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


About this study

The purpose of this study is to 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 MK-4280 or lenvatinib. The primary hypotheses are as follows: In participants receiving pembrolizumab in combination with either MK-4280 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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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 or B-Raf mutations AND absence of ALK or ROS1 gene rearrangements).
  • Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
  • Male/female participants who are at least 18 years of age on the day of signing the informed consent.
  • 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.
  • The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main study without participating in Future Biomedical Research.
  • Provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. 
    • Note:  If sending newly cut slides, they should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Procedures Manual).
  • Participants must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization.
  • Has an Eastern Cooperative  Oncology Group (ECOG) performance status of 0 to 1.
  • Has adequate organ function as defined below:
  • Hematological
    • Absolute neutrophil count (ANC) ≥1500/μL;
    • Platelets ≥00 000/μL;
    • Hemoglobin ≥.0 g/dL or ≥.6 mmol/L*.
  • Renal
    • Creatinine OR Measured or calculated** creatinine clearance (GFR can also be used in place of creatinine or CrCl);
    • ≤1.5 × ULN OR ≥0 mL/min for participant with creatinine levels >1.5 × institutional ULN.
  • Hepatic
    • Total bilirubin ≤.5 ×ULN OR direct bilirubin ≤LN for participants with total bilirubin levels >1.5 × ULN;
    • AST (SGOT) and ALT (SGPT) ≤.5 × ULN (≤ × ULN for participants with liver metastases).
  • Coagulation
    • International normalized ratio (INR) OR prothrombin time (PT);
    • Activated partial thromboplastin time (aPTT) ≤.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal;
  • Specimens must be collected within 10 days prior to the start of study treatment.

* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

** Creatinine clearance (CrCl) should be calculated per institutional standard.

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. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
  • Has had an allogenic tissue/solid organ transplant.
  • A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment (see Appendix 5). If the urine test cannot be confirmed as negative, a serum pregnancy test will be required.
    • Note: in the event that 24 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for participant to start receiving study medication.
  • Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥ 1 g/24 h will be ineligible.
  • Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. Participants who have had major surgery within 3 weeks prior to first dose of study intervention.
    • Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
  • 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. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
  • 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.
    • Note: Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of 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 (e.g., CTLA-4, OX 40, CD137).
  • Has received previous treatment with another agent targeting the LAG-3 receptor.
  • Has received previous treatment with another agent targeting VEGF or the VEGF receptor.
  • Has received prior anticancer therapy including investigational agents within 4 weeks prior to randomization.
    • Note: Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
    • Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
  • 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. Participants must have recovered from all radiation-related toxicities to Grade ≤1, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
  • Has received a live vaccine within 30 days prior to the first dose of study treatment.
    • Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Aaron Mansfield, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Yanyan Lou, M.D., Ph.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information


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Additional contact information

Cancer-related trials contact form

Phone: 855-776-0015 (toll-free)

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