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

• ClinicalTrials.gov Identifier: NCT03516981
• Recruitment Status: Active, not recruiting
• First Posted: May 7, 2018
• Last Update Posted: August 26, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: April 27, 2018
• First Posted Date: May 7, 2018
• Last Update Posted Date: August 26, 2022
• Actual Study Start Date: October 1, 2018
• Estimated Primary Completion Date: June 28, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 27, 2018)

Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) [ Time Frame: Up to ~2 years ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 27, 2018)

• Progression Free Survival (PFS) per RECIST 1.1 [ Time Frame: Up to ~2 years ]
  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.
• Overall Survival (OS) [ Time Frame: Up to ~2 years ]
  OS is defined as the time from randomization to death due to any cause.
• Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to ~2 years ]
  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.
• Number of Participants Discontinuing Study Drug Due to AEs [ Time Frame: Up to ~2 years ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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)
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Non-Small Cell Lung Cancer

Intervention

• Biological: Pembrolizumab
  200 mg pembrolizumab solution for intravenous (IV) infusion administered Q3W
  Other Name: MK-3475
• Biological: Favezelimab
  200 mg or 800 mg favezelimab solution for IV infusion administered Q3W
  Other Name: MK-4280
• Drug: Lenvatinib
  20 mg lenvatinib capsules administered orally once daily
  Other Name: MK-7902
• Drug: Quavonlimab
  Quavonlimab solution for IV infusion administered at the RP2D (dose and schedule based on study NCT03179436)
  Other Name: MK-1308

Study Arms

• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Quavonlimab
• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Favezelimab
• 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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Lenvatinib
• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Quavonlimab
• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Favezelimab
• 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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Lenvatinib
• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Quavonlimab
• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Favezelimab
• 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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Lenvatinib
• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Quavonlimab
• 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).
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Favezelimab
• 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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Lenvatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: September 30, 2019): 318
• Original Estimated Enrollment (submitted: April 27, 2018): 288
• Estimated Study Completion Date: June 28, 2025
• Estimated Primary Completion Date: June 28, 2025 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Hong Kong, Ireland, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Singapore, South Africa, Spain, Switzerland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT03516981
• Other Study ID Numbers: 3475-495; MK-3475-495 ( Other Identifier: Merck Protocol Number ); 194621 ( Registry Identifier: Japic-CTI ); KEYNOTE-495 ( Other Identifier: Merck ); 2022-500990-16-00 ( Registry Identifier: EU CT Number ); 2017-003134-85 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: August 2022