Background: Most lymphomas, including classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and indolent B-cell lymphomas, are not readily curable in the relapsed/refractory (R/R) setting; new treatment options are urgently needed. Pembrolizumab, a humanized antibody against programmed death 1 (PD-1), has demonstrated effective antitumor activity and acceptable safety in patients with R/R cHL and R/R primary mediastinal large B-cell lymphoma. Lymphocyte activation gene-3 (LAG-3) is a cell surface immunomodulatory receptor commonly coexpressed with PD-1 on exhausted T cells and may serve as an escape pathway for lymphoma subjected to PD-1 blockade. Dual blockade of PD-1 and LAG-3 showed synergistic activity in mouse models of colon adenocarcinoma and fibrosarcoma. MK-4280 is a humanized anti-LAG-3 monoclonal antibody that blocks the interaction between LAG-3 and its ligand MHC class II. This study will evaluate the safety and efficacy of MK-4280 plus pembrolizumab in patients with selected hematologic malignancies.
Methods: This Phase I/II multisite study (NCT03598608) will have a safety lead-in phase to establish the preliminary recommended phase 2 dose (RP2D) followed by an efficacy expansion phase. In the safety lead-in phase, a modified toxicity probability interval design will be used to establish RP2D of MK-4280 plus pembrolizumab. Dose-limiting toxicities will be assessed during the first cycle. The study will enroll patients with PD-1/PD-L1 inhibitor-naive cHL (cohort 1), PD-1/PD-L1 inhibitor-refractory R/R cHL (cohort 2), R/R DLBCL (cohort 3), and R/R indolent B-cell lymphoma (cohort 4). Additional eligibility criteria are age ≥18 y, ECOG PS 0/1, adequate organ function, and the standard eligibility criteria for pembrolizumab studies, such as no prior receipt of anti-PD-1 antibody and no active infection necessitating systemic therapy. Patients will receive pembrolizumab 200 mg Q3W and MK-4280 for 35 cycles or until disease progression, unacceptable toxicity, or withdrawal from study. Tumor response will be assessed by CT/PET Q12W to confirm complete response or as clinically indicated, using revised response criteria for malignant lymphoma. Patients will be monitored for adverse events (AEs) until 30 days after study treatment end (90 days for serious AEs). Primary objective is to determine safety and tolerability and establish a preliminary RP2D. Secondary objectives are objective response rate per investigator review and pharmacokinetics of MK-4280 and pembrolizumab. Exploratory objectives are overall survival, progression-free survival, presence of circulating MK-4280 antibodies, target engagement of MK-4280, and biomarkers associated with response/resistance. At least 14 patients will be enrolled in the safety lead-in phase; approximately 120 patients (30 per cohort) will be enrolled in the efficacy expansion phase.
Citation Format: Gareth P. Gregory, Pier L. Zinzani, John Palcza, Jane A. Healy, Robert J. Orlowski, Akash Nahar, Philippe Armand. Anti-LAG-3 antibody MK-4280 in combination with pembrolizumab for the treatment of hematologic malignancies: A Phase I/II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT106.