Study of Pembrolizumab Given With Ipilimumab or Placebo in Participants With Untreated Metastatic Non-Small Cell Lung Cancer (NSCLC) (MK-3475-598/KEYNOTE-598)

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo in Previously Untreated, Stage IV, Metastatic Non-small Cell Lung Cancer Subjects Whose Tumors Are PD-L1 Positive (TPS ≥ 50%) (KEYNOTE-598)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03302234
• Other study ID #: 3475-598
• Secondary ID: MK-3475-598KEYNO
• Status: Completed
• Phase: Phase 3
• Start date: December 14, 2017
• Est. completion date: September 7, 2022

Study information

• Verified date: September 2023
• 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 determine the efficacy of pembrolizumab given in combination with either ipilimumab or placebo as first-line treatment in participants with metastatic non-small cell lung cancer (NSCLC). The primary hypothesis of this study is that overall survival (OS) and/or progression-free survival (PFS) is prolonged in participants who receive pembrolizumab and ipilimumab compared to those who receive pembrolizumab and placebo.

With Amendment 6 (effective date: 11-Dec-2020), active participants, investigator, and sponsor personnel or delegate(s) involved in the treatment administration or clinical evaluation of the participants will be unblinded. Participants will discontinue ipilimumab and placebo and participants who remain on treatment will receive open-label pembrolizumab only.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 568
• Est. completion date: September 7, 2022
• Est. primary completion date: September 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of Stage IV metastatic non-small cell lung cancer (NSCLC) (American Joint Committee on Cancer version 8)

• Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by investigator

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

• Has a life expectancy of at least 3 months

• Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated

• Female participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study therapy

• Female participants of reproductive potential must agree to use contraception starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication

Exclusion Criteria:

• Has received prior systemic chemotherapy/other targeted or biological antineoplastic therapy treatment for their Stage IV metastatic NSCLC

• Has a tumor that harbors an epidermal growth factor receptor (EGFR)-sensitizing (activating) mutation or an anaplastic lymphoma kinase (ALK) translocation

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

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

• Has received prior radiotherapy within 2 weeks of start of study therapy or received lung radiation therapy of >30 Gray (Gy) within 6 months of the first dose of study therapy

• Has recovered from all radiation-related toxicities, does not require corticosteroids, and has not had radiation pneumonitis

• Is receiving systemic steroid therapy =7 days prior to the first dose of study therapy or receiving any other form of immunosuppressive medication

• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers

• Has known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis

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

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study therapy

• Has a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease

• Has had an allogeneic tissue/solid organ transplant

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

• 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 tuberculosis

• Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial

• Is a regular user of any illicit drugs or had a recent history of substance abuse

• Is pregnant or breast feeding or expecting to conceive starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication

• Has severe hypersensitivity to pembrolizumab and/or any of its excipients and/or to ipilimumab and/or any of its excipients

• Has a c-ros oncogene 1 (ROS1) mutation

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung

Intervention

Biological:
• Pembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
• Ipilimumab
Administered as an IV infusion every 6 weeks (Q6W)

Other:
• Placebo
Normal saline solution administered as an IV infusion Q6W

Locations

Country	Name	City	State
Argentina	Hospital Aleman ( Site 0208)	Buenos Aires
Argentina	Hospital Privado Centro Medico Cordoba ( Site 0206)	Cordoba
Argentina	Centro Oncologico Riojano Integral ( Site 0203)	La Rioja
Argentina	Instituto de Oncologia de Rosario ( Site 0200)	Rosario
Argentina	Sanatorio Britanico ( Site 0205)	Rosario
Argentina	Sanatorio Parque ( Site 0201)	Rosario	Santa Fe
Argentina	Centro Medico San Roque ( Site 0207)	Tucuman
Argentina	Centro de Investigaciones Clinicas - Clinica Viedma ( Site 0202)	Viedma	Rio Negro
Australia	Chris OBrien Lifehouse ( Site 2100)	Camperdown
Australia	The Townsville Hospital ( Site 2103)	Douglas
Australia	St Vincents Hospital Melbourne ( Site 2101)	Fitzroy
Australia	Fiona Stanley Hospital ( Site 2105)	Perth	Western Australia
Australia	Mater Cancer Care Centre ( Site 2102)	South Brisbane	Queensland
Brazil	Fundacao Pio XII - Hospital de Cancer de Barretos ( Site 0312)	Barretos
Brazil	CEPON Centro de Pesquisa Oncológicas ( Site 0307)	Florianopolis
Brazil	Hospital Nossa Senhora da Conceicao ( Site 0306)	Porto Alegre	RS
Brazil	Inst de Medicina Integral Professor Fernando Figueira- IMIP ( Site 0302)	Recife	Pernambuco
Brazil	Clinica de Hematologia e Oncologia Viver Ltda ( Site 0305)	Santa Maria	Rio Grande Do Sul
Brazil	Escola Paulista de Medicina - UNIFESP ( Site 0304)	Sao Paulo	SP
Brazil	Hospital Alemao Oswaldo Cruz ( Site 0311)	Sao Paulo	SP
Brazil	Hospital do Servidor Publico do Estado ( Site 0308)	Sao Paulo
Brazil	Instituto do Cancer de Sao Paulo - ICESP ( Site 0300)	Sao Paulo	SP
Canada	Tom Baker Cancer Centre ( Site 0119)	Calgary	Alberta
Canada	CIUSSS du Saguenay-Lac-St-Jean ( Site 0115)	Chicoutimi	Quebec
Canada	CISSS de la Monteregie-Centre ( Site 0100)	Greenfield Park	Quebec
Canada	CISSS-CA Hotel-Dieu de Levis ( Site 0108)	Levis	Quebec
Canada	CIUSSS Ouest de l'Ile - St-Mary's Hospital ( Site 0107)	Montreal	Quebec
Canada	St-Jerome Medical Research Inc ( Site 0113)	St-Jerome	Quebec
Canada	CancerCare Manitoba ( Site 0106)	Winnipeg	Manitoba
Chile	Instituto Nacional del Cancer ( Site 0406)	Santiago
Chile	Pontificia Universidad Catolica de Chile ( Site 0404)	Santiago
Chile	Soc. Prosalud Montes y Orlandi Ltda (Orlandi Oncologia) ( Site 0401)	Santiago
Chile	Clinica Universidad Catolica del Maule ( Site 0413)	Talca	El Maule
Chile	Hospital Clinico Vina del Mar ( Site 0400)	Vina del Mar
Colombia	Centro de Investigacion Clinica del Country ( Site 0500)	Bogota
Colombia	Clinica Colsanitas S.A. Sede Clinica Universitaria Colombia ( Site 0506)	Bogota
Colombia	Hospital Pablo Tobon Uribe ( Site 0505)	Medellin	Antioquia
Colombia	Oncomedica S.A. ( Site 0502)	Monteria
Colombia	Instituto Cancerologico de Narino Ltda ( Site 0504)	Pasto
France	Institut Bergonie ( Site 0803)	Bordeaux
France	CHU de Brest. Hopital Morvan ( Site 0800)	Brest
France	Centre Hopitalier Intercommunal Creteil ( Site 0802)	Creteil
France	Centre Hospitalier Le Mans ( Site 0804)	Le Mans
France	C.H.R.U de Lille - Hopital Calmette ( Site 0805)	Lille
France	Hopital Nord du Marseille ( Site 0808)	Marseille	Cedex 20
France	Hopital Tenon ( Site 0810)	Paris
France	Nouvel Hopital Civil ( Site 0809)	Strasbourg
France	CHU de Toulouse - Hopital Larrey ( Site 0801)	Toulouse
Germany	Evangelische Lungenklinik Berlin ( Site 0903)	Berlin
Germany	HELIOS Klinikum Emil von Behring ( Site 0905)	Berlin
Germany	Vivantes Klinikum Spandau ( Site 0910)	Berlin
Germany	SRH Waldklinikum Gera GmbH ( Site 0907)	Gera
Germany	LungenClinic Grosshansdorf GmbH ( Site 0908)	Grosshansdorf
Germany	Universitaetsklinikum Heidelberg ( Site 0900)	Heidelberg
Germany	Universitaetsklinikum Leipzig ( Site 0919)	Leipzig
Germany	Universitaetsklinikum Schleswig Holstein. ( Site 0918)	Luebeck
Hungary	Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 1502)	Budapest
Hungary	Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 1506)	Budapest
Hungary	Orszagos Onkologiai Intezet ( Site 1509)	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont ( Site 1511)	Debrecen
Hungary	Veszprem Megyei Tudogyogyintezet ( Site 1503)	Farkasgyepu
Hungary	Petz Aladar Megyei Oktato Korhaz ( Site 1505)	Gyor
Hungary	Bekes Megyei Pandy Kalman Korhaz. ( Site 1507)	Gyula
Hungary	Fejer Megyei Szent Gyorgy Egyetemi Oktato Korhaz ( Site 1504)	Szekesfehervar
Hungary	Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 1501)	Szolnok
Ireland	Beaumont Hospital ( Site 1312)	Dublin
Ireland	St James Hospital ( Site 1401)	Dublin
Ireland	University Hospital Limerick ( Site 1403)	Limerick
Italy	ASST Spedali Civili ( Site 1001)	Brescia
Italy	Ospedale Mater Salutis ( Site 1005)	Legnago	Verona
Italy	Istituto Europeo di Oncologia ( Site 1007)	Milano
Italy	Ospedale San Gerardo ASST Monza ( Site 1002)	Monza
Italy	AORN dei Colli Plesso Monaldi ( Site 1003)	Napoli
Italy	Ospedale Santa Maria della Misericordia ( Site 1008)	Perugia
Italy	Humanitas Research Hospital ( Site 1004)	Rozzano	Milano
Italy	IRCCS Casa Sollievo della Sofferenza ( Site 1009)	San Giovanni Rotondo (FG)	Foggia
Korea, Republic of	Asan Medical Center ( Site 2302)	Seoul
Korea, Republic of	Samsung Medical Center ( Site 2301)	Seoul
Korea, Republic of	Seoul National University Hospital ( Site 2303)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 2300)	Seoul
Latvia	Pauls Stradins Clinical University Hospital ( Site 1100)	Riga
Latvia	Riga East Clinical University Hospital ( Site 1111)	Riga
Mexico	Grupo Medico Camino SC ( Site 0607)	Ciudad de Mexico
Mexico	Hospital Civil de Guadalajara Fray Antonio Alcalde ( Site 0603)	Guadalajara	Jalisco
Mexico	Medical Care and Research S.A. de C.V. ( Site 0602)	Merida	Yucatan
Mexico	Medica Sur S.A.B de C.V. ( Site 0608)	Mexico City
Mexico	Avix Investigacion Clinica S.C. ( Site 0600)	Monterrey	N.l.
Mexico	Oncologica de Puebla SA de CV ( Site 0606)	Puebla
Peru	Centro Especializado de Enfermedades Neoplasicas SRL-CEEN SRL ( Site 0710)	Arequipa
Peru	Instituto Regional de Enfermedades Neoplasicas del Sur IRENSUR ( Site 0704)	Arequipa
Peru	Hospital Nacional Guillermo Almenara Irigoyen ( Site 0705)	La Victoria	Lima
Peru	Clinica Internacional Sede San Borja ( Site 0701)	Lima
Peru	Hospital Nacional Cayetano Heredia ( Site 0706)	Lima
Peru	Clinica Peruano Americana S.A. ( Site 0703)	Trujillo
Poland	Powiatowe Centrum Zdrowia w Brzezinach ( Site 1615)	Brzeziny
Poland	Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 1609)	Bydgoszcz
Poland	Przychodnia Lekarska Komed ( Site 1602)	Konin
Poland	Szpital Wojewodzki w Koszalinie im. Mikolaja Kopernika ( Site 1614)	Koszalin	Zachodniopomorskie
Poland	Samodzielny Publiczny Zespol Gruzlicy i Chorob Pluc ( Site 1607)	Olsztyn
Poland	MED-POLONIA Sp. z o.o. ( Site 1605)	Poznan
Poland	Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie ( Site 1600)	Warszawa
Poland	Dolnoslaskie Centrum Onkologii. ( Site 1616)	Wroclaw	Dolnoslaskie
South Africa	Clinton Onclogy Clinic ( Site 1804)	Alberton	Gauteng
South Africa	Universitas Annex National Hospital ( Site 1800)	Bloemfontein	Free State
South Africa	University of Stellenbosch and Tygerberg Hospital ( Site 1810)	Cape Town
South Africa	Vincent Pallotti Hospital ( Site 1811)	Cape Town
South Africa	Dr G.A. Landers Specialist Oncologist ( Site 1803)	Durban
South Africa	Charlotte Maxeke Johannesburg Academic Hospital ( Site 1806)	Johannesburg
South Africa	Sandton Oncology Medical Group PTY LTD ( Site 1807)	Johannesburg
South Africa	GVI Oncology Clinical Research Centre ( Site 1802)	Kraaifontein
South Africa	Wilgers Oncology Centre ( Site 1808)	Pretoria	Gauteng
Spain	Hospital Germans Trias i Pujol ( Site 1207)	Badalona	Barcelona
Spain	Hospital Universitari Vall d Hebron ( Site 1211)	Barcelona
Spain	Hospital San Pedro de Alcantara ( Site 1208)	Caceres	Extremadura
Spain	Hospital Duran i Reynals ( Site 1201)	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario Insular de Gran Canaria ( Site 1203)	Las Palmas de Gran Canaria	Gran Canaria
Spain	Hospital Fundacion Jimenez Diaz - Clin. Concepcion ( Site 1209)	Madrid
Spain	Hospital Universitario Virgen del Rocio ( Site 1200)	Sevilla
Taiwan	Changhua Christian Hospital ( Site 2406)	Changhua
Taiwan	Chang Gung Medical Foundation - Kaohsiung ( Site 2404)	Kaohsiung
Taiwan	China Medical University Hospital ( Site 2403)	Taichung
Taiwan	National Cheng Kung University Hospital ( Site 2401)	Tainan
Taiwan	Mackay Memorial Hospital ( Site 2405)	Taipei
Taiwan	National Taiwan University Hospital ( Site 2400)	Taipei
Taiwan	Chang Gung Memorial Hospital - Linkou Branch ( Site 2402)	Taoyuan
Thailand	Chulalongkorn Hospital ( Site 2561)	Bangkok
Thailand	Pramongkutklao Hospital ( Site 2564)	Bangkok
Thailand	Siriraj Hospital ( Site 2562)	Bangkok
Thailand	Khon Kaen University ( Site 2565)	Khon Kaen
Thailand	Bangkok Hospital Chiangmai ( Site 2560)	Mueang	Chiang Mai
Thailand	Ramathibodi Hospital. ( Site 2563)	Ratchthevee	Bangkok
Turkey	Acibadem Adana Hastanesi ( Site 1904)	Adana
Turkey	Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 1908)	Ankara
Turkey	Uludag Universitesi Tip Fakultesi ( Site 1914)	Bursa
Turkey	Ankara Sehir Hastanesi ( Site 1903)	Cankaya - Ankara
Turkey	Trakya Uni. Tip Fakultesi ( Site 1911)	Edirne
Turkey	Istanbul Universitesi Cerrahpasa Tip Fakultesi ( Site 1906)	Istanbul
Turkey	Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi ( Site 1912)	Istanbul
Turkey	Ege Universitesi Tip Fakultesi Hastanesi ( Site 1901)	Izmir
Turkey	Medical Park Izmir Hospital ( Site 1900)	Izmir
Turkey	Kocaeli Universitesi Tip Fakultesi ( Site 1909)	Kocaeli
Turkey	Inonu Universitesi Tip Fakultesi ( Site 1907)	Malatya
Turkey	Karadeniz Teknik Universitesi ( Site 1910)	Trabzon
Ukraine	Cherkasy Regional Hospital ( Site 2020)	Cherkasy
Ukraine	Regional Clinical Onco Dispensary_ State Medical University ( Site 2012)	Chernivtsy
Ukraine	Dnipropetrovsk City Multidiscipline Clinical Hosp.4 of DRC ( Site 2000)	Dnipropetrovsk
Ukraine	MI Prykarpatskyi Clinical Oncology Centrum ( Site 2009)	Ivano-Frankivsk
Ukraine	PP PPC Acinus Medical and Diagnostic Centre ( Site 2002)	Kropyvnytskyi
Ukraine	MI Kryviy Rih Center of Dnipropetrovsk Regional Council ( Site 2005)	Kryviy Rih	Dnipropetrovsk Region
Ukraine	Kyiv City Clinical Oncological Center ( Site 2014)	Kyiv
Ukraine	National Cancer Institute of the MoH of Ukraine ( Site 2015)	Kyiv
Ukraine	Lviv State Oncology Regional Treatment and Diagnostic Center ( Site 2003)	Lviv
Ukraine	MI Odessa Regional Oncological Centre ( Site 2004)	Odesa
United Kingdom	Belfast City Hospital ( Site 1302)	Belfast
United Kingdom	Royal Free NHS Foundation Trust ( Site 1324)	London
United Kingdom	St. Georges University Hospital NHS Foundation Trust ( Site 1321)	London
United Kingdom	The Royal Marsden NHS Foundation Trust.. ( Site 1327)	London
United Kingdom	The Christie NHS Foundation Trust ( Site 1301)	Manchester
United Kingdom	Mount Vernon Cancer Centre ( Site 1307)	Northwood
United Kingdom	The Royal Marsden NHS Foundation Trust. ( Site 1326)	Sutton	Surrey
United Kingdom	Royal Cornwall Hospital ( Site 1325)	Truro	Cornwall
United Kingdom	Royal Wolverhampton Hospitals NHS Trust ( Site 1323)	Wolverhampton
United States	Texas Oncology-Arlington South ( Site 8006)	Arlington	Texas
United States	Boston Medical Center ( Site 0025)	Boston	Massachusetts
United States	Disney Family Cancer Center ( Site 0035)	Burbank	California
United States	Lahey Hospital & Medical Center ( Site 0020)	Burlington	Massachusetts
United States	University of Tennessee Erlanger Oncology & Hematology ( Site 0026)	Chattanooga	Tennessee
United States	Mid Ohio Oncology/Hematology Inc. ( Site 0003)	Columbus	Ohio
United States	The Ohio State University Wexner Medical Center ( Site 0016)	Columbus	Ohio
United States	Texas Oncology-Methodist Dallas Cancer Center ( Site 8000)	Dallas	Texas
United States	Texas Oncology-Flower Mound ( Site 8007)	Flower Mound	Texas
United States	Greenville Health System ( Site 8010)	Greenville	South Carolina
United States	Tennessee Cancer Specialists ( Site 0017)	Knoxville	Tennessee
United States	Texas Oncology-Longview Cancer Center ( Site 8009)	Longview	Texas
United States	University of Wisconsin Carbone Cancer Center ( Site 0004)	Madison	Wisconsin
United States	Medical College of Wisconsin Clinical Cancer Center ( Site 0027)	Milwaukee	Wisconsin
United States	Pacific Cancer Care ( Site 0001)	Monterey	California
United States	Icahn School of Medicine at Mount Sinai ( Site 0034)	New York	New York
United States	Florida Hospital Cancer Institute ( Site 0009)	Orlando	Florida
United States	Mercy Health-Paducah Medical Oncology and Hematology ( Site 0018)	Paducah	Kentucky
United States	Mayo Clinic Cancer Center ( Site 0007)	Phoenix	Arizona
United States	Providence Cancer Institute, Franz Clinic - Eastside ( Site 0031)	Portland	Oregon
United States	John Wayne Cancer Institute ( Site 0021)	Santa Monica	California
United States	New England Cancer Specialists ( Site 0019)	Scarborough	Maine
United States	Holy Name Medical Center ( Site 0022)	Teaneck	New Jersey
United States	Northwest Cancer Specialists, P.C. ( Site 8001)	Vancouver	Washington
United States	Virginia Mason Memorial- North Star Lodge Cancer Center ( Site 0033)	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Chile,  Colombia,  France,  Germany,  Hungary,  Ireland,  Italy,  Korea, Republic of,  Latvia,  Mexico,  Peru,  Poland,  South Africa,  Spain,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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 analysis were censored at the date of last known contact. The median survival (in months) and the associated 95% confidence intervals (CIs) were reported using Kaplan-Meier method was used. Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and predominant tumor history (squamous versus non-squamous) was used to estimate hazard ratio (HR) and 95% CIs for first course study treatment per protocol.	Up to approximately 32 months (through data cut-off date: 01 Sep 2020)
Primary	Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR)	PFS was defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. PD is defined as =20% increase in sum of diameters of target lesions. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of =5 mm. The appearance of one or more new lesions is also considered PD. RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The median survival (in months) and associated 95% CIs were reported using Kaplan-Meier method. Cox regression model with Efron's method of tie handling with treatment as covariate stratified by ECOG performance status (0 vs. 1), geographic region of the enrolling site (East Asia vs. non-East Asia), and predominant tumor history (squamous vs. non-squamous) was used to estimate HR and 95% CIs for first course study treatment per protocol.	Up to approximately 32 months (through data cut-off date 01 Sep 2020)
Secondary	Objective Response Rate (ORR) Per RECIST 1.1 Based on BICR	ORR was defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 by BICR. 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. Per protocol the ORR was calculated using the Miettinen & Nurminen method stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and predominant tumor history (squamous versus non-squamous) for the first course of study treatment.	Up to approximately 32 months (data cut-off date 01 Sep 2020)
Secondary	Duration of Response (DOR) Per RECIST 1.1 Based on BICR	For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or confirmed PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until PD or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. 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. Per protocol, the DOR for all participants who experienced a CR or PR was presented for the first course of study treatment.	Up to approximately 32 months (data cut-off date 01 Sep 2020)
Secondary	Time to True Deterioration (TTD) in Cough, Pain in Chest, and Shortness of Breath	TTD was defined as the time to the first onset of a 10-point or greater score deterioration from baseline in any one of the 3 symptoms (cough, pain in chest or shortness of breath), confirmed by a second adjacent 10-point or greater score deterioration from baseline. Cough was based on EORTC QLQ-LC13 question 1, pain in chest was based on EORTC QLQ-LC13 question 10, and shortness of breath was based on EORTC QLQ-C30 question 8. Per protocol, TTD was reported for first course study treatment.	Up to approximately 32 months (data cut-off date 01 Sep 2020)
Secondary	Number of Participants Who Experienced an Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can 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. Per protocol, the number of participants who experienced an AE were reported for the first course of study treatment and follow up.	Up to approximately 27 months
Secondary	Number of Participants Who Discontinued Study Treatment Due to an AE	An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can 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. Per protocol, the number of participants who discontinued study treatment due to an AE were reported for the first course of study treatment.	Up to approximately 24 months
Secondary	Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Scale Score to Week 18	The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" were scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores were standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. Per protocol, the change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score were presented for first course study treatment.	Baseline, Week 18

External Links

•   Merck Clinical Trials Information