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)
- Trial ID
- 2022-500990-16-00
- Protocol
- MK-3475-495
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **clinical activity** of specific pembrolizumab-based combinations in patients with advanced non-small cell lung cancer, as assessed by the objective response rate (ORR). This is clinically relevant as it aims to determine the efficacy of pembrolizumab in combination therapies, potentially leading to improved treatment outcomes for patients with this advanced stage of cancer.
Secondary objectives include:
- Evaluating the clinical activity of specific pembrolizumab-based combinations by assessing progression-free survival (PFS) and overall survival (OS). These metrics will be independently assessed in each biomarker-defined group, providing insights into the long-term benefits and survival outcomes associated with these therapies.
- Determining the safety and tolerability of pembrolizumab in combination with MK-1308, MK-4280, or lenvatinib. Safety and tolerability will also be independently assessed in each biomarker-defined group, ensuring a comprehensive understanding of the risk profile associated with these combination therapies.
Participants
The clinical trial involves a total of **182 participants** diagnosed with **Stage IV non-small cell lung cancer**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific criteria, including a histologically- or cytologically-confirmed diagnosis of Stage IV NSCLC, and the absence of certain genetic mutations that would indicate alternative primary therapies. All participants have measurable disease as per RECIST 1.1 guidelines and maintain an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population, and participants are required to have adequate organ function. Lifestyle considerations such as diet and physical activity are not specified, but male participants must agree to use contraception and refrain from donating sperm during and after the treatment period, while female participants must not be pregnant or breastfeeding and must adhere to contraceptive guidance if of childbearing potential.
Plans and Procedures
The clinical trial is designed to evaluate the **clinical activity** of pembrolizumab-based combination therapies in patients with **Stage IV non-small cell lung cancer**. This is a Phase II, randomized, double-blind, controlled study aimed at assessing the **objective response rate** (ORR) as the primary endpoint, with secondary endpoints including **progression-free survival** (PFS), **overall survival** (OS), and the incidence of adverse events (AEs). The trial is expected to run from December 2018 to June 2025, with participant involvement lasting up to 78 weeks, depending on the treatment arm.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of Stage IV non-small cell lung cancer, measurable disease per RECIST 1.1, and adequate organ function. Following the screening, participants will be randomized to receive either the investigational combination therapy or a control. The investigational products include **lenvatinib** (administered orally), **quavonlimab**, **pembrolizumab**, and **favezelimab** (administered via intravenous infusion). The maximum treatment period for these therapies ranges from 24 to 78 weeks, depending on the specific regimen.
Study visits will include regular follow-up assessments to monitor the efficacy and safety of the treatment, with evaluations conducted according to RECIST 1.1 criteria. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent by the participant. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Lenvatinib** is provided in a capsule form, with a maximum daily dose of 20 mg. It is administered orally, and the treatment period can extend up to 78 weeks. The total maximum dose for the duration of the study is 47,660 mg. Lenvatinib is a chemical substance developed by Merck & Co. Inc., and it is not formulated for pediatric use.
**Quavonlimab** is administered as a solution for infusion, with a maximum daily dose of 25 mg. The route of administration is intravenous infusion, and the treatment period is limited to 24 weeks, with a total maximum dose of 425 mg. Quavonlimab is an immunological protein-based substance, specifically a humanized monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4, developed by Merck & Co. Inc.
**Pembrolizumab**, marketed as KEYTRUDA, is provided as a concentrate for solution for infusion. The maximum daily dose is 200 mg, administered via intravenous infusion. The treatment period is 24 weeks, with a total maximum dose of 7,000 mg. Pembrolizumab is a biological protein-based substance, also developed by Merck Sharp & Dohme B.V., and is not intended for pediatric use.
**Favezelimab** is another solution for infusion, with a maximum daily dose of 800 mg. It is administered intravenously, with a treatment period of 24 weeks and a total maximum dose of 28,000 mg. Favezelimab is an immunological protein-based substance, specifically an anti-LAG3 monoclonal antibody, developed by Merck & Co. Inc.
Throughout the study, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the clinical activity of these pembrolizumab-based combinations in the treatment of advanced non-small cell lung cancer.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, as determined by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). This primary endpoint will evaluate the clinical activity of pembrolizumab-based combination therapies in patients with advanced non-small cell lung cancer (NSCLC). Secondary endpoints include **Progression Free Survival (PFS)**, **Overall Survival (OS)**, the number of participants experiencing adverse events (AEs), and the number of participants discontinuing the study drug due to AEs. These endpoints will provide a comprehensive assessment of the treatment's efficacy and safety profile.
Measurements will be conducted at specified intervals throughout the trial, with data collection and analysis adhering to standardized protocols to ensure accuracy and reliability. The trial aims to provide insights into the efficacy of pembrolizumab-based therapies, contributing to the understanding of treatment outcomes in advanced NSCLC.
Inclusion and Exclusion 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 19 Dec 2018 | 32 |
 Poland | Not Recruiting | 19 Dec 2018 | 30 |
 Spain | Not Recruiting | 19 Dec 2018 | 22 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
favezelimab | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 800 | 24 | PRD6003525 |
quavonlimab | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 25 | 24 | PRD6003431 |
Lenvatinib | Test | CAPSULE | ORAL USE | 20 | 78 | PRD9414231 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 24 | PRD4323105 |
Lenvatinib | Test | CAPSULE | ORAL USE | 20 | 78 | PRD9414230 |