A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (MK-3475-495/KEYNOTE-495)

Advanced Non-Small Cell Lung Cancer Clinical Trial

Official title:

A Phase 2 Precision Oncology Study of Biomarker-Directed, Pembrolizumab-(MK-3475, SCH 900475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (KEYNOTE-495; KeyImPaCT)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03516981
• Other study ID #: 3475-495
• Secondary ID: MK-3475-49519462
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 1, 2018
• Est. completion date: June 28, 2025

Study information

• Verified date: February 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will investigate the utility of biomarker-based triage for study participants with advanced non-small cell lung cancer (NSCLC) without prior systemic therapy. Study participants within groups defined by a biomarker-based classifier (gene expression profile [GEP] and tumor mutational burden [TMB]) will be randomized to receive pembrolizumab in combination with quavonlimab (MK-1308), favezelimab (MK-4280), or lenvatinib. The primary hypotheses are as follows: In participants receiving pembrolizumab in combination with either quavonlimab, favezelimab, or lenvatinib, the Objective Response Rate (ORR) will be 1) greater than 5% among participants with low GEP and low TMB, 2) greater than 20% among participants with low GEP and high TMB, 3) greater than 20% among participants with high GEP and low TMB, and 4) greater than 45% among participants with high GEP and high TMB.

Description:

After Amendment 5, participants can receive 800 mg of favezelimab every 3 weeks (Q3W)

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 318
• Est. completion date: June 28, 2025
• Est. primary completion date: June 28, 2025
• 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 (American Joint Committee on Cancer [AJCC] v 8) NSCLC and has not had prior systemic therapy for advanced disease
• Has confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1- (ROS1-), or B isoform of rapidly accelerated fibrosarcoma- (B-Raf-) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR mutations, B-Raf mutations, ALK gene rearrangements, and ROS1 gene rearrangements)
• Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology
• Male participants must agree to use contraception during the treatment period and for =120 days, after the last dose of study treatment and refrain from donating sperm during this period. Male participants with pregnant partners must agree to use a condom
• Female participants eligible to participate if not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to follow contraceptive guidance during the treatment period and for =120 days after the last dose of study treatment
• Provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Has adequate organ function

Exclusion Criteria:

• Has significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability, significant cardiovascular impairment, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram
• Prolongation of QTc interval to >480 milliseconds (ms)
• Has symptomatic ascites or pleural effusion
• Has had an allogenic tissue/solid organ transplant
• WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment
• Has not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy, or has had major surgery within 3 weeks prior to first dose of study intervention
• Has preexisting =Grade 3 gastrointestinal or non-gastrointestinal fistula, gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
• Radiographic evidence of major blood vessel invasion/infiltration
• Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
• Has received prior systemic chemotherapy treatment for metastatic/recurrent NSCLC
• Has current NSCLC disease that can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation
• Is expected to require any other form of systemic or localized antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection)
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T cell receptor
• Has received previous treatment with another agent targeting the Lymphocyte-activation gene 3 (LAG-3) receptor
• Has received previous treatment with another agent targeting vascular endothelial growth factor (VEGF) or the VEGF receptor
• Has received prior anticancer therapy including investigational agents within 4 weeks prior to randomization
• Has received prior radiotherapy within 2 weeks of start of study treatment or received lung radiation therapy of >30 Gy within 6 months prior to the first dose of study intervention
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study treatment
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has severe hypersensitivity (=Grade 3) to pembrolizumab, favezelimab, or lenvatinib and/or any of its excipients
• 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 history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study
• 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 (females and males) after the last dose of study treatment.

Related Conditions & MeSH terms

• Advanced Non-Small Cell Lung Cancer
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms

Intervention

Biological:
• Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion administered Q3W
• Favezelimab
200 mg or 800 mg favezelimab solution for IV infusion administered Q3W

Drug:
• Lenvatinib
20 mg lenvatinib capsules administered orally once daily
• Quavonlimab
Quavonlimab solution for IV infusion administered at the RP2D (dose and schedule based on study NCT03179436)

Locations

Country	Name	City	State
Australia	Blacktown Hospital Western Sydney Local Health District ( Site 0200)	Blacktown	New South Wales
Australia	Gallipoli Medical Research Foundation ( Site 0202)	Brisbane	Queensland
Australia	Fiona Stanley Hospital ( Site 0201)	Murdoch	Western Australia
Canada	CIUSSS du Saguenay-Lac-St-Jean ( Site 0305)	Chicoutimi	Quebec
Canada	CIUSSS Ouest de l Ile - St-Mary s Hospital ( Site 0310)	Montreal	Quebec
Canada	Jewish General Hospital ( Site 0307)	Montreal	Quebec
Canada	The Ottawa Hospital ( Site 0306)	Ottawa	Ontario
Canada	Princess Margaret Cancer Centre ( Site 0309)	Toronto	Ontario
Canada	Sunnybrook Health Science Centre ( Site 0304)	Toronto	Ontario
Hong Kong	Prince of Wales Hospital ( Site 1801)	Hong Kong
Hong Kong	Queen Mary Hospital ( Site 1800)	Hong Kong
Ireland	St James Hospital ( Site 2200)	Dublin
Ireland	Mid Western Cancer Centre ( Site 2201)	Limerick
Italy	AULSS21 Regione Veneto Ospedale Mater Salutis - Legnago ( Site 0701)	Legnago	Verona
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori ( Site 0702)	Meldola	Emilia-Romagna
Italy	Azienda Ospedaliera Papardo ( Site 0706)	Messina
Italy	Seconda Universita degli Studi di Napoli ( Site 0704)	Napoli
Italy	AOU San Luigi Gonzaga di Orbassano ( Site 0707)	Orbassano	Torino
Italy	Fondazione Policlinico Universitario A. Gemelli ( Site 0703)	Roma
Italy	Istituto Clinico Humanitas Research Hospital ( Site 0700)	Rozzano	Lombardia
Italy	Azienda Ospedaliera Universitaria Senese ( Site 0705)	Siena
Japan	National Cancer Center Hospital ( Site 2001)	Tokyo
Japan	The Cancer Institute Hospital of JFCR ( Site 2000)	Tokyo
Korea, Republic of	Seoul National University Bundang Hospital ( Site 0803)	Seongnam-si	Kyonggi-do
Korea, Republic of	Samsung Medical Center ( Site 0805)	Seoul
Korea, Republic of	Seoul National University Hospital ( Site 0800)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 0802)	Seoul
Korea, Republic of	Asan Medical Center ( Site 0801)	Songpa-gu	Seoul
Poland	MED-POLONIA Sp. z o.o. ( Site 0907)	Poznan	Wielkopolskie
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie (	Warszawa	Mazowieckie
Poland	Dolnoslaskie Centrum Onkologii. ( Site 0993)	Wroclaw	Dolnoslaskie
Russian Federation	Republican Clinical Oncology Dispensary of Tatarstan MoH ( Site 1005)	Kazan	Tatarstan, Respublika
Russian Federation	N.N. Blokhin NMRCO ( Site 1000)	Moscow	Moskva
Russian Federation	The Loginov Moscow Clinical Scientific Center ( Site 1008)	Moscow	Moskva
Russian Federation	Budgetary Healthcare Institution of Omsk Region Clinical Oncology Dispensary-Chemotherapy #1 ( Site	Omsk	Omskaya Oblast
Russian Federation	SBHI Leningrad Regional Clinical Hospital ( Site 1001)	Saint Petersburg	Sankt-Peterburg
Russian Federation	St Petersburg City Clinical Oncology Dispensary ( Site 1002)	St. Petersburg	Sankt-Peterburg
Russian Federation	Republican Clinical Oncology Dispensary of Republic of Bashkortostan ( Site 1003)	Ufa	Baskortostan, Respublika
Singapore	National Cancer Centre Singapore ( Site 1900)	Singapore	Central Singapore
Singapore	National University Hospital ( Site 1901)	Singapore	South West
South Africa	MPOC ( Site 2310)	Groenkloof Pretoria	Gauteng
South Africa	Cape Town Oncology Trials Pty Ltd ( Site 2312)	Kraaifontein	Western Cape
South Africa	Wits Clinical Research ( Site 2313)	Parktown-Johannesburg	Gauteng
South Africa	Univ. Pretoria and Steve Biko Academic Hospitals ( Site 2315)	Pretoria	Gauteng
South Africa	Sandton Oncology Medical Group PTY LTD ( Site 2316)	Sandton	Gauteng
South Africa	Umhlanga Oncolgy Center ( Site 2311)	Umhlanga	Kwazulu-Natal
South Africa	Vaal Triangle Oncology Centre ( Site 2314)	Vereeniging	Gauteng
Spain	Hospital General Universitari Vall d Hebron ( Site 1100)	Barcelona
Spain	Hospital Universitario 12 de Octubre ( Site 1102)	Madrid
Spain	Hospital Universitario Ramon y Cajal ( Site 1101)	Madrid
Switzerland	Universitaetsspital Basel ( Site 2104)	Basel	Basel-Stadt
Switzerland	Kantonsspital Graubuenden ( Site 2103)	Chur	Grisons
Switzerland	Hopitaux Universitaires de Geneve HUG ( Site 2106)	Geneva	Geneve
Switzerland	Kantonsspital St. Gallen ( Site 2102)	St. Gallen	Aargau
Switzerland	Universitaetsspital Zuerich ( Site 2100)	Zuerich	Zurich
Taiwan	Kaohsiung Chang Gung Memorial Hospital ( Site 1203)	Kaohsiung
Taiwan	National Cheng Kung University Hospital ( Site 1202)	Tainan
Taiwan	National Taiwan University Hospital ( Site 1200)	Taipei
Taiwan	Taipei Veterans General Hospital ( Site 1204)	Taipei
United Kingdom	Cambridge University Hospitals NHS Trust ( Site 1306)	Cambridge	Cambridgeshire
United Kingdom	University College London Hospital NHS Foundation Trust ( Site 1308)	London	London, City Of
United Kingdom	Derriford Hospital ( Site 1301)	Plymouth
United States	University of Maryland ( Site 0136)	Baltimore	Maryland
United States	Emily Couric Clinical Cancer Center ( Site 0134)	Charlottesville	Virginia
United States	Oncology Hematology Care ( Site 8005)	Cincinnati	Ohio
United States	John Theurer Cancer Center at Hackensack University Medical Center ( Site 0112)	Hackensack	New Jersey
United States	Texas Oncology-Memorial City ( Site 8006)	Houston	Texas
United States	Mayo Clinic Florida ( Site 0115)	Jacksonville	Florida
United States	University of Wisconsin- Madison Carbone Cancer Center ( Site 0130)	Madison	Wisconsin
United States	Yale University School of Medicine ( Site 0100)	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center ( Site 0113)	New York	New York
United States	Weill Cornell Medical College ( Site 0138)	New York	New York
United States	University of Pennsylvania ( Site 0132)	Philadelphia	Pennsylvania
United States	UPMC Cancer Center/Hillman Cancer Center ( Site 0104)	Pittsburgh	Pennsylvania
United States	Mayo Clinic Rochester - St. Mary's Hospital ( Site 0117)	Rochester	Minnesota
United States	University of California Davis Comprehensive Cancer Center ( Site 0137)	Sacramento	California
United States	University of California San Francisco ( Site 0111)	San Francisco	California
United States	UCLA Hematology/Oncology -Santa Monica ( Site 0108)	Santa Monica	California
United States	Arizona Oncology Associates, PC- HAL ( Site 8001)	Tempe	Arizona
United States	Texas Oncology-Tyler ( Site 8003)	Tyler	Texas
United States	Northwest Cancer Specialists, P.C. ( Site 8000)	Vancouver	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Hong Kong,  Ireland,  Italy,  Japan,  Korea, Republic of,  Poland,  Russian Federation,  Singapore,  South Africa,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

References & Publications (1)

Gutierrez M, Lam WS, Hellmann MD, Gubens MA, Aggarwal C, Tan DSW, Felip E, Chiu JWY, Lee JS, Yang JC, Garon EB, Finocchiaro G, Ahn MJ, Luft A, Landers GA, Basso A, Ma H, Kobie J, Palcza J, Cristescu R, Fong L, Snyder A, Yuan J, Herbst RS. Biomarker-direct — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)	ORR was defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline sum diameters) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by local site.	Up to ~2 years
Secondary	Progression Free Survival (PFS) per RECIST 1.1	PFS is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by local site.	Up to ~2 years
Secondary	Overall Survival (OS)	OS is defined as the time from randomization to death due to any cause.	Up to ~2 years
Secondary	Number of Participants Experiencing Adverse Events (AEs)	An AE is any untoward medical occurrence in participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants in each treatment arm experiencing an AE will be reported.	Up to ~2 years
Secondary	Number of Participants Discontinuing Study Drug Due to AEs	An AE is any untoward medical occurrence in participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants in each treatment arm that discontinued study drug due to an AE will be reported.	Up to ~2 years

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary