Phase II Study of Naratuximab Emtansine Plus Rituximab in DLBCL

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Adding the antibody-drug conjugate naratuximab emtansine to rituximab resulted in favorable overall survival and complete response rates for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), with a manageable safety profile. These findings from a phase II study were presented by Levy et al at the European Hematology Association 2021 Virtual Congress (LB1903).

Naratuximab emtansine consists of a humanized anti-CD37 antibody, K7153A, conjugated via a thioether-based linker to a cytotoxic maytansinoid, DM1.

Study Details

A total of 100 patients were recruited into the open-label phase II study. The trial consisted of 80 patients with relapsed and/or refractory DLBCL—10 were primary refractory, 24 were refractory to the last line of treatment, 62 had Ann Arbor stage III or IV disease, and 35 had received at least two prior systemic therapies. Of the 80, 76 were retained in the final analysis. Enrollment also included 20 patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma who were not candidates for stem cell transplantation and had received one to six lines of prior treatment.

The study had two phases. In phase I, all patients were given 0.7 mg/kg of naratuximab emtansine in combination with 375 mg/m2 of rituximab every 3 weeks. Phase II included patients with relapsed and/or refractory DLBCL alone. Phase II’s cohort A received the phase I treatment regimen, whereas cohort B received a weekly regimen of 0.4, 0.2, and 0.2 mg/kg of naratuximab emtansine administered on days 1, 8, and 15, combined with 375 mg/m2 of rituximab on day 1. A total of six cycles were administered, with a possibility to extend treatment.

The primary endpoints of the study were treatment-emergent adverse events and overall response rate.

Safety Profile

About 81% of patients experienced grade ≥ 3 treatment-emergent adverse events, including neutropenia (54%), leukopenia (19%), lymphopenia (17%), and thrombocytopenia (12%). In addition, about 8% of patients discontinued treatment with naratuximab emtansine due to a treatment-emergent adverse event.

Treatment-emergent adverse events linked with free DM1 included liver events in 3% of patients—toxic hepatitis, elevated gamma-glutamyl transferase levels, and high alkaline phosphatase levels—with no sequelae. Neuropathy was reported in 2% of patients.

Efficacy Results

The combination treatment showed durable responses:

  • Overall response rate: 44.7%
  • Complete response rate: 31.6%
  • Partial response rate: 13.2%.

In both cohorts of patients with relapsed and/or refractory DLBCL, the overall response rate was 50%. The complete response rate was 43.4% in cohort A and 33.3% in cohort B. The median duration of follow-up was 15 months. Further pharmacokinetic data showed an acceptable systemic release of cytotoxic DM1 and catabolites, full CD37 target engagement, and B-cell depletion.

The study authors concluded: “The combination of naratuximab emtansine plus rituximab resulted in good overall response and complete response rates, durable responses, a manageable safety profile, and full CD37 target engagement. Consequently, naratuximab emtansine plus rituximab could be considered an attractive option for the treatment of relapsed/refractory DLBCL.”

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