Naratuximab Emtansine/Rituximab Combo Elicits Clinical Activity in Relapsed/Refractory DLBCL

The combination of naratuximab emtansine (Nara; Debio 1562, formerly IMGN529) and rituximab (Rituxan) yielded deep responses, and a duration of response that was not reached in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to findings from a phase 2 trial (NCT02564744) presented during the European Hematology Association (EHA) 2021 Virtual Congress.¹

Moshe Yair Levy, MD, director of hematologic malignancies research, Texas Oncology-Baylor Charles A. Sammons Cancer Center, suggested during the presentation that the combination regimen could be a new treatment option for patients with relapsed/refractory DLBCL, including frail and heavily pretreated patients.

Naratuximab emtansine is an antibody-drug conjugate (ADC) comprised of the humanized anti-CD37 antibody K7153A, which is conjugated through a thioether-based linked to the cytotoxic maytansinoid DM1. CD37 is a surface marker on B lymphocytes and is highly expressed in non-Hodgkin lymphomas (NHLs). “It’s also an intern Thierry Facon, MD alizable cell surface antigen, which lends itself well to an antibody-drug construct,” Levy noted. “Nara is the most advanced CD37-targeted antibody-drug conjugate in clinical development in diffuse large B-cell lymphoma.”

Previously in a phase 1 study (NCT01534715), naratuximab emtansine monotherapy showed a manageable safety profile and an objective response rate (ORR) of 22% in patients with DLBCL.²

“But what they found is that if you co-administer this ADC with rituximab, you're actually going to get more internalization of the CD37 monoclonal antibody, therefore more payload delivered to your target cells. So, this led to this phase 2 study,” Levy said.

The open-label, multicenter phase 2 study had an adaptive design.1 The safety run-in in part 1 included patients with relapsed/refractory NHL, including 9 with DLBCL and 8 with other NHLs. Patients were treated with 0.7 mg/kg naratuximab emtansine every 3 weeks on day 1 of the cycle followed by rituximab 375 mg/m2. This was followed by a run-in expansion with 2 cohorts including 8 patients with relapsed/refractory DLBCL in cohort 1 and 12 patients with other NHLs in cohort 2, all treated at the same schedule.

In part 2 of the study, only patients with DLBCL were enrolled and were treated with different dose schedules in the 2 cohorts. In cohort A, 33 patients were treated at the same every 3 week schedule and in cohort B, 30 patients were treated on a weekly schedule with 0.4 mg/kg naratuximab emtansine on day 1 of the 3-week cycle as well as on days 8 and 15 at 0.2 mg/kg followed by rituximab 375 mg/m2 on day 1.

ORR by Lugano classification was the primary end point, and other trial objectives were safety in terms of treatment-emergent adverse events (TEAEs), changes in laboratory tests, and changes in ECG and vital signs.

The overall trial enrolled patients with an ECOG performance status of 0 to 2 who had received 1 to 6 prior lines of treatment. Those with central nervous system (CNS) lymphomas were excluded, but patients with double- or triple-hit lymphoma, bulky disease, and transformed lymphoma were eligible for enrollment. Additionally, there were no limits on life expectancy in the trial, so it was “a very inclusive type of study,” according to Levy.

In part 1, patients were required to have a confirmed diagnosis of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. Prior allogeneic stem cell transplant was not allowed. Then in part 2, patients were required to have a confirmed diagnosis of relapsed/refractory DLBCL and ineligibility for stem cell transplant.

Patients in the study ranged from 29 to 88 years old and were mostly male with Ann Arbor stage III or IV disease and extra-nodal disease involvement. In patients with DLBCL treated with the every-3-week schedule, the median number of prior therapies was 2, and 1 among patients treated with the weekly regimen. Forty percent of patients were refractory to their last treatment in the every-3-week group and 13.3% were refractory in the weekly group.

As of data cutoff on January 13, 2021, 36.0% of patients with DLBCL treated every 3 weeks in cohort A had completed ≥6 cycles of treatment, as did 50% treated with weekly naratuximab emtansine in cohort B, and 60% of patients with NHL treated every 3 weeks in cohort 2. After 6 cycles, patients could request an extension.

The median number of treatment cycles was 3 (range, 1-38) in cohort A, 5.5 (range, 1-30) in cohort B, and 7 (range, 1-52) in cohort 2. Discontinuation of both drugs—as protocol designated that if naratuximab emtansine was to be discontinued, rituximab would be as well—was primarily due to progressive disease across the study groups; adverse events leading to death were reported in 2 patients.

Of the 76 evaluable patients with DLBCL, the ORR was 44.7% and complete responses (CRs) were reported in 31.6%. In cohort A, the ORR was 50% and CRs were observed in 43.3%. In cohort B, the ORR was also 50% and CRs were reported in 33.3%.

Among patients with non-bulky DLBCL, the ORR was 50.8%. Patients treated in the third line or beyond who were not primary refractory showed an ORR of 46.4% and a CR rate of 32.1%.

The median duration of response was not reached after a median of 15 months of follow-up (95% CI, 9-18). Sixty-six percent of responders had a response lasting more than a year.

Grade 3/4 TEAEs were mostly hematologic and manageable, including most commonly neutropenia (54.0%), leukopenia (19.0%), lymphopenia (17.0%), and thrombocytopenia (12.0%). Additionally, 3 grade ≥3 liver TEAEs and 2 grade ≥3 non-serious neuropathy cases were reported.

He noted that no granulocyte colony stimulating factor was mandated in the trial; “if it was, we probably would have seen a difference in the toxicity profile from the complication of cytopenias.”

Grade 5 TEAEs were reported in 10 patients, only 2 of these, however, were considered related to treatment. Common serious adverse events included pneumonia/lung infection (5.0%), febrile neutropenia (4.0%), and general physical health deterioration (3.0%). Eight patients discontinued treatment due to a TEAE and 6 patients required a dose reduction.

“[This] speaks to just how fragile this group of patients was, and the rather liberal inclusion criteria that allowed people irrespective of the amount of time we thought they had left,” Levy said.

“This is, in my viewpoint, very exciting therapy,” Levy said. “Clearly we have a need for another target in diffuse large B-cell lymphoma, and this certainly seems to compare quite favorably to other ADCs that we have seen in the space.”

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. Presented at: 2021 EHA Congress; June 9-17, 2021; Virtual. Abstract LBA1903.
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. 2018;36(5):869-876. doi:10.1007/s10637-018-0570-4