A phase 2 study of naratuximab emtansine, a CD37-targeting antibody-drug conjugate, plus rituximab found it has promising safety and efficacy for patients with Diffuse Large B-Cell Lymphoma (DLBCL) and other B-cell non-Hodgkin’s lymphomas (B-NHLs), according to data presented at the 2021 Annual ASH Meeting.

CD37, a lymphocyte surface marker, is highly expressed in B-NHL, said Moshe Y Levy, MD, Baylor Charles A. Sammons Cancer Center, Dallas, Texas, and co-investigators.

Thus, Dr Levy et al aimed to evaluate the safety and efficacy of naratuximab emtansine plus rituximab, and to characterize pharmacokinetics and pharmacodynamics in patients with relapsed or refractory (R/R) B-NHL.

The study happened in 2 parts, enrolling 100 patients with R/R B-NHL who were not candidates for stem cell transplant and had 1 to 6 prior lines of therapy.

The first part—which included a safety run-in followed by an expansion—had patients receive 0.7mg/kg of naratuximab emtansine in combination with 375 mg/m² of rituximab every 3 weeks (cohort A).

The second part enrolled only R/R DLBCL patients and assigned them to either cohort A’s regimen or to a weekly regimen of 0.4, 0.2, and 0.2 mg/kg naratuximab emtansine given on days 1, 8, and 15 of 21-day cycles combined with 375 mg/m² of rituximab on day 1 for 6 cycles with the possibility of extension (cohort B).

The primary end points were safety and ORR. To investigate CD37 target engagement, pharmacokinetics and pharmacodynamics evaluations included antibody-drug conjugate and DM1 catabolites’ systemic levels and receptor occupancy on peripheral blood mononuclear cells (PBMCs). Patients from both cohorts were asked to fill in the FACT-Lym quality of life questionnaire (QoL). Patients were considered efficacy evaluable (EE) if they had 1 baseline and at least 1 post-baseline tumor assessment or an assessment of clinical progression. The follow-up period was up to 1 year after the patients first dose.

Out of 100 total patients (80 DLBCL, 14 follicular lymphoma [FL], 6 mantle cell lymphoma [MCL]), 81 experienced a grade ≥3 treatment emergent adverse events (TEAEs), the most common being neutropenia in 54, leukopenia in 19, lymphopenia in 17, and thrombocytopenia in 12.

Of the 80 DLBCL patients, 10 were primary refractory, 24 were refractory to the last line of therapy, 62 had Ann Arbor stage III/IV, and 35 had received at least 2 prior systemic therapies. The ORR for 76 EE DLBCL patients was 44.7 percent, with 24 CR and 10 PR. In addition, 9 patients observed stable disease and 33 had progressive disease.  The median duration of response was not met (lower 95% CI, 12 months). The median duration of follow-up in responders was 15 months (95% CI, 9-18 months).

In the 14 FL patients, the ORR was 57 percent, with 5 complete responses (CR), 3 partial responses (PR), 3 stable disease (SD), and 3 progressive disease (PD). The median duration of response 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 patients, 4 were EE, of which 2 had CR and 2 had PD.

In Part 1, 16 DLBCL patients were EE, of which 6 were primary refractory and 10 were refractory to the last line of therapy. The ORR for this group was 25 percent.

In Part 2, 30 patients were EE in each of the 2 cohorts (A and B), enrolling many relapsed patients. The ORR was 50% for each cohort. The CR rate for cohort A was 43.3% and for cohort B was 33.3%.

PK levels fully engaged the CD39 target on PBMCs, and a relationship between PK exposure and efficacy identified by the study investigators. Data showed acceptable systemic release of cytotoxic DM1 and catabolites. DLBCL patients in cohorts A and B showed a clinically meaningful improvement of 3 points on average in the Lymphoma Subscale of the FACT-Lym QoL.

“The combination of naratuximab emtansine plus rituximab resulted in good OR and CR 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 R/R B-NHL. The treatment was well tolerated and contributed to the patient’s well-being, as demonstrated by the QoL results,” concluded Dr Levy et al.—Emily Bader 

Levy MY, Jagadeesh D, Grudeva-Popova Z, et al. 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. Presented at: the 2021 ASH Annual Meeting. Dec 11-14, 2021. Abstract 526.