Clinical trial NCT03516981: A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (MK-3475-495/KEYNOTE-495)
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Advanced Non-Small Cell Lung Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-05-07
Enrollment: 318
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)
timeFrame: Up to ~2 years
Secondary outcomes:
measure: Progression Free Survival (PFS) per RECIST 1.1
timeFrame: Up to ~2 years
measure: Overall Survival (OS)
timeFrame: Up to ~2 years
measure: Number of Participants Experiencing Adverse Events (AEs)
timeFrame: Up to ~2 years
measure: Number of Participants Discontinuing Study Drug Due to AEs
timeFrame: Up to ~2 years
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Arizona Oncology Associates, PC- HAL ( Site 8001)
state: Arizona
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center ( Site 0137)
state: California
city: San Francisco
country: United States
facility: University of California San Francisco ( Site 0111)
state: California
city: Santa Monica
country: United States
facility: UCLA Hematology/Oncology -Santa Monica ( Site 0108)
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine ( Site 0100)
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Florida ( Site 0115)
state: Florida
city: Baltimore
country: United States
facility: University of Maryland ( Site 0136)
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic Rochester - St. Mary's Hospital ( Site 0117)
state: Minnesota
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center ( Site 0112)
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center ( Site 0113)
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College ( Site 0138)
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care ( Site 8005)
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania ( Site 0132)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Center/Hillman Cancer Center ( Site 0104)
state: Pennsylvania
city: Houston
country: United States
facility: Texas Oncology-Memorial City ( Site 8006)
state: Texas
city: Tyler
country: United States
facility: Texas Oncology-Tyler ( Site 8003)
state: Texas
city: Charlottesville
country: United States
facility: Emily Couric Clinical Cancer Center ( Site 0134)
state: Virginia
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C. ( Site 8000)
state: Washington
city: Madison
country: United States
facility: University of Wisconsin- Madison Carbone Cancer Center ( Site 0130)
state: Wisconsin
city: Blacktown
country: Australia
facility: Blacktown Hospital Western Sydney Local Health District ( Site 0200)
state: New South Wales
city: Brisbane
country: Australia
facility: Gallipoli Medical Research Foundation ( Site 0202)
state: Queensland
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital ( Site 0201)
state: Western Australia
city: Ottawa
country: Canada
facility: The Ottawa Hospital ( Site 0306)
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Science Centre ( Site 0304)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0309)
state: Ontario
city: Chicoutimi
country: Canada
facility: CIUSSS du Saguenay-Lac-St-Jean ( Site 0305)
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital ( Site 0307)
state: Quebec
city: Montreal
country: Canada
facility: CIUSSS Ouest de l Ile - St-Mary s Hospital ( Site 0310)
state: Quebec
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital ( Site 1801)
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital ( Site 1800)
city: Dublin
country: Ireland
facility: St James Hospital ( Site 2200)
city: Limerick
country: Ireland
facility: Mid Western Cancer Centre ( Site 2201)
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori ( Site 0702)
state: Emilia-Romagna
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas Research Hospital ( Site 0700)
state: Lombardia
city: Orbassano
country: Italy
facility: AOU San Luigi Gonzaga di Orbassano ( Site 0707)
state: Torino
city: Legnago
country: Italy
facility: AULSS21 Regione Veneto Ospedale Mater Salutis - Legnago ( Site 0701)
state: Verona
city: Messina
country: Italy
facility: Azienda Ospedaliera Papardo ( Site 0706)
city: Napoli
country: Italy
facility: Seconda Universita degli Studi di Napoli ( Site 0704)
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli ( Site 0703)
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese ( Site 0705)
city: Tokyo
country: Japan
facility: National Cancer Center Hospital ( Site 2001)
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR ( Site 2000)
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital ( Site 0803)
state: Kyonggi-do
city: Songpa-gu
country: Korea, Republic of
facility: Asan Medical Center ( Site 0801)
state: Seoul
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital ( Site 0800)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 0802)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 0805)
city: Wroclaw
country: Poland
facility: Dolnoslaskie Centrum Onkologii. ( Site 0993)
state: Dolnoslaskie
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie (
state: Mazowieckie
city: Poznan
country: Poland
facility: MED-POLONIA Sp. z o.o. ( Site 0907)
state: Wielkopolskie
city: Ufa
country: Russian Federation
facility: Republican Clinical Oncology Dispensary of Republic of Bashkortostan ( Site 1003)
state: Baskortostan, Respublika
city: Moscow
country: Russian Federation
facility: The Loginov Moscow Clinical Scientific Center ( Site 1008)
state: Moskva
city: Moscow
country: Russian Federation
facility: N.N. Blokhin NMRCO ( Site 1000)
state: Moskva
city: Omsk
country: Russian Federation
facility: Budgetary Healthcare Institution of Omsk Region Clinical Oncology Dispensary-Chemotherapy #1 ( Site
state: Omskaya Oblast
city: Saint Petersburg
country: Russian Federation
facility: SBHI Leningrad Regional Clinical Hospital ( Site 1001)
state: Sankt-Peterburg
city: St. Petersburg
country: Russian Federation
facility: St Petersburg City Clinical Oncology Dispensary ( Site 1002)
state: Sankt-Peterburg
city: Kazan
country: Russian Federation
facility: Republican Clinical Oncology Dispensary of Tatarstan MoH ( Site 1005)
state: Tatarstan, Respublika
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore ( Site 1900)
state: Central Singapore
city: Singapore
country: Singapore
facility: National University Hospital ( Site 1901)
state: South West
city: Groenkloof Pretoria
country: South Africa
facility: MPOC ( Site 2310)
state: Gauteng
city: Parktown-Johannesburg
country: South Africa
facility: Wits Clinical Research ( Site 2313)
state: Gauteng
city: Pretoria
country: South Africa
facility: Univ. Pretoria and Steve Biko Academic Hospitals ( Site 2315)
state: Gauteng
city: Sandton
country: South Africa
facility: Sandton Oncology Medical Group PTY LTD ( Site 2316)
state: Gauteng
city: Vereeniging
country: South Africa
facility: Vaal Triangle Oncology Centre ( Site 2314)
state: Gauteng
city: Umhlanga
country: South Africa
facility: Umhlanga Oncolgy Center ( Site 2311)
state: Kwazulu-Natal
city: Kraaifontein
country: South Africa
facility: Cape Town Oncology Trials Pty Ltd ( Site 2312)
state: Western Cape
city: Barcelona
country: Spain
facility: Hospital General Universitari Vall d Hebron ( Site 1100)
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal ( Site 1101)
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre ( Site 1102)
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen ( Site 2102)
state: Aargau
city: Basel
country: Switzerland
facility: Universitaetsspital Basel ( Site 2104)
state: Basel-Stadt
city: Geneva
country: Switzerland
facility: Hopitaux Universitaires de Geneve HUG ( Site 2106)
state: Geneve
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden ( Site 2103)
state: Grisons
city: Zuerich
country: Switzerland
facility: Universitaetsspital Zuerich ( Site 2100)
state: Zurich
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang Gung Memorial Hospital ( Site 1203)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital ( Site 1202)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital ( Site 1200)
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital ( Site 1204)
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Trust ( Site 1306)
state: Cambridgeshire
city: London
country: United Kingdom
facility: University College London Hospital NHS Foundation Trust ( Site 1308)
state: London, City Of
city: Plymouth
country: United Kingdom
facility: Derriford Hospital ( Site 1301)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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-directed, pembrolizumab-based combination therapy in non-small cell lung cancer: phase 2 KEYNOTE-495/KeyImPaCT trial interim results. Nat Med. 2023 Jul;29(7):1718-1727. doi: 10.1038/s41591-023-02385-6. Epub 2023 Jul 10.