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Phase 2 study of pembrolizumab-based combination therapy in patients with microsatellite instability-high or mismatch repair-deficient stage IV colorectal cancer
Background
The PD-1 inhibitor pembrolizumab has shown robust clinical activity in patients with mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (CRC). However, given the response rate of 45% with first-line pembrolizumab monotherapy demonstrated in KEYNOTE-177, there is room for improvement. Targeting a different pathway such as CTLA-4, LAG-3, TIGIT, or ILT4 using a second checkpoint inhibitor may improve the efficacy of PD-1 inhibition. This ongoing, open-label, multicenter, multiarm, randomized, phase 2 trial (NCT04895722) will enroll patients in 2 cohorts, A and B. This study will evaluate efficacy and safety of coformulated pembrolizumab and anti–CTLA-4 quavonlimab compared with pembrolizumab monotherapy in chemotherapy-refractory stage IV dMMR/MSI-H CRC in cohort A. In cohort B, the study will evaluate the efficacy and safety of 4 pembrolizumab-based combinations (coformulated pembrolizumab with either quavonlimab, anti–LAG-3 favezelimab, or anti-TIGIT vibostolimab; anti-ILT4 antibody MK-4830 given sequentially with pembrolizumab) compared with pembrolizumab monotherapy in previously untreated stage IV dMMR/MSI-H CRC.
Trial design
This trial will enroll patients aged ≥18 years with histologically confirmed dMMR/MSI-H stage IV CRC that is measurable by investigator, per RECIST v1.1, and confirmed by blinded independent central review (BICR). Cohort A will include patients who experienced disease progression after the following therapies: chemotherapy (fluoropyrimidine, irinotecan, and oxaliplatin), with or without anti-VEGF antibody, and anti-EGFR antibody for patients with left-sided tumors that are RAS wild type. Cohort B will include patients who have not been previously treated for metastatic disease. Additional eligibility criteria for both cohorts include ECOG performance status 0 or 1, adequate organ function, and availability of archival or newly obtained tissue sample. Patients with autoimmune disease, active CNS metastases, and those who received systemic therapy within 4 weeks or radiotherapy within 2 weeks before intervention will be excluded. Patients in cohort A will be randomly assigned 1:1 to receive either coformulated quavonlimab 25 mg/pembrolizumab 400 mg IV Q6W or pembrolizumab 400 mg IV Q6W. Patients in cohort B will be randomly assigned 1:1:1:1:1 to receive coformulated quavonlimab 25 mg/pembrolizumab 400 mg IV Q6W, favezelimab 800 mg/pembrolizumab 200 mg IV Q3W, vibostolimab 200 mg/pembrolizumab 200 mg IV Q3W, MK-4830 800 mg + pembrolizumab 200 mg IV Q3W (given sequentially), or pembrolizumab 400 mg IV Q6W. Patients will be stratified by RAS mutation (mutant vs wild type). Treatment will continue for ≤2 years or until unacceptable toxicity, disease progression, confirmed CR (after ≥6 months of study treatment and patients have received ≥6 weeks of treatment after initial CR), or withdrawal from study. Disease assessment will be performed by CT or MRI at screening (within 28 days before treatment) and every 9 weeks thereafter. For both cohorts, primary end point is ORR by BICR per RECIST v1.1; secondary end points are ORR assessed by investigator, duration of response and PFS assessed by BICR and by investigator per RECIST v1.1, OS, and safety and tolerability graded per NCI CTCAE v5.0. Enrollment in this trial is ongoing.
Clinical trial identification
ClinicalTrials.gov, NCT04895722.
Legal entity responsible for the study
The authors.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosures
T. André: Honoraria (self): Amgen, Astra-Zeneca, Bristol-Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Haliodx, Kaleido Biosciences, Merck & Co., Inc., Pierre Fabre, Sanofi, Servier et , Merck & Co., Inc, Servier; Advisory / Consultancy: Astellas Pharma, BMS, Gritstone Oncology,Transgène,Roche/Ventana, Seagen, Merck & Co., Inc, Sevier; Research grant / Funding (institution): BMS, Seagen, GSK; Travel / Accommodation / Expenses: BMS, Merck & Co., Inc. S. Yalcin: Honoraria (self): Pfizer, Merck Serono, Gen ilac, Amgen, Novartis, Abbott, Natera; Advisory / Consultancy: Pfizer, Merck Serono, Amgen, Abbott; Speaker Bureau / Expert testimony: Gen ilac, Eczacibasiıı, Amgen, Merck Serono, Roche, Abbott; Travel / Accommodation / Expenses: Gen ilac, Amgen, Roche. A. Odeleye-Ajakaye: Full / Part-time employment: MERCK & CO, INC. P. Leconte: Shareholder / Stockholder / Stock options: MSD; Full / Part-time employment: MSD. D. Fogelman: Shareholder / Stockholder / Stock options: Merck, GTX; Full / Part-time employment: Merck. T. Kim: Research grant / Funding (institution): Genentech, AstraZeneca, Sanofi-Aventis. All other authors have declared no conflicts of interest.
© 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved.
