Relapsed / refractory LDGCB has a prolonged duration of response with Naratuximab Emtansine Plus Rituximab
Results from a phase 2 trial (NCT02564744) of naratuximab emtansine (Nara; Debio 1562, formerly IMGN529) and rituximab (Rituxan) showed that profound and lasting responses were obtained in patients with diffuse lymphoma to relapsed or refractory large B cells (DLBCL), according to a presentation at the 2021 virtual congress of the European Hematology Association (EHA).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 may be a new treatment option for patients with DLBCL relapsed / refractory, including frail and heavily pretreated patients. the patients.
Naratuximab emtansine is an antibody-drug conjugate (ADC) composed of the humanized anti-CD37 antibody K7153A, which is conjugated with a thioether linked to the cytotoxic maytansinoid DM1. CD37 is a surface marker on B lymphocytes and is highly expressed in non-Hodgkin lymphoma (NHL). “He is also a trainee Thierry Facon, MD tradeable cell surface antigen, which lends itself well to antibody-drug construction,” noted Levy. “Nara is the most advanced CD37 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 actually get more internalization of the CD37 monoclonal antibody, so more payload delivered to your target cells. So that led to this Phase 2 study, ”Levy said.
The open-label, multicentre phase 2 study had an adaptive design.1 The safety run-in in Part 1 included patients with relapsed / refractory NHL, 9 with LDGCB and 8 with other NHL . Patients were treated with 0.7 mg / kg naratuximab emtansine every 3 weeks on cycle day 1 followed by rituximab 375 mg / m2. This was followed by an initial expansion with 2 cohorts comprising 8 patients with relapsed / refractory LDGCB in cohort 1 and 12 patients with other NHL in cohort 2, all treated on the same schedule.
In part 2 of the study, only patients with DLBCL were included and were treated with different dosage regimens in the 2 cohorts. In cohort A, 33 patients were treated according to the same schedule every 3 weeks and in cohort B, 30 patients were treated on a weekly schedule with 0.4 mg / kg naratuximab emtansine on day 1 of cycle 3 weeks as well as on days 8 and 15 at 0.2 mg / kg followed by rituximab 375 mg / m2 on day 1.
The ORR according to the Lugano classification was the primary endpoint, and the other trial objectives were safety in terms of treatment-related adverse events (TEAEs), changes in laboratory tests and changes in ECG and vital signs.
The overall trial recruited patients with an ECOG performance index of 0 to 2 who had received 1 to 6 previous 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 recruitment. 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 LDGCB, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. A previous allogeneic stem cell transplant was not allowed. Then, in part 2, patients were to have a confirmed diagnosis of relapsed / refractory LDGCB and ineligibility for stem cell transplantation.
The patients in the study were between 29 and 88 years old and were mostly men with stage III or IV Ann Arbor disease and extranodal involvement. In patients with DLBCL treated with the every 3 weeks regimen, the median number of previous treatments was 2 and 1 in patients treated with the weekly regimen. Forty percent of patients were refractory to their last treatment in the every 3 weeks group and 13.3% were refractory in the weekly group.
As of the data cut-off date of January 13, 2021, 36.0% of patients with LDGCB treated every 3 weeks in cohort A had completed ≥ 6 cycles of treatment, as had 50% treated with naratuximab emtansine weekly in cohort B , and 60% of NHL patients 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. the protocol stated that if naratuximab emtansine were to be discontinued, so would rituximab – was mainly due to disease progression in study groups; adverse events leading to death were reported in 2 patients.
Of the 76 evaluable patients with LDGCB, the ORR was 44.7% and complete responses (CR) 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 LDGCB, the ORR was 50.8%. Patients treated on the third line or beyond who were not primary refractory presented 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 respondents had a response that lasted more than a year.
Grade 3/4 ADEs were predominantly hematologic and manageable, most commonly including neutropenia (54.0%), leukopenia (19.0%), lymphopenia (17.0%), and thrombocytopenia (12, 0%). In addition, 3 grade ≥3 hepatic AETRs and 2 cases of non-severe grade ≥3 neuropathy were reported.
He noted that no granulocyte colony stimulating factor was required in the assay; “If that was the case, we would probably have seen a difference in the toxicity profile versus the complication of cytopenias.”
Grade 5 ATEs were reported in 10 patients, but only 2 of them were considered to be treatment-related. Common serious adverse events included pneumonia / lung infection (5.0%), febrile neutropenia (4.0%), and general deterioration in physical health (3.0%). Eight patients discontinued treatment due to an ATE and 6 patients required dose reduction.
“[This] is a testament to the fragility of this patient group and the rather liberal inclusion criteria that allowed people whatever time we thought they had left, ”said Levy.
“This is, in my opinion, a very exciting therapy,” said Levy. “It’s clear that we need another target in diffuse large B-cell lymphoma, and it certainly seems to compare quite favorably to other ADCs we’ve seen in space.”
1. Levy MY, Grudeva-Popova Z, Trneny M, et al. Safety and efficacy of naratuximab emtansine plus rituximab targeting CD37 in diffuse large B-cell lymphoma and other non-Hodgkin’s B-cell lymphomas – a phase 2 study. Presented at: EHA Congress 2021; June 9-17, 2021; Virtual. Abstract LBA1903.
2. Stathis A, Flinn IW, Madan S, et al. Safety, tolerability and preliminary activity of IMGN529, an antibody-drug conjugate targeted against CD37, in patients with relapsed or refractory non-Hodgkin’s B-cell lymphoma: a dose-escalating phase I study. Invest in new drugs. 2018; 36 (5): 869-876. doi: 10.1007 / s10637-018-0570-4