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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03516981




Registration number
NCT03516981
Ethics application status
Date submitted
27/04/2018
Date registered
7/05/2018
Date last updated
26/02/2024

Titles & IDs
Public title
A Study of Biomarker-Directed, Pembrolizumab (MK-3475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (MK-3475-495/KEYNOTE-495)
Scientific 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)
Secondary ID [1] 0 0
MK-3475-495
Secondary ID [2] 0 0
3475-495
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Non-Small Cell Lung Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Pembrolizumab
Treatment: Other - Favezelimab
Treatment: Drugs - Lenvatinib
Treatment: Drugs - Quavonlimab

Experimental: GEP low TMB low: Pembrolizumab + Quavonlimab - Participants receive pembrolizumab 200 mg Q3W plus quavonlimab at the Recommended Phase 2 Dose (\[RP2D\], dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP low TMB low: Pembrolizumab + Favezelimab - Participants receive pembrolizumab 200 mg Q3W plus favezelimab 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP low TMB low: Pembrolizumab + Lenvatinib - Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.

Experimental: GEP low TMB hi: Pembrolizumab + Quavonlimab - Participants receive pembrolizumab 200 mg Q3W plus quavonlimab at the RP2D (dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP low TMB hi: Pembrolizumab + Favezelimab - Participants receive pembrolizumab 200 mg Q3W plus favezelimab 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP low TMB hi: Pembrolizumab + Lenvatinib - Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.

Experimental: GEP hi TMB low: Pembrolizumab + Quavonlimab - Participants receive pembrolizumab 200 mg Q3W plus quavonlimab at the RP2D (dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP hi TMB low: Pembrolizumab + Favezelimab - Participants receive pembrolizumab 200 mg Q3W plus favezelimab 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP hi TMB low: Pembrolizumab + Lenvatinib - Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.

Experimental: GEP hi TMB hi: Pembrolizumab + Quavonlimab - Participants receive pembrolizumab 200 mg Q3W plus quavonlimab at the RP2D (dose and schedule based on study NCT03179436) until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP hi TMB hi: Pembrolizumab + Favezelimab - Participants receive pembrolizumab 200 mg Q3W plus favezelimab 200 mg or 800 mg Q3W until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years).

Experimental: GEP hi TMB hi: Pembrolizumab + Lenvatinib - Participants receive pembrolizumab 200 mg Q3W plus lenvatinib 20 mg once daily until disease progression, or until the participant has received 35 administrations of pembrolizumab (approximately 2 years). Participants completing 35 infusions of pembrolizumab may continue with lenvatinib alone until disease progression or toxicity.


Treatment: Other: Pembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion administered Q3W

Treatment: Other: Favezelimab
200 mg or 800 mg favezelimab solution for IV infusion administered Q3W

Treatment: Drugs: Lenvatinib
20 mg lenvatinib capsules administered orally once daily

Treatment: Drugs: Quavonlimab
Quavonlimab solution for IV infusion administered at the RP2D (dose and schedule based on study NCT03179436)
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)
Timepoint [1] 0 0
Up to ~2 years
Secondary outcome [1] 0 0
Progression Free Survival (PFS) per RECIST 1.1
Timepoint [1] 0 0
Up to ~2 years
Secondary outcome [2] 0 0
Overall Survival (OS)
Timepoint [2] 0 0
Up to ~2 years
Secondary outcome [3] 0 0
Number of Participants Experiencing Adverse Events (AEs)
Timepoint [3] 0 0
Up to ~2 years
Secondary outcome [4] 0 0
Number of Participants Discontinuing Study Drug Due to AEs
Timepoint [4] 0 0
Up to ~2 years

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/10/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
28/06/2025
Actual
Sample size
Target
318
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
Blacktown Hospital Western Sydney Local Health District ( Site 0200) - Blacktown
Recruitment hospital [2] 0 0
Gallipoli Medical Research Foundation ( Site 0202) - Brisbane
Recruitment hospital [3] 0 0
Fiona Stanley Hospital ( Site 0201) - Murdoch
Recruitment postcode(s) [1] 0 0
2148 - Blacktown
Recruitment postcode(s) [2] 0 0
4120 - Brisbane
Recruitment postcode(s) [3] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Maryland
Country [6] 0 0
United States of America
State/province [6] 0 0
Minnesota
Country [7] 0 0
United States of America
State/province [7] 0 0
New Jersey
Country [8] 0 0
United States of America
State/province [8] 0 0
New York
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
United States of America
State/province [12] 0 0
Virginia
Country [13] 0 0
United States of America
State/province [13] 0 0
Washington
Country [14] 0 0
United States of America
State/province [14] 0 0
Wisconsin
Country [15] 0 0
Canada
State/province [15] 0 0
Ontario
Country [16] 0 0
Canada
State/province [16] 0 0
Quebec
Country [17] 0 0
Hong Kong
State/province [17] 0 0
Hong Kong
Country [18] 0 0
Ireland
State/province [18] 0 0
Dublin
Country [19] 0 0
Ireland
State/province [19] 0 0
Limerick
Country [20] 0 0
Italy
State/province [20] 0 0
Emilia-Romagna
Country [21] 0 0
Italy
State/province [21] 0 0
Lombardia
Country [22] 0 0
Italy
State/province [22] 0 0
Torino
Country [23] 0 0
Italy
State/province [23] 0 0
Verona
Country [24] 0 0
Italy
State/province [24] 0 0
Messina
Country [25] 0 0
Italy
State/province [25] 0 0
Napoli
Country [26] 0 0
Italy
State/province [26] 0 0
Roma
Country [27] 0 0
Italy
State/province [27] 0 0
Siena
Country [28] 0 0
Japan
State/province [28] 0 0
Tokyo
Country [29] 0 0
Korea, Republic of
State/province [29] 0 0
Kyonggi-do
Country [30] 0 0
Korea, Republic of
State/province [30] 0 0
Seoul
Country [31] 0 0
Poland
State/province [31] 0 0
Dolnoslaskie
Country [32] 0 0
Poland
State/province [32] 0 0
Mazowieckie
Country [33] 0 0
Poland
State/province [33] 0 0
Wielkopolskie
Country [34] 0 0
Russian Federation
State/province [34] 0 0
Baskortostan, Respublika
Country [35] 0 0
Russian Federation
State/province [35] 0 0
Moskva
Country [36] 0 0
Russian Federation
State/province [36] 0 0
Omskaya Oblast
Country [37] 0 0
Russian Federation
State/province [37] 0 0
Sankt-Peterburg
Country [38] 0 0
Russian Federation
State/province [38] 0 0
Tatarstan, Respublika
Country [39] 0 0
Singapore
State/province [39] 0 0
Central Singapore
Country [40] 0 0
Singapore
State/province [40] 0 0
South West
Country [41] 0 0
South Africa
State/province [41] 0 0
Gauteng
Country [42] 0 0
South Africa
State/province [42] 0 0
Kwazulu-Natal
Country [43] 0 0
South Africa
State/province [43] 0 0
Western Cape
Country [44] 0 0
Spain
State/province [44] 0 0
Barcelona
Country [45] 0 0
Spain
State/province [45] 0 0
Madrid
Country [46] 0 0
Switzerland
State/province [46] 0 0
Aargau
Country [47] 0 0
Switzerland
State/province [47] 0 0
Basel-Stadt
Country [48] 0 0
Switzerland
State/province [48] 0 0
Geneve
Country [49] 0 0
Switzerland
State/province [49] 0 0
Grisons
Country [50] 0 0
Switzerland
State/province [50] 0 0
Zurich
Country [51] 0 0
Taiwan
State/province [51] 0 0
Kaohsiung
Country [52] 0 0
Taiwan
State/province [52] 0 0
Tainan
Country [53] 0 0
Taiwan
State/province [53] 0 0
Taipei
Country [54] 0 0
United Kingdom
State/province [54] 0 0
Cambridgeshire
Country [55] 0 0
United Kingdom
State/province [55] 0 0
London, City Of
Country [56] 0 0
United Kingdom
State/province [56] 0 0
Plymouth

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT03516981
Trial related presentations / publications
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.
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03516981