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

Completed · Phase 2

Conditions studied: Advanced Non-Small Cell Lung Cancer

In brief

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.

Key facts

Study ID

NCT03516981

Run by

Merck Sharp & Dohme LLC

People needed

245

Starts

2018-10-01

Expected to finish

2025-06-13

Last updated by the study team

2026-06-08

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• 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

You may not qualify if…

• 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

Where it is running

• 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
• Yale University School of Medicine ( Site 0100) — New Haven, Connecticut, United States
• Mayo Clinic Florida ( Site 0115) — Jacksonville, Florida, United States
• University of Maryland ( Site 0136) — Baltimore, Maryland, United States
• Mayo Clinic Rochester - St. Mary's Hospital ( Site 0117) — Rochester, Minnesota, United States
• John Theurer Cancer Center at Hackensack University Medical Center ( Site 0112) — Hackensack, New Jersey, 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
• Oncology Hematology Care ( Site 8005) — Cincinnati, Ohio, United States
• University of Pennsylvania ( Site 0132) — Philadelphia, Pennsylvania, United States
• UPMC Cancer Center/Hillman Cancer Center ( Site 0104) — Pittsburgh, Pennsylvania, United States
• Texas Oncology-Memorial City ( Site 8006) — Houston, Texas, United States
• Texas Oncology-Tyler ( Site 8003) — Tyler, Texas, United States
• Emily Couric Clinical Cancer Center ( Site 0134) — Charlottesville, Virginia, United States
• Northwest Cancer Specialists, P.C. ( Site 8000) — Vancouver, Washington, United States
• University of Wisconsin- Madison Carbone Cancer Center ( Site 0130) — Madison, Wisconsin, United States
• 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, Australia
• The Ottawa Hospital ( Site 0306) — Ottawa, Ontario, Canada
• Sunnybrook Health Science Centre ( Site 0304) — Toronto, Ontario, Canada
• Princess Margaret Cancer Centre ( Site 0309) — Toronto, Ontario, Canada
• Arizona Oncology Associates, PC- HAL ( Site 8001) — Tempe, Arizona, United States

Full record on ClinicalTrials.gov

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