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

Abstract

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 (12.5%) were primary refractory, 24 (30%) were refractory to last line, 62 (78%) had Ann Arbor stage III/IV, and 35 (44%) had received at least 2 prior systemic cancer therapies. The ORR in the 76 EE DLBCL pts was 44.7%, with 24 (31.6%) complete responses (CR) and 10 (13.2%) partial responses (PR). In addition, 9 (11.8%) stable disease (SD) and 33 (43.4%) progressive disease (PD) were observed. 30 pts were efficacy evaluable in each of the two major cohorts (A and B) of Part 2, enrolling mainly relapsed pts. ORR was 50% in each cohort (CR rate: 43.3% in cohort A; 33.3% in cohort B). In Part 1, 16 DLBCL pts were EE, of which 6 were primary refractory and 10 were refractory to last line. ORR in this group was 25%. Median duration of response (mDoR) in the 76 evaluable DLBCL pts was not reached (lower 95% confidence interval [CI] 12 months). Median duration of follow-up in responders was 15 months (95% CI 9-18 months). In the 14 FL pts, the ORR was 57%: 5 CR, 3 PR, 3 SD, and 3 PD; the mDoR in this population was not reached (lower 95% CI: 19 months), with a median duration of follow-up of 21.8 months (95% CI 19.1 - not reached). Of the 6 MCL pts, 4 were efficacy evaluable: 2 CR and 2 PD. Due to the low number of pts, the DoR curves are not presented. PK levels were sufficient to fully engage the CD37 target on PBMCs. A relationship between PK exposure and efficacy was identified. Data showed acceptable systemic release of cytotoxic DM1 and catabolites. DLBCL responders in cohorts A and B demonstrated on average a clinically meaningful improvement of 3 points (standard deviation: 6.6) in the Lymphoma Subscale of the FACT-Lym QoL. Summary/Conclusion: The combination of nara + RTX resulted in good OR and CR rates, durable responses, a manageable safety profile, and full CD37 target engagement. Consequently, nara + RTX could be considered an attractive option for the treatment of R/R B-NHL. The treatment was well tolerated and contributed to the pts' well-being, as demonstrated by the QoL results. Figure 1 Figure 1. Disclosures Levy: Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Grudeva-Popova: University Hospital St George: Current Employment; Roche: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Jurczak: Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. André: Johnson & Johnson: Research Funding; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Roche: Other: Travel/accomodation/expenses, Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding; Pharmacyclics: Research Funding; Millenium: Research Funding; ATARA: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data safety monitoring board; Rafael: Research Funding; Debiopharm: Research Funding. Rechavi-Robinson: Debiopharm International SA: Current Employment. Toffanin: Debiopharm International SA: Current Employment. Micallef: F. Hoffmann La Roche: Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Attinger: Debiopharm International SA: Current Employment. Rouits: Debiopharm International SA: Current Employment, Patents & Royalties. Roubaudi-Fraschini: Debiopharm International SA: Current Employment. Orfanos: Debiopharm International SA: Current Employment; F. Hoffmann La Roche: Ended employment in the past 24 months. Dymkowska: CANTARGIA AB: Consultancy; AUREALIS OY: Consultancy; Debiopharm International SA: Consultancy; Morphosys AG: Consultancy. Nauwelaerts: Novartis Pharmaceuticals AG, Basel: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Woei-a-Jin: University Hospitals Leuven, Belgium: Current Employment; Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Kyowa Kirin: Research Funding.

PI3Kδ activation, IL6 over-expression, and CD37 loss cause resistance to the targeting of CD37-positive lymphomas with the antibody-drug conjugate naratuximab emtansine

“…To understand potential mechanisms of resistance that could occur in patients treated with naratuximab emtansine or with other anti-CD37 directed therapies, we have kept two DLBCL cell lines under drug pressure for many months, leading to two different models of resistance to naratuximab emtansine, that nonetheless retain sensitivity to the payload DM1. The two models also showed resistance to combining the ADC with rituximab, which has promising early clinical data (31).…”

“…In DLBCL, CD37 expression has been reported between 40% and 90% of cases across multiple studies performed using different antibodies (10,(14)(15)(16). CD37-directed antibody-and, more recently, cellular-based approaches have shown preclinical (7,(10)(11)(12)(13)(14)(17)(18)(19)(20)(21)(22)(23) and early promising clinical activity (24)(25)(26)(27)(28)(29)(30)(31)(32). Among the CD37-targeting agents, naratuximab emtansine (Debio 1562, IMGN529) is an antibody-drug conjugate (ADC) that incorporates the anti-CD37 humanized IgG1 monoclonal antibody K7153A conjugated to the maytansinoid DM1, as payload, via the thioether linker, Nsuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) (10).…”

“…The overall response rate (ORR) was 13% across all patients and 22% in DLBCL patients, including the only observed complete remission (CR) (27). In preliminary results of a phase 2 trial exploring the combination of naratuximab emtansine with the anti-CD20 monoclonal antibody rituximab (18), based on positive preclinical data (18), the ORR was 45% in 76 patients with DLBCL with 24 CRs (32%), 57% in 14 patients with follicular lymphoma (five CR), 50% in four MCL patients (2 CR) (31). Here, we studied the pattern of activity of naratuximab emtansine across a large panel of cell lines derived from DLBCL and other lymphoma subtypes and characterized two resistance mechanisms to the ADC.…”

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

“…A first-in-human clinical trial is evaluating GEN3009 in patients with R/R B-NHL ( Table 4 ). Naratuximab emtansine (IMGN529, Debio1562) is an ADC anti-CD37 mAb conjugated to maytansine-derived microtubule disruptor; it was investigated alone in CLL and R/R B-NHL (NCT01534715) [ 337 ], and in combination with rituximab in R/R DLBCL, FL and MCL (NCT02564744), where the treatment was well-tolerated and resulted in complete response rates and a manageable safety profile [ 338 ]. The second ADC, AGS67E, is an anti-CD37 mAb conjugated to monomethyl auristatin E, that showed a favorable safety profile in a phase I clinical trial in patients with CLL and R/R B-NHL (NCT02175433) [ 339 ].…”

Monoclonal Antibodies in the Treatment of Diffuse Large B-Cell Lymphoma: Moving beyond Rituximab

“…Preclinical data supporting that rituximab may augment the anti-tumor activity of naratuximab emtansine [111] have triggered a phase II trial of naratuximab emtansine combined with rituximab in patients with R/R NHL (NCT02564744). Preliminary results on 100 patients, including 80 patients with DLBCL, have demonstrated ORR of 50%, including 43% CRs, with mDOR not being reached during a median follow-up of 15 months [112]. AGS67E, another anti-CD37 antibody-drug conjugate, has been evaluated in the setting of R/R DLBCL, albeit the results of a small phase I trial have not been promising [113].…”