Safety and Efficacy of CD37-Targeting Naratuximab Emtansine PLUS Rituximab in Diffuse Large B-Cell Lymphoma and Other NON-Hodgkin'S B-Cell Lymphomas - a Phase 2 Study

▪ Background: Naratuximab emtansine (nara, Debio 1562, formerly IMGN529) is an antibody-drug conjugate (ADC) consisting of a humanized anti-CD37 antibody, K7153A, conjugated via a thioether-based linker to a cytotoxic maytansinoid, DM1. CD37, a lymphocyte surface marker, is highly expressed in B-NHL. A Phase 1 monotherapy study of nara revealed a good safety profile and promising efficacy (22% overall response rate [ORR] in DLBCL at all doses). In preclinical models of B-NHL, nara demonstrated synergistic antitumor activity when combined with rituximab (RTX). Aim: The aim of thisopen-label Phase 2 study was to evaluate the safety and efficacy of nara + RTX and to characterize pharmacokinetics (PK) and pharmacodynamics (PDy) in patients (pts) with relapsed and/or refractory (R/R) B-NHL. Methods: R/R B-NHL pts who were not candidates for stem cell transplant, with 1-6 prior lines of treatment, were recruited to two study parts. In Part 1, which included a safety run-in followed by an expansion, pts received 0.7 mg/kg nara in combination with 375 mg/m 2 RTX every 3 weeks (Q3W). In Part 2, only R/R DLBCL pts were included. Pts were assigned either to the Q3W regimen (cohort A), or to a weekly regimen of 0.4, 0.2, and 0.2 mg/kg nara administered on days 1, 8 and 15 of 21-day cycles combined with 375 mg/m 2 RTX on day 1 (cohort B). Six cycles of treatment were administered with possible extension. Primary endpoints were safety and ORR. PK and PDy evaluations included ADC and DM1 catabolites' systemic levels and receptor occupancy on peripheral blood mononuclear cells (PBMCs), to investigate CD37 target engagement. Pts from cohorts A and B were requested to fill in the FACTLym quality of life questionnaire (QoL). Pts with double/triple hit lymphoma, bulky disease, and up to 6 prior lines of treatment for DLBCL were allowed. There was no limit on life expectancy. Pts were considered efficacy evaluable (EE) if they had one baseline and at least one post-baseline tumor assessment or an assessment of clinical progression. Tumor assessment by CT was acceptable. The follow-up period was up to 1 year after last pt first dose (NCT02564744). Results: 100 pts were enrolled in the study: 80 DLBCL, 14 follicular lymphoma (FL) and 6 mantle cell lymphoma (MCL) pts; 81 pts (81%) experienced grade ≥ 3 treatment emergent adverse events, the most common being neutropenia 54 (54%), leukopenia 19 (19%), lymphopenia 17 (17%), and thrombocytopenia 12 (12%). Of the 80 DLBCL pts, 10 (12