The combination of the CD37-targeting antibody-drug conjugate naratuximab emtansine and rituximab yielded deep and long-lasting responses in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), in a phase II trial presented during the 2021 European Hematology Association (EHA) Virtual Congress.1
“The combination resulted in an objective response rate of 44.7%, with almost one-third being complete responses. The safety profile of naratuximab emtansine plus rituximab was tolerable and manageable, with mainly hematologic adverse events, as expected with B-cell–depleting therapies,” said Moshe Yair Levy, MD, Director of Hematologic Malignancies Research, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas.
The combination [naratuximab emtansine plus rituximab] resulted in an objective response rate of 44.7%, with almost one-third being complete responses.— Moshe Yair Levy, MD
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Dr. Levy highlighted the poor prognosis of patients with refractory aggressive lymphomas such as DLBCL. Although several new treatments have been recently approved, more are needed. “Clearly, the field has changed a lot in the past few years…, but there is still a high unmet need. New targets need to be identified as well, and one such target is CD37,” he said.
About the Regimen
Naratuximab emtansine is the most advanced CD37-targeted antibody-drug conjugate in clinical development in DLBCL. It consists of a humanized anti-CD37 antibody, K7153A, conjugated with a thioether-based linker to the cytotoxic maytansinoid, DM1. CD37 is a surface marker on B lymphocytes and is highly expressed in non-Hodgkin lymphomas, including about 90% of DLBCLs. It is also an internalizable cell-surface antigen, which “lends itself well” to antibody-drug conjugates, according to Dr. Levy.
A previous phase I study demonstrated responses in 22% of patients receiving naratuximab emtansine monotherapy.2 When the antibody-drug conjugate is co-administered with rituximab, however, there is greater internalization of the CD37 antibody and therefore more payload delivered to the target cells. This led to the phase II study of this combination, Dr. Levy said.
About the Study
The open-label, multicenter phase II study of 100 patients had an adaptive design. Part 1 was a safety run-in/expansion phase that included patients with relapsed or refractory non-Hodgkin lymphoma, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. Part 2 included only patients with DLBCL who were ineligible for stem cell transplantation.
In total, 80 patients with DLBCL were treated under two different dosing schedules for naratuximab emtansine. Part 1 included 17 patients with DLBCL; part 2 included 33 patients in cohort A (dosed every 3 weeks) and 30 in cohort B (dosed weekly). The dosing schedules were as follows:
Every-3-week regimen (n = 50): naratuximab emtansine at 0.7 mg/kg on day 1 followed by rituximab at 375 mg/m2 in 21-day cycles
Weekly regimen (n = 30): naratuximab emtansine at 0.4 mg/kg on day 1 followed by rituximab at 375 mg/m2 and naratuximab emtansine at 0.2 mg/kg on days 8 and 15 in 21-day cycles.
Patients were ineligible for stem cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and had received one to six prior lines of treatment. Exclusions included central nervous system lymphomas, prior allogeneic transplantation, prior treatment with an anti–CD37-targeting agent, and response duration up to 8 weeks after the last treatment or up to 24 weeks after the first line.
“This was a very inclusive trial,” Dr. Levy emphasized. It allowed patients with double- or triple-hit lymphoma, bulky disease, and transformed lymphoma, which other trials have often excluded. In addition, there was no limit on life expectancy, creating a “fragile” patient population.
Most had stage III or IV disease (80%) and extranodal involvement (63%). Approximately half the patients were being treated in the third line or later. Many of the patients had primary refractory disease. The primary endpoints were objective response rate and treatment-emergent adverse events, including clinically significant changes in laboratory tests, electrocardiograms, and vital signs.
High Response Rates With Both Dosing Schedules
As Dr. Levy explained, two dosing schedules of naratuximab emtansine were evaluated based on a relatively fast half-life. “We wanted to see whether giving it weekly, getting continuous site occupancy, would produce better outcomes. However, we saw no clinically relevant differences between the two schedules,” he reported.
Of the 76 evaluable patients with DLBCL, the objective response rate was 44.7%, with 31.6% of patients achieving complete responses. In both cohorts A and B, the response rate was 50%, with complete responses observed in 43.3% of the every-3-week cohort and 33.3% of the weekly cohort.
In addition, the response rate was 46.4% among patients treated in the third line or beyond who did not have primary refractory disease. The median duration of response was not reached after 15 months of follow-up. Responses lasting more than 1 year were observed in 66% of responders, Dr. Levy reported.
KEY POINTS
- Naratuximab emtansine, an antibody-drug conjugate targeting CD37, was combined with rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma in an open-label phase II trial of 80 patients.
- Of 76 evaluable patients, the objective response rate was 44.7%, with 31.6% of patients achieving complete responses.
- Response rates were similar whether patients received naratuximab emtansine weekly or every 3 weeks.
Safety Profile
According to Dr. Levy, grade 3 or 4 treatment-emergent adverse events were mostly hematologic and manageable, including neutropenia (54%), leukopenia (19%), lymphopenia (17%), and thrombocytopenia (12%). He noted that growth factors were not mandated in the study. Eight patients discontinued naratuximab emtansine/rituximab, and six needed dose reductions due to adverse events.
There were 10 deaths, with just 2 thought to be possibly related to the investigational product (pneumonitis and left-ventricular failure in a patient with preexisting cardiac disease). “This speaks to just how fragile this group of patients was and the rather liberal inclusion criteria that allowed people to enroll irrespective of the amount of time we thought they had left,” explained Dr. Levy.
“In my viewpoint, this is very exciting therapy. Clearly, we need another target in DLBCL, and this certainly seems to compare quite favorably to other antibody-drug conjugates we have seen in the space,” Dr. Levy concluded.
DISCLOSURE: Dr. Levy has served as a speaker or consultant for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Jazz, Karyopharm, MorphoSys, Seattle Genetics, Takeda, and TG Therapeutics.
REFERENCES
1. Levy MY, Grudeva-Popova Z, Trneny M, 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. 2021 European Hematology Association Congress. Abstract LB1903. Presented June 12, 2021.
2. Stathis A, Flinn IW, Madan S, et al: Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: A dose-escalation, phase I study. Invest New Drugs 36:869-876, 2018.
