osaka
Japan	National Hospital Organization Kinki-chuo Chest Medical Center ( Site 0608)	Sakai	Osaka
Japan	Sendai Kousei Hospital ( Site 0602)	Sendai	Miyagi
Japan	Shizuoka Cancer Center Hospital and Research Institute ( Site 0607)	Sunto-gun	Shizuoka
Japan	The Cancer Institute Hospital of JFCR ( Site 0606)	Tokyo
Japan	National Hospital Organization Yamaguchi Ube Medical Center ( Site 0601)	Ube	Yamaguchi
Japan	Wakayama Medical University Hospital ( Site 0612)	Wakayama
Japan	Kanagawa Cancer Center ( Site 0618)	Yokohama	Kanagawa
Korea, Republic of	Inje University Haeundae Paik Hospital ( Site 0905)	Busan
Korea, Republic of	National Cancer Center ( Site 0904)	Goyang-si
Korea, Republic of	Asan Medical Center ( Site 0901)	Seoul
Korea, Republic of	Samsung Medical Center ( Site 0902)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 0903)	Seoul
New Zealand	Canterbury Regional Cancer & Blood Services ( Site 0701)	Christchurch
Poland	Przychodnia Lekarska Komed ( Site 0769)	Konin
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla II ( Site 0768)	Krakow
Poland	Centrum Onkologii Ziemi Lubelskiej im. sw. Jana z Dukli ( Site 0767)	Lublin
Poland	SKPP UM im. Karola Marcinkowkiego w Poznaniu ( Site 0766)	Poznan
Poland	Wielkopolskie Centrum Pulmonologii i Torakochirurgii ( Site 0762)	Poznan
Poland	Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu ( Site 0756)	Torun
Poland	Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie ( Site 0751)	Warszawa
Poland	Mazowiecki Szpital Onkologiczny ( Site 0757)	Wieliszew	Mazowieckie
Poland	Dolnoslaskie Centrum Onkologii we Wroclawiu ( Site 0771)	Wroclaw
Russian Federation	Belgorod Regional Oncology Dispensary ( Site 0804)	Belgorod
Russian Federation	N.N. Blokhin NMRCO ( Site 0801)	Moscow
Russian Federation	SBI of Stavropol region Pyatigorskiy Oncologic dispensary ( Site 0811)	Pyatigorsk
Russian Federation	Municipal Clinical Oncology Center ( Site 0802)	Saint Petersburg
Russian Federation	SBHI Leningrad Regional Clinical Hospital ( Site 0803)	Saint Petersburg
Spain	Complejo Hospitalario Universitario de A Coruna ( Site 0953)	A Coruna
Spain	Hospital del Mar ( Site 0956)	Barcelona
Spain	Hospital Universitari Vall d Hebron ( Site 0951)	Barcelona
Spain	Hospital Ciudad de Jaen ( Site 0957)	Jaen
Spain	Hospital Universitario Insular de Gran Canaria ( Site 0952)	Las Palmas de Gran Canaria	Gran Canaria
Spain	Hospital General Universitario Gregorio Maranon ( Site 0958)	Madrid
Spain	Hospital Universitario Fundacion Jimenez Diaz ( Site 0954)	Madrid
Spain	Hospital Clinico Universitario de Valencia ( Site 0955)	Valencia
Switzerland	Kantonsspital Graubuenden ( Site 1403)	Chur
Switzerland	CHUV Centre Hospitalier Universitaire Vaudois ( Site 1405)	Lausanne
Switzerland	Universitaetsspital Zuerich ( Site 1404)	Zuerich
Taiwan	Kaohsiung Chang Gung Memorial Hospital of the C.G.M.F. ( Site 1005)	Kaohsiung
Taiwan	China Medical University Hospital. ( Site 1003)	Taichung
Taiwan	Taichung Veterans General Hospital ( Site 1007)	Taichung
Taiwan	Chi Mei Medical Center Liuying ( Site 1006)	Tainan
Taiwan	National Cheng Kung University Hospital ( Site 1004)	Tainan
Taiwan	National Taiwan University Hospital ( Site 1001)	Taipei
Taiwan	Taipei Veterans General Hospital ( Site 1002)	Taipei
Turkey	Baskent University Adana Dr. Turgut Noyan EAH ( Site 1057)	Adana
Turkey	Ankara UTF ( Site 1055)	Ankara
Turkey	Dr. Abdurrahman Yurtaslan Ankara Onkoloji EAH ( Site 1053)	Ankara
Turkey	Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 1060)	Ankara
Turkey	Trakya Uni. Tip Fakultesi ( Site 1063)	Edirne
Turkey	Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 1058)	Istanbul
Turkey	Medeniyet Uni. Goztepe Egitim ve Arast. Hast. ( Site 1064)	Istanbul
Turkey	Medipol Hastanesi ( Site 1066)	Istanbul
Turkey	Ege Universitesi Tip Fakultesi ( Site 1052)	Izmir	Bornova
Turkey	Medical Park Izmir Hospital ( Site 1051)	Izmir
Turkey	Kocaeli Universitesi Tip Fakultesi ( Site 1061)	Kocaeli
Turkey	Inonu Universitesi Tip Fakultesi ( Site 1059)	Malatya
United Kingdom	Birmingham Heartlands Hospital ( Site 1162)	Birmingham
United Kingdom	St James s University Hospital ( Site 1161)	Leeds
United Kingdom	North Middlesex Hospital ( Site 1151)	London
United Kingdom	Maidstone Hospital ( Site 1155)	Maidstone
United Kingdom	Mount Vernon Cancer Centre ( Site 1156)	Northwood
United States	University of Michigan ( Site 1217)	Ann Arbor	Michigan
United States	Texas Oncology ( Site 8002)	Austin	Texas
United States	Weinberg Cancer Institute at Franklin Square ( Site 1210)	Baltimore	Maryland
United States	Memorial Sloan-Kettering Cancer Center At Basking Ridge ( Site 1226)	Basking Ridge	New Jersey
United States	Beth Israel Deaconess Medical Center ( Site 1206)	Boston	Massachusetts
United States	Dana-Farber Cancer Institute [Boston] ( Site 1201)	Boston	Massachusetts
United States	Massachusetts General Hospital ( Site 1203)	Boston	Massachusetts
United States	Montefiore Einstein Center for Cancer Care - Main site ( Site 1204)	Bronx	New York
United States	Montefiore Medical Center ( Site 1222)	Bronx	New York
United States	Rush University Medical Center ( Site 1215)	Chicago	Illinois
United States	Memorial Sloan-Kettering Cancer Center at Commack ( Site 1227)	Commack	New York
United States	Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 8003)	Dallas	Texas
United States	Henry Ford Health System ( Site 1221)	Detroit	Michigan
United States	Duke University Medical Center ( Site 1214)	Durham	North Carolina
United States	North Shore University Health System ( Site 1216)	Evanston	Illinois
United States	Bon Secours St. Francis Health Sytem ( Site 1212)	Greenville	South Carolina
United States	Memorial Sloan Kettering Cancer Center ( Site 1229)	Harrison	New York
United States	Hattiesburg Clinic ( Site 1205)	Hattiesburg	Mississippi
United States	Comprehensive Cancer Centers of Nevada ( Site 8004)	Henderson	Nevada
United States	Baptist Health Medical Group Oncology, LLC ( Site 8000)	Miami	Florida
United States	Memorial Sloan Kettering Cancer Center- Monmouth ( Site 1225)	Middletown	New Jersey
United States	Minnesota Oncology Hematology, PA ( Site 8001)	Minneapolis	Minnesota
United States	Community Hospital ( Site 1207)	Munster	Indiana
United States	Tennessee Oncology, PLLC/The Sarah Cannon Research Institute ( Site 1230)	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center ( Site 1211)	New York	New York
United States	Memorial Sloan Kettering Cancer Center - Rockville Centre ( Site 1228)	Rockville Centre	New York
United States	Mercy Hospital Saint Louis ( Site 1213)	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Chile,  France,  Germany,  Hungary,  Ireland,  Israel,  Japan,  Korea, Republic of,  New Zealand,  Poland,  Russian Federation,  Spain,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

References & Publications (1)

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, Gümüs M, Kato T, Kalemkerian GP, Luo Y, Ebiana V, Pietanza MC, Kim HR; KEYNOTE-604 Investigators. Pembrolizuma — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)

External Links

•   Merck Oncology Clinical Trials Information