Contributions
Abstract: LB1903
Type: Oral Presentation
Session title: Late-Breaking Oral Session
Background
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).
Aims
The aim of this open-label Phase 2 study was 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 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/m2 RTX every 3 weeks (Q3W). In Part 2, only R/R DLBCL pts were included. Pts were assigned to either 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, respectively (cohort B), combined with 375 mg/m2 RTX on day 1. Six cycles of treatment were administered with possible extension. Primary endpoints were treatment emergent adverse events (TEAEs) and ORR. Safety is reported in all pts; efficacy in DLBCL pts only. Pharmacokinetics (PK) and pharmacodynamics evaluations included receptor occupancy to investigate CD37 target engagement. 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 and 20 other B-NHL pts, of whom 81 (81%) experienced grade ≥3 TEAEs, the most common being neutropenia 54 (54%), leukopenia 19 (19%), lymphopenia 17 (17%) and thrombocytopenia 12 (12%). Eight (8%) pts discontinued nara due to a TEAE. Only very few grade ≥3 TEAEs, known to be associated with free DM1, were reported: 3 (3%) pts with liver events (1 toxic hepatitis, 1 GGT increased, 1 ALP increased) with no sequelae; and 2 (2%) pts with neuropathy (1 motor and 1 sensory). 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 at least 2 prior systemic cancer therapies. Of the 80 DLBCL pts, 76 were efficacy evaluable, i.e. had one baseline and at least one post-baseline tumor assessment or an assessment of clinical progression. The ORR was 44.7%, with 24 (31.6%) complete responses (CR), 10 (13.2%) partial responses. In addition, 9 (11.8%) stable disease and 33 (43.4%) progressive disease were observed. 30 pts were efficacy evaluable in each of the two major cohorts (A and B).ORR was 50% in each cohort (CR rate: 43.3% in cohort A; 33.3% in cohort B). Median duration of response in the 76 DLBCL pts was not reached, (lower 95% confidence interval 12 months). Median duration of follow-up in responders was 15 months. PK data showed acceptable systemic release of cytotoxic DM1 and catabolites. Treatment resulted in full peripheral target engagement and B-cell depletion.
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 DLBCL.
Keyword(s): DLBCL, Monoclonal antibody, Non-Hodgkin's lymphoma, Targeted therapy
Abstract: LB1903
Type: Oral Presentation
Session title: Late-Breaking Oral Session
Background
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).
Aims
The aim of this open-label Phase 2 study was 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 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/m2 RTX every 3 weeks (Q3W). In Part 2, only R/R DLBCL pts were included. Pts were assigned to either 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, respectively (cohort B), combined with 375 mg/m2 RTX on day 1. Six cycles of treatment were administered with possible extension. Primary endpoints were treatment emergent adverse events (TEAEs) and ORR. Safety is reported in all pts; efficacy in DLBCL pts only. Pharmacokinetics (PK) and pharmacodynamics evaluations included receptor occupancy to investigate CD37 target engagement. 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 and 20 other B-NHL pts, of whom 81 (81%) experienced grade ≥3 TEAEs, the most common being neutropenia 54 (54%), leukopenia 19 (19%), lymphopenia 17 (17%) and thrombocytopenia 12 (12%). Eight (8%) pts discontinued nara due to a TEAE. Only very few grade ≥3 TEAEs, known to be associated with free DM1, were reported: 3 (3%) pts with liver events (1 toxic hepatitis, 1 GGT increased, 1 ALP increased) with no sequelae; and 2 (2%) pts with neuropathy (1 motor and 1 sensory). 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 at least 2 prior systemic cancer therapies. Of the 80 DLBCL pts, 76 were efficacy evaluable, i.e. had one baseline and at least one post-baseline tumor assessment or an assessment of clinical progression. The ORR was 44.7%, with 24 (31.6%) complete responses (CR), 10 (13.2%) partial responses. In addition, 9 (11.8%) stable disease and 33 (43.4%) progressive disease were observed. 30 pts were efficacy evaluable in each of the two major cohorts (A and B).ORR was 50% in each cohort (CR rate: 43.3% in cohort A; 33.3% in cohort B). Median duration of response in the 76 DLBCL pts was not reached, (lower 95% confidence interval 12 months). Median duration of follow-up in responders was 15 months. PK data showed acceptable systemic release of cytotoxic DM1 and catabolites. Treatment resulted in full peripheral target engagement and B-cell depletion.
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 DLBCL.
Keyword(s): DLBCL, Monoclonal antibody, Non-Hodgkin's lymphoma, Targeted therapy