PHASE II STUDY OF DURVALUMAB (ANTI–PD‐L1) COMBINED WITH EITHER R‐CHOP OR LENALIDOMIDE AND R‐CHOP IN PREVIOUSLY UNTREATED, HIGH‐RISK DIFFUSE LARGE B‐CELL LYMPHOMA

Abstract

Introduction: The PD-1/PD-L1 pathway is used by tumor cells as an essential immune checkpoint and may serve as a promising target to improve anticancer immune response. High expression of PD-L1 in diffuse large B-cell lymphoma (DLBCL) has been shown to be a negative prognostic factor for overall survival. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal antibody that selectively blocks PD-L1 from binding to PD-1 and CD80. Early preclinical and clinical activity of durvalumab supports further study in high-risk DLBCL subtypes. The primary study objective is to evaluate the clinical activity of durvalumab with R-CHOP in non-activated B-cell-like (non-ABC; Arm A) and durvalumab with lenalidomide + R-CHOP (R2-CHOP) in ABC (Arm B) previously untreated DLBCL. Methods: This represents a phase II, open-label, two-arm, global, multicenter study of durvalumab in combination with R-CHOP or R2-CHOP in patients with previously untreated, high-risk DLBCL (MEDI4736-DLBCL-001; EUDRACT 2015-005173-20; NCT03003520). High-risk DLBCL is defined as Ann Arbor stage III/IV or II with bulky disease (≥7.0 cm), in addition to intermediate-high/high IPI ≥3 or NCCN-IPI ≥4. For study inclusion, patients must also have CD20+ DLBCL, ECOG performance status 0-2, and no prior antilymphoma treatment. During induction cycle 1, all patients receive durvalumab + R-CHOP21 concurrent with gene expression profiling using NanoString technology to determine cell-of-origin. From cycle 2 onwards, non-ABC patients (Arm A) receive intravenous (IV) durvalumab 1125 mg on day 1 plus R-CHOP21 for a total of 6 or 8 cycles; ABC patients (Arm B) receive oral lenalidomide 15 mg/day on days 1-14 in addition to durvalumab + R-CHOP21. Responding patients in both arms will have consolidation with durvalumab 1500 mg IV day 1 of every 28-day cycle for up to 12 months from induction cycle 1, day 1. The primary endpoint is 2-year progressionfree survival (PFS); secondary endpoints include safety (per NCI CTCAE v4.03) and clinical response to treatment in biomarker-defined subpopulations (tumor and peripheral blood); exploratory endpoints are PFS at 12 months, PK/PD, and complete response rate. Conclusions: The target enrollment is 120 patients, with recruitment ongoing. This study examines the clinical potential for combined durvalumab ± lenalidomide with standard R-CHOP in high-risk DLBCL.