Advanced Non-Small Cell Lung Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
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)
Interventions
BIOLOGICALPembrolizumab
200 mg pembrolizumab solution for intravenous (IV) infusion administered Q3W
BIOLOGICALFavezelimab
200 mg or 800 mg favezelimab solution for IV infusion administered Q3W
DRUGLenvatinib
20 mg lenvatinib capsules administered orally once daily
DRUGQuavonlimab
Quavonlimab solution for IV infusion administered at the RP2D (dose and schedule based on study NCT03179436)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 80 months | 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 radiologic review. The percentage of participants who experience CR or PR as assessed by local site radiologic review with confirmatory assessment per RECIST 1.1 is presented. Participants were assigned to 1 of 4 biomarker-defined groups (GEP low/TMB low, GEP low/TMB high, GEP high/TMB low, and GEP high/TMB high) and randomized within-group to receive a combination treatment of study interventions. Per protocol, no participants within GEP Low/TMB Low biomarker group were assigned to receive Pembrolizumab + Favezelimab 800 mg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Up to approximately 80 months | PFS was defined as the time from allocation to the first documented progressive disease (PD) or death due to any cause, whichever occurs first according to Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by local site radiologic review. PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. The PFS for all participants is presented. Participants were assigned to 1 of 4 biomarker-defined groups (GEP low/TMB low, GEP low/TMB high, GEP high/TMB low, and GEP high/TMB high) and randomized within-group to receive a combination treatment of study interventions. Per protocol, no participants within GEP Low/TMB Low biomarker group were assigned to receive Pembrolizumab + Favezelimab 800 mg. |
| Overall Survival (OS) | Up to approximately 80 months | OS was defined as the time from the date of allocation to death due to any cause. The OS for all participants is presented. Participants were assigned to 1 of 4 biomarker-defined groups (GEP low/TMB low, GEP low/TMB high, GEP high/TMB low, and GEP high/TMB high) and randomized within-group to receive a combination treatment of study interventions. Per protocol, no participants within GEP Low/TMB Low biomarker group were assigned to receive Pembrolizumab + Favezelimab 800 mg. |
| Number of Participants Experiencing Adverse Events (AEs) | Up to approximately 80 months | An AE was defined as 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 is reported. |
| Number of Participants Discontinuing Study Drug Due to AEs | Up to approximately 39 months | An AE was defined as 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 is reported. |
Countries
Australia, Canada, Hong Kong, Ireland, Italy, Japan, Poland, Russia, Singapore, South Africa, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
Participants were screened for the status of 2 clinically validated, independent next generation biomarkers: T cell-inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Participants were then assigned to 1 of 4 biomarker-defined groups (GEP low/TMB low, GEP low/TMB high, GEP high/TMB low, and GEP high/TMB high) and then randomized to different interventions.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 66.2 Years STANDARD_DEVIATION 9.5 |
| Biomarker Defined Subgroups GEP High / TMB High | 21 Participants |
| Biomarker Defined Subgroups GEP High / TMB Low | 22 Participants |
| Biomarker Defined Subgroups GEP Low / TMB High | 43 Participants |
| Biomarker Defined Subgroups GEP Low / TMB Low | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 230 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 22 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 56 Participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 71 / 81 | 63 / 83 | 25 / 30 | 36 / 51 |
| other Total, other adverse events | 76 / 80 | 75 / 82 | 25 / 30 | 47 / 51 |
| serious Total, serious adverse events | 42 / 80 | 39 / 82 | 14 / 30 | 31 / 51 |
Outcome results
None listed