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 (2021)

Introduction: Naratuximab emtansine (nara, Debio 1562, formerly IMGN529) is an antibody-drug conjugate 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-cell non-Hodgkin lymphoma (B-NHL), including diffuse large B-cell lymphoma (DLBCL). In preclinical models of B-NHL, nara demonstrated strong antitumor activity, further enhanced by co-administration of rituximab (RTX). 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). Here we report results from an open label Phase 2 study to evaluate the safety and efficacy of nara in combination with RTX in patients (pts) with relapsed and/or refractory (R/R) DLBCL and other forms of B-NHL. Methods: R/R B-NHL pts with 1-6 prior lines of treatment were recruited to two study parts. In Part 1, which included a safety run-in, pts received 0.7 mg/kg nara in combination with 375 mg/m2 RTX every 3 weeks (Q3W). In Part 2, only R/R DLBCL pts were included. Pts were assigned to either the Q3W regimen, or to a weekly regimen of 0.4, 0.2, and 0.2 mg/kg nara administered on days 1, 8, and 15, respectively, combined with 375 mg/m2 RTX on day 1. Treatment was administered for 6 cycles with possible extension. Primary endpoints were treatment emergent adverse events (TEAEs) and ORR. Safety is reported in all pts; efficacy only in DLBCL pts. Data cut-off was 30-Sep-2020, when the trial was still ongoing; final data from the end of study will be available in the full presentation (FP) (NCT02564744). Results: 100 pts were enrolled in the study: 80 DLBCL and 20 other B-NHL pts, of whom 82 (82%) experienced grade ≥3 TEAEs, the most common being neutropenia 54 (54%), lymphopenia 17 (17%) and thrombocytopenia 11 (11%). Only 10 (10%) pts discontinued nara due to a TEAE. Only very few grade ≥3 TEAEs, known to be associated with free DM1, were reported: 1 (1%) serious AE of toxic hepatitis with no sequelae; and 2 (2%) cases of non-serious neuropathy (1 motor and 1 sensory). At the time of data cutoff, of the 80 DLBCL pts, 74 (32% refractory to 1st and/or last line) were efficacy evaluable (had one screening assessment and at least one post-baseline tumor assessment or clinical progressive disease [PD]). The ORR was 43.2%, with 24 (32.4%) complete responses and 8 (10.8%) partial responses. In addition, 11 (14.9%) stable disease and 31 (41.9%) PD were observed. Median duration of response was not reached, (95% confidence interval 10.4 - NA months [mo]). Median duration of follow-up in responders was 13.7 mo. Conclusions: The combination of nara with RTX was well tolerated, with a manageable safety profile of expected, mainly hematological AEs. A preliminary analysis shows promising efficacy. Final data, regimen comparison, and related analyses will be available in the FP. The research was funded by: Debiopharm International S.A. Keywords: Molecular Targeted Therapies, Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract M. Trneny Consultant or advisory role: Celgene, Janssen, Gilead, Bristol-Meyers Squibb, Amgen, Abbvie, Takeda, F. Hoffmann-La Roche Ltd, MorphoSys, Incyte Honoraria: Janssen, Gilead, Bristol-Meyers Squibb, Amgen, Abbvie, Takeda, F. Hoffmann-La Roche Ltd, MorphoSys, Incyte Educational grants: Abbvie, Gilead, Bristol-Meyers Squibb, Takeda, F. Hoffmann-La Roche Ltd., Janssen W. Jurczak Consultant or advisory role: Mei pharma, Debiopharm, Loxo, Takeda, Acerta, Astra Zeneca, Beigene Research funding: GSK, Acerta, Astra Zeneca, Bayer, Beigene, Nordic Nanovector, Incyte, Debiopharm, Genenthech, Janssen, Loxo, Mei Pharma, Morphosys, Takeda, TG Therapeutics, Gilead S. Nasta Consultant or advisory role: Merck (DSMB) Honoraria: Morphosys (Advisory Board) Research funding: Debiopharm, ATARA, Roche, Rafael, Takeda/Millenium, Pharmacyclics D. Rechavi-Robinson Employment or leadership position: Employed by Debiopharm International S.A. S. Toffanin Employment or leadership position: Employed by Debiopharm International S.A. S. Micallef Employment or leadership position: Debiopharm International - R&D; Biostatistics & Data Management - Biostatistics Program Lead A. Attinger Employment or leadership position: Debiopharm International S.A. E. Rouits Employment or leadership position: Debiopharm International S.A. M. Dymkowska Consultant or advisory role: Debiopharm International S.A., Argenx BV, MorphoSys AG, Aurealis OY H. Nauwelaerts Employment or leadership position: Debiopharm International S.A.