Clinical Trial of Lurbinectedin as Single-agent or in Combination With Irinotecan Versus Topotecan or Irinotecan in Patients With Relapsed Small-cell Lung Cancer (LAGOON)

Relapsed Small Cell Lung Cancer Clinical Trial

Official title:

A Randomized, Multicenter, Open-label, Phase III Study of Lurbinectedin Single-Agent or Lurbinectedin in Combination With Irinotecan Versus Investigator's Choice (Topotecan or Irinotecan) in Relapsed Small Cell Lung Cancer Patients (LAGOON Trial)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05153239
• Other study ID #: PM1183-C-008-21
• Status: Recruiting
• Phase: Phase 3
• Start date: July 22, 2022
• Est. completion date: April 2026

Study information

• Verified date: April 2024
• Source: PharmaMar
• Contact: José Antonio Lopez-Vilariño, MD
• Phone: 0034 91 823 4564
• Email: jalopez-vilarino[@]pharmamar.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and compare the activity and safety of two experimental arms consisting of lurbinectedin as single agent (Group A) or the combination of lurbinectedin with irinotecan (Group B) versus Investigator's Choice (topotecan or irinotecan) as control arm (Group C), in Small-cell Lung Cancer (SCLC) patients who failed one prior platinum-containing line.

Description:

Approximately 705 Adult SCLC patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 who have failed one prior platinum-containing line with CTFI ≥ 30 days and controlled asymptomatic and pretreated Central Nervous System metastases will be enrolled and assigned to each treatment arm.

Central randomization will be implemented; patients will be assigned to each treatment arm at a 1:1:1 ratio.

An Independent Data Monitoring Committee (IDMC) will oversee the conduct of the study. The IDMC should have access to unblinded efficacy and safety data throughout the trial to enable timely and informed judgments about risks and benefits.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 705
• Est. completion date: April 2026
• Est. primary completion date: April 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Voluntary written informed consent of the patient obtained before any study-specific procedure

2. Age=18 years

3. Histologically or cytologically confirmed diagnosis of SCLC.

4. One prior line of platinum-containing chemotherapy with/without anti-PD-1 or anti-PD-L1 (Note: at least 70% of patients included in the study have to be pretreated with anti-PD-1 or anti-PD-L1)

5. Chemotherapy-free interval (CTFI, time from the last dose of first-line platinum-containing chemotherapy to the occurrence of progressive disease) = 30 days (independent of the immunotherapy maintenance, if applicable)

6. Patients with history of Central Nervous System (CNS) metastases can participate provided they are pretreated and radiologically stable (i.e., without evidence of progression) for at least 4 weeks by repeated imaging (note: repeated imaging should be performed during study screening), asymptomatic, and without requirement of steroid treatment for at least 7 days before the first dose of study treatment

7. Eastern Cooperative Oncology Group (ECOG) PS = 2

8. Adequate hematological, renal, metabolic and hepatic function:

1. Hemoglobin = 9.0 g/dL [patients may have received prior red blood cell (RBC) transfusion, if clinically indicated]; absolute neutrophil count (ANC) = 2.0 x 10^9/L, and platelet count = 100 x 10^9/L.

2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3.0 x upper limit of normal (ULN).

3. Total bilirubin = 1.5 x ULN or direct bilirubin = ULN.

4. Albumin = 3.0 g/dL.

5. Calculated creatinine clearance (CrCL) = 30 mL/min (using Cockcroft and Gault's formula).

9. At least three weeks since last prior antineoplastic treatment and recovery to grade = 1 from any adverse event (AE) related to previous anticancer treatment (excluding sensory neuropathy, anemia, asthenia and alopecia, all grade = 2) according to the National Cancer InstituteCommon Terminology Criteria for Adverse Events (NCICTCAE) v.5.

10. Prior radiotherapy (RT): At least two weeks since completion of prophylactic cranial irradiation (PCI), and to any other site not previously specified.

11. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to seven months after treatment discontinuation. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.

Exclusion Criteria:

1. Platinum-naïve patients or patients pretreated with more than one prior chemotherapy regimen (including patients re-challenged with same initial regimen).

2. Prior treatment with lurbinectedin, trabectedin, PM14, or topoisomerase I inhibitors (irinotecan, topotecan, etc.).

3. Active or untreated CNS metastases and/or carcinomatous meningitis.

4. Patients with limited-stage disease who are candidates for local or regional therapy, including PCI, thoracic RT or both, must have been offered that option and completed treatment or refused it prior to randomization.

5. Concomitant diseases/conditions:

1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.

2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.

3. Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C.

4. Known Gilbert's disease.

5. Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture. Presence of external drainages.

6. Ongoing, treatment-requiring, non-neoplastic chronic liver disease of any origin. For Hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For Hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. Subjects taking hepatitis related antiviral therapy within six months prior to the first dose of study drugs will also be excluded.

7. Intermittent or continuous oxygen requirement within two weeks prior to randomization. Patients with confirmed or suspected diagnosis of diffuse interstitial lung disease or pulmonary fibrosis.

8. Patients with a second invasive malignancy treated with chemotherapy and/or RT. Patients with a previous malignancy that was completely resected with curative intention three or more years prior to randomization, except treated in situ carcinoma of the cervix, basal or squamous cell skin carcinoma, and in situ transitional cell bladder carcinoma and who has been continuously in remission since then will be permitted.

9. Limitation of the patient's ability to comply with the treatment or to follow the protocol.

10. Documented or suspected invasive fungal infections requiring systemic treatment within 12 weeks of randomization.

11. Known human immunodeficiency virus (HIV) infection.

12. Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or subocclusion or paralysis.

13. Evident symptomatic pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days.

14. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study (e.g.; COVID-19 disease).

6. RT in more than 35% of the bone marrow.

7. History of previous bone marrow and/or stem cell transplantation and allogenic transplant.

8. Patient has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of inactivated vaccines is allowed.

9. Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).

10. History of allergy or hypersensitivity to any of the study drugs or any of their excipients.

11. Women who are pregnant or breast feeding and fertile patients (men and women) who are not able to use a highly effective method of contraception

Related Conditions & MeSH terms

• Lung Neoplasms
• Relapsed Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Intervention

Drug:
• Irinotecan
Irinotecan 75 mg/m² intravenously Days 1 & 8 q3wk
• Lurbinectedin
Lurbinectedin 3.2 mg/m² will be administered intravenously on Day 1 q3wk
• Irinotecan
For patients aged <70 years: irinotecan 350 mg/m² intravenously Day 1 q3wk For patients aged =70 years: irinotecan 300 mg/m² intravenously Day 1 q3wk
• Topotecan
Topotecan 2.3 mg/m² oral or 1.5 mg/m² intravenously Days 1-5 q3wk
• Lurbinectedin
Lurbinectedin 2.0 mg/m² will be administered intravenously on Day 1 q3wk

Locations

Country	Name	City	State
Australia	BRICC - Ballarat Health Services	Ballarat Central	Victoria
Australia	Box Hill Hospital Eastern Health Clinical School	Box Hill	Victoria
Australia	The Chris Obrien Lifehouse	Camperdown	New South Wales
Australia	Northern Beaches Hospital	Frenchs Forest
Australia	Gosford Hospital GH - Central Coast Cancer Centre	Gosford
Australia	Austin Hospital- Medical Oncology Unit	Heidelberg
Australia	St John of God Murdoch Hospital	Murdoch
Australia	Cancer Care Wollongong	Wollongong
Austria	University Hospital Salzburg	Salzburg
Austria	Medizinische Universitaet Wien	Vienna
Belgium	Algemeen Ziekenhuis AZ Klina - Borstkliniek	Brasschaat
Belgium	Grand Hopital de Charleroi GHdC - Hopital Saint Joseph	Charleroi
Belgium	Antwerp University Hospital	Edegem	Antwerp
Belgium	Centre Hospitalier Chretien CHC - MontLegia	Liège
Belgium	CHR de la Citadelle	Liège
Belgium	CHU Liege	Liège
Belgium	Az Sint Maarten Mechelen	Mechelen
Belgium	Centre Hospitalier Universitaire (CHU) Ambroise Pare	Mons
Brazil	Fundacao Pio XII - Hospital de Cancer de Barretos - Hospital de Amor	Barretos
Brazil	Oncocentro-Centro de Oncologia do Parana	Curitiba	Parana
Brazil	ONCOSITE - Centro de Pesquisa Clinica em Oncologia Ltda	Ijuí
Brazil	Nucleo de Oncologia da Bahia - NOB	Ondina	Salvador
Brazil	Hospital Sao Lucas da PUCRS	Porto Alegre
Brazil	Irmandade daSanta Casa de Misericordia de Porto Alegre	Porto Alegre
Brazil	Instituto Nacional de Cancer - Ministrio da Sade	Rio De Janeiro
Brazil	UPCO - Hospital de Clinicas de Porto Alegre	Santa Cecília	Porto Alegre
Bulgaria	Multiprofile Hospital for Active Treatment - Uni Hospital OOD Department of Medical Oncology	Panagyurishte
Bulgaria	Complex Oncology Center - Plovdiv EOOD, First Department of Medical Oncology and Oncological Diseases in Gastroenterology	Plovdiv
Bulgaria	Multiprofile Hospital for Active Treatment Serdika EOOD Second Department of Medical Oncology	Sofia
Bulgaria	Specialized hospital for active treatment of oncological diseases	Sofia
Canada	Hamilton Health Sciences -Juravinski Cancer Centre	Hamilton	Ontario
Canada	Hôpital de la Cité-de-la- Santé	Laval	Quebec
Canada	CISSS de la Montérégie-Centre - Hôpital Charles LeMoyne	Longueuil	Quebec
Canada	McGill University Health Centre (MUHC)	Montréal
Canada	Southlake Regional Health Centre	Newmarket	Ontario
Canada	University Health Network - Princess Margaret Hospital	Toronto
Chile	Centro de Estudios Clínicos SAGA	Santiago de Chile
Chile	Clinica Alemana de Santiago	Santiago de Chile
Chile	Clínica Santa María	Santiago de Chile
Chile	Fundación Arturo López Pérez	Santiago de Chile
Chile	Hospital Clinico Universidad de Chile	Santiago de Chile
Chile	James Lind Centro de Investigación del Cáncer	Temuco	Araucania
Chile	Clinical Research Chile SpA	Valdivia	Los Ríos
Denmark	Aalborg University Hospital	Aalborg
Denmark	Sjællands Universitetshospital	Næstved
Denmark	Sønderborg Sygehus	Sønderborg
Denmark	Vejle Hospital	Vejle
France	Hopital Jean Minjoz	Besancon
France	AssAP-HP - Hopital Ambroise-Pare	Boulogne-Billancourt
France	Hopital Morvan CHU de Brest	Brest
France	Centre François Baclesse	Caen
France	CHU de Caen - Hopital Cote de Nacre	Caen
France	Centre Hospitalier Intercommunal de Creteil (CHIC)	Créteil
France	Centre Hospitalier Universitaire CHU De Limoges	Limoges
France	CHU de Nantes	Nantes
France	Bichat-Claude Bernard Hospital	Paris
France	CHU Reims - Hpital Maison Blanche	Reims
France	Hopital Civil / Nouvel Hopital Civil	Strasbourg
France	Hospital Foch	Suresnes
France	Gustave Roussy	Villejuif
Georgia	High Technology Hospital Medcenter	Batumi
Georgia	Institute Of Clinical Oncology	Tbilisi
Georgia	JSC Evex Hospitals "Caraps Medline"	Tbilisi
Georgia	LTD Cancer Research Centre	Tbilisi
Georgia	New Hospitals	Tbilisi
Georgia	Todua Clinic	Tbilisi
Germany	Zentralklinik Bad Berka GmbH	Bad Berka
Germany	Charite - Universitaetsmedizin Berlin	Berlin
Germany	Evangelische Lungenklinik Berlin	Berlin
Germany	Klinikum Bremen Ost	Bremen
Germany	Helios St. Johannes Klinikum	Duisburg
Germany	Klinikum Esslingen GmbH	Esslingen
Germany	Universittsklinikum Freiburg	Freiburg
Germany	Asklepios Fachklinik München-Gauting	Gauting
Germany	LungenClinic Grosshansdorf	Großhansdorf	Schleswig Holstein
Germany	Universitaetsklinikum Halle Saale	Halle
Germany	Krankenhaus Martha-Maria Halle gGmbH	Halle (saale)
Germany	Thoraxclinic Heidelberg GmbH	Heidelberg
Germany	Vincentius-Diakonissen-Kliniken gAG Karlsruhe	Karlsruhe
Germany	Klinikum Kassel - Medizinische Klinik IV	Kassel
Germany	Klinik Loewenstein gGmbH	Löwenstein
Germany	Universitaetsmedizin Mannheim	Mannheim
Germany	Staedtisches Klinikum München - Bogenhausen	München
Germany	Sana Klinikum Offenbach	Offenbach
Hungary	Debreceni Egyetem - Klinikai Kozpont	Debrecen
Hungary	Veszprem Megyei Tudogyogyintezet Farkasgyepu	Farkasgyepu
Hungary	Bacs-Kiskun County Hospital	Kecskemét
Hungary	Hetenyi G Korhaz, Onkologiai Kozpont	Szolnok
Hungary	Pulmonology Hospital Torokbalint	Törökbálint
Israel	Rambam Health Care Campu	Haifa
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Rabin Medical Center	Petah tikva
Israel	The Chaim Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	A.O. SS. Antonio e Biagio e Cesare Arrigo di Alessandria	Alessandria
Italy	Azienda Ospedaliero Universitaria delle Marche	Ancona
Italy	IRCCS Centro di Riferimento Oncologico	Aviano
Italy	IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola Malpighi Oncologia medica	Bologna
Italy	Azienda Ospedaliera Univ. Policlinico G Rodolico San Marco	Catania
Italy	A.O. Santa Croce e Carle, Ospedale Carle	Cuneo
Italy	AOU Careggi	Florence
Italy	ASL 3 Genovese Oncologia Medica Villa Scassi	Genova
Italy	IRCCS Istituto Clinico Humanitas - Cancer Center	Milan
Italy	Universita degli Studi della Campania Luigi Vanvitelli	Napoli
Italy	Ospedale Maggiore di Novara	Novara
Italy	Azienda Ospedaliero-Universitaria San Luigi Gonzaga	Orbassano
Italy	Oncologia Medica II Istituto Oncologico Veneto IRCCS	Padova
Italy	Azienda USL di Piacenza	Piacenza
Italy	Irccs-Crob	Rionero In Vulture
Italy	Fondazione Policlinico Universitario Campus Bio-Medico	Roma
Italy	IFO Regina Elena	Roma
Italy	Azienda Ospedaliera Univ. Senese Policlinico Le Scotte	Siena
Italy	ASST Valtellina e Alto Lario Ospedale di Sondrio	Sondrio
Italy	ASST Sette Laghi	Varese
Japan	Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital	Bunkyo-Ku	Tokyo
Japan	Kyushu University Hospital	Fukuoka-shi	Fukuoka
Japan	Osaka Habikino Medical Center	Habikino	Osaka-Fu
Japan	Kansai Medical University Hospital	Hirakata-shi	Osaka
Japan	Hirosaki University Hospital	Hirosaki	Aomori
Japan	Izumi City General Hospital	Izumi	Osaka
Japan	Kanagawa Cancer Center	Izumi	Osaka
Japan	Kanazawa University Hospital	Kanazawa	Ishikawa
Japan	Kishiwada City Hospital	Kishiwada	Osaka
Japan	Kobe City Medical Center General Hospital	Kobe	Hyogo
Japan	The Cancer Institute Hospital Of JFCR	Koto-Ku	Tokyo
Japan	Ohara HealthCare Foundation Kurashiki Central Hospital	Kurashiki	Okayama
Japan	Sendai Kousei Hospital	Sendai	Miyagi
Japan	Center Hospital of the National Center for Global Health and Medicine	Shinjuku-Ku	Tokyo
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si
Korea, Republic of	CHA Bundang Medical Center, CHA University	Gyeonggi-do
Korea, Republic of	The Catholic University of Korea, St.Vincents Hospital	Gyeonggi-do
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Kangbuk Samsung Hospital	Seoul
Korea, Republic of	Seoul Metropolitan Government-Seoul National University Boramae Medical Center	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Poland	II Klinika Chorob Pluc i Gruzlicy	Bialystok
Poland	Szpitale Pomorskie Sp. z o.o., Oddzial Onkologii K	Gdynia
Poland	Wojewódzkie Wielospecjalistyczne Centrum Onkologii	Lódz
Poland	Specjalistyczna Praktyka Lekarska Slawomir Mandziuka	Lublin
Poland	Szpital Specjalistyczny w Prabutach Sp. z o.o	Prabuty
Poland	Mrukmed. Lekarz Beata Madej-Mruk i Partner. Sp.p	Rzeszów
Poland	Specjalistyczny Szpital Onkologiczny NU-MED sp. Z	Tomaszów Mazowiecki
Romania	Sc Oncopremium Team Srl	Baia Mare
Romania	Medisprof srl	Cluj-Napoca
Romania	Centrul de Oncologie Sfantu Nectarie	Craiova
Romania	Oncolab SRL	Craiova
Romania	Ovidius Clinical Hospital	Ovidiu
Romania	Oncocenter Oncologie clinica S.R.L	Timisoara
Spain	Hospital Teresa Herrera C.H.U.A.	A Coruña
Spain	Institut Català d Oncologia (ICO) - Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Reina Sofía	Córdoba
Spain	Institut Catala d'Oncologia (ICO) - Hospital Duran i Reynals	L'Hospitalet De Llobregat	Barcelona
Spain	Complejo Hospitalario Materno-Insular de Gran Canaria	Las Palmas De Gran Canaria	Gran Canaria
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	Clínica Universidad de Navarra	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Fundación Jimenez Díaz	Madrid
Spain	Hospital Universitario HM Sanchinarro	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	Hospital Regional Universitario Málaga Hospital Civil	Málaga
Spain	Clínica Universidad de Navarra	Pamplona	Navarra
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitari i Politècnic La Fe	Valencia
Spain	Hospital Clínico Universitario de Valladolid	Valladolid
Spain	Complexo Hospitalario Universitario De Vigo (CHUVI) - Hospital Xeral	Vigo	Pontevedra
Spain	Hospital Clínico Universitario Lozano Bleza	Zaragoza
Switzerland	University Hospital Basel	Basel
Switzerland	Istituto Oncologico della Svizzera Italiana	Bellinzona
Switzerland	Spital Thurgau - Kantonspital Frauenfeld	Frauenfeld
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Kantonsspital Baselland	Liestal
Switzerland	Spital Thurgau - Kantonsspital Muensterlingen	Münsterlingen
Switzerland	HFR Freiburg Kantonsspital	Villars-sur-Glâne
Taiwan	Changhua Christian Hospital	Chang Hua
Taiwan	Buddhist Dalin Tzu Chi Hospital	Dalin	Chiayi
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	National Taiwan University Cancer Center	Taipei
Taiwan	Linkou Chang Gung Memorial Hospital	Taoyuan
Turkey	Bagcilar Medipol Mega University Hospital	Bagcilar	Istambul
Turkey	Liv Hospital Ankara	Çankaya	Ankara
Turkey	Kocaeli University Hospital	Izmit	Kocaeli
Turkey	Goztepe Prof. Dr. Suleyman Yalcin City Hospital	Kadiköy	Istambul
Turkey	Medicalpark Seyhan Hospital	Seyhan	Adana
United Kingdom	Belfast Health and Social Care Trust	Belfast
United Kingdom	The Princess Alexandra Hospital	Harlow
United Kingdom	Guys and St Thomas NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Clatterbridge Hospital	Wirral
United Kingdom	The Royal Wolverhampton NHS Trust	Wolverhampton
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Ironwood Cancer & Research Centers	Chandler	Arizona
United States	Florida Cancer Specialists - South	Fort Myers	Florida
United States	Oncology Hematology West, PC (Grand Island)	Grand Island	Nebraska
United States	Genesis Cancer and Blood	Hot Springs	Arkansas
United States	Duly Health and Care	Joliet	Illinois
United States	Norton Cancer Institue, Downtown	Louisville	Kentucky
United States	Froedtert Hospital/Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Oncology Hematology West, PC dba Nebraska Cancer Specialists	Omaha	Nebraska
United States	FirstHealth Outpatient Cancer Center	Pinehurst	North Carolina
United States	Florida Cancer Specialists - North	Saint Petersburg	Florida
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	MultiCare Regional Cancer Center - Tacoma	Tacoma	Washington
United States	Florida Cancer Specialists - Panhandle	Tallahassee	Florida
United States	Florida Cancer Specialists - East	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
PharmaMar

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  Denmark,  France,  Georgia,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Poland,  Romania,  Spain,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Overall survival (OS) will be calculated from the date of randomization to the date of death or last contact (in this case, survival will be censored on that date).	From the date of randomization to the date of death or last contact, up to 39 months
Secondary	Progression-free survival by IRC (Independent Review Committee)	Progression-free survival (PFS) will be calculated from the date of randomization to the date of documented progression per RECIST v.1.1 (Progressive disease is declared when there is an increase in sum of target disease = 20%) or death (regardless of the cause of death). If the patient receives further antitumor therapy, withdraws from the study, or is lost to follow-up before progressive disease (PD), PFS will be censored at the date of last evaluable tumor assessment before the date of subsequent antitumor therapy.	From the date of randomization to the date of progressive disease, death or last tumor assessment or further anticancer treatment, up to 39 months
Secondary	Progression-free survival by IA (Investigator Assessment)	Progression-free survival (PFS) will be calculated from the date of randomization to the date of documented progression per RECIST v.1.1 (Progressive disease is declared when there is an increase in sum of target disease = 20%) or death (regardless of the cause of death). If the patient receives further antitumor therapy, withdraws from the study, or is lost to follow-up before progressive disease (PD), PFS will be censored at the date of last evaluable tumor assessment before the date of subsequent antitumor therapy.	From the date of randomization to the date of progressive disease, death or last tumor assessment or further anticancer treatment, up to 39 months
Secondary	Overall response rate by IRC	Overall response rate (ORR) will be the percentage of patients with complete or partial response as the best response obtained in any evaluation according to RECIST v.1.1. Progressive disease is declared when there is an increase in sum of target disease = 20%, stable disease when the change is > -30% and = 20%, partial response when there is a decrease in sum of target disease = 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.	From the date of randomization to the date of death or last contact, up to 39 months
Secondary	Overall response rate by IA	Overall response rate (ORR) will be the percentage of patients with complete or partial response as the best response obtained in any evaluation according to RECIST v.1.1. Progressive disease is declared when there is an increase in sum of target disease = 20%, stable disease when the change is > -30% and = 20%, partial response when there is a decrease in sum of target disease = 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.	From the date of randomization to the date of death or last contact, up to 39 months
Secondary	Overall survival rate at 12 months	Overall survival rate at 12 months is defined as the percentage of people who are still alive at 12 months after randomization.	At 12 months
Secondary	Overall survival rate at 24 months	Overall survival rate at 24 months is defined as the percentage of people who are still alive at 24 months after randomization.	At 24 months
Secondary	Progression-free survival rate at 6 months by IRC	Progression-free survival rate at 6 months is defined as the percentage of people who remain free from progression at 6 months after randomization	At 6 months
Secondary	Progression-free survival rate at 6 months by IA	Progression-free survival rate at 6 months is defined as the percentage of people who remain free from progression at 6 months after randomization	At 6 months
Secondary	Progression-free survival rate at 12 months by IRC	Progression-free survival rate at 12 months is defined as the percentage of people who remain free from progression at 12 months after randomization	At 12 months
Secondary	Progression-free survival rate at 12 months by IA	Progression-free survival rate at 12 months is defined as the percentage of people who remain free from progression at 12 months after randomization	At 12 months
Secondary	Duration of response by IRC	Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever occurs first) to the date of documented PD or death. Progressive disease is declared when there is an increase in sum of target disease = 20%, stable disease when the change is > -30% and = 20%, partial response when there is a decrease in sum of target disease = 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.	From the date of first documentation of complete or partial response to the date of documented progression disease, death or last contact, up to 39 months
Secondary	Duration of response by IA	Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever occurs first) to the date of documented PD or death. Progressive disease is declared when there is an increase in sum of target disease = 20%, stable disease when the change is > -30% and = 20%, partial response when there is a decrease in sum of target disease = 30%, and complete response when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each.	From the date of first documentation of complete or partial response to the date of documented progression disease, death or last contact, up to 39 months
Secondary	Patient-reported outcomes	To measure the quality of life of patients, the Lung Cancer Symptom Scale (LCSS) questionnaire will be analyzed.	At baseline and every six weeks (± one week) until end of treatment, up to 39 months