Odronextamab Is Active With Acceptable Benefit–Risk Profile in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Odronextamab (REGN1979), is a novel CD20xCD3 bispecific antibody, continues to show intriguing antitumor activity and an acceptable safety profile in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including those who have previously received chimeric antigen receptor (CAR) T-cell therapy, according to longer follow-up of a phase 1 study presented at the 2020 ASH Annual Meeting & Exposition.¹

Data showed that in patients who previously received CAR T-cell therapy (n = 24), a particularly difficult-to-treat population, the objective response rate (ORR) was 33% and the complete response (CR) rate was 21%. CRs appeared durable, with 100% of CRs still ongoing; 1 patient has maintained a CR for 20 months, which is still ongoing, lead study author Rajat Bannerji, MD, PhD, a hematologist/Oncologist, and chief of Hematologic Malignancies at Rutgers Cancer Institute of New Jersey, said in a virtual presentation during the meeting.

“Odronextamab is a novel CD20 x CD3 bispecific antibody which offers an off-the-shelf, primarily outpatient treatment option for patients with relapsed/refractory B-NHL,” Bannerji said. “In this first-in-human phase 1 trial, odronextamab has demonstrated compelling antitumor activity, including durable complete responses in heavily pretreated patients with follicular lymphoma and DLBCL.”

In patients with relapsed/refractory DLBCL who had not previously received CAR T-cell therapy (n = 11), the ORR was 55%, all of which were CRs. Eighty-three percent of CRs were durable and 1 patient remains in an ongoing CR with 21 months of follow-up.

Additionally, in those with relapsed/refractory follicular lymphoma (n = 30), the ORR was 90% and the CR rate was 70%. The CRs appeared to be durable (81%), and the median duration of CR was not reached.

Results also showed that the agent had an acceptable benefit–risk profile, with grade 3 being the highest grade for cytokine release syndrome (CRS) and was mostly transient, occurring with initial or intermediate step-up doses. Additionally, odronextamab was administered up to 320 mg weekly without dose-limiting toxicities (DLTs) or reaching the maximum-tolerated dose (MTD).

Odronextamab is an off-the-shelf, CD20 x CD3 bispecific antibody that binds to CD3 on T cells and CD20 on malignant B cells, which triggers T-cell–mediated cytotoxicity independent of T-cell receptor recognition. The agent is administered intravenously in the outpatient setting.

At the 2019 ASH Annual Meeting, earlier findings of the phase 1 findings of odronextamab showed preliminary signs of safety and efficacy in this patient population.2 The dose-escalation portion of the trial is now complete, Bannerji explained.

In the phase 1 study, dexamethasone is given as premedication, followed by split and step-up doses of odronextamab, which are used to mitigate the risk for CRS during weeks 1 and 2 of treatment. Odronextamab is given weekly for 12 weeks and then continued every 2 weeks until disease progression or study discontinuation. Investigators assessed for response every 12 weeks, according to Lugano criteria.

To be eligible for enrollment, patients had to have CD20-positive relapsed/refractory B-cell NHL, had prior treatment with an anti-CD20 antibody, an ECOG performance status of 0 to 1, and adequate organ function.

The primary end points are safety, tolerability, and DLTs; key secondary end points included antitumor activity, pharmacokinetics, and the recommended phase 2 dose.

The median age was 67.0 years (range, 27-89), 70.6% of patients were male, and the ECOG performance status was 1 in 58.1% of patients. A total 86.8% of patients had an Ann Arbor stage III to IV disease, and 33.8% of patients had bulky disease.

Patients had B-cell NHL, which comprised diffuse large B-cell lymphoma (DLBCL; 57.4%), grade 1-3a follicular lymphoma (27.9%), mantle cell lymphoma (8.8%), marginal zone lymphoma (4.4%), and other (1.5%). The median number of prior lines of therapy was 3 (range, 1-11), and 7.4% of patients underwent prior autologous stem cell transplant and 25.7% had previously received CAR T-cell therapy. Most patients (80.1%) were refractory to their most recent line of therapy, 83.1% to an anti-CD20 antibody, and 67.6% to an alkylator therapy. A total 66.9% of patients were double refractory to an alkylator and an anti-CD20 antibody.

Of the 136 patients enrolled on the study to date, treatment is ongoing in 7 (5.1%) and the study is ongoing for 24 patients. Of the patients who discontinued treatment (72.8%), reasons included disease progression (36.8%), death (14.0%), patient or physician decision/withdrawal of consent (11.0%), other (9.6%), adverse event (AE; 0.7%), and missing data (0.7%). Thirteen patients have completed the trial.

Regarding safety, 92.6% of all treatment-emergent AEs (TEAEs) were treatment-related; 44.9% of all serious TEAEs were related to therapy. The treatment-related mortality rate was 3.7%, which Bannerji said was in line with other studies of relapsed lymphomas.

The most frequent grade 3 or higher TEAEs occurring in at least 10% of patients included anemia (24.3%; grade 1-3 at baseline in 22%), lymphopenia (20.6%; transient), neutropenia (18.4%; febrile, 2.2%), and hypophosphatemia (18.4%; transient). Nine patients discontinued therapy because of TEAEs, which included cytomegalovirus infection (grade 1; n = 1), fatigue (grade 1; n = 1), pneumonia (grade 2; n = 2); hemolysis, fatigue pneumonia, toxoplasmosis, and tumor lysis syndrome (grade 3; n = 1 each); as well as abscess (n = 1), which was unrelated to the study drug.

No patients discontinued odronextamab due to CRS or neurotoxicity; overall, 5.9% of patients had a TEAE that led to treatment discontinuation. Additionally, no dose-dependent increases in toxicity were observed.

CRS occurred in 61% of patients, at grade 1 (35.3%), grade 2 (18.4%), grade 3 (6.6%), and grade 4 (0.7%). The majority of CRS events were mild or moderate in severity, and the majority of the grade 3 or higher CRS events occurred with initial or intermediate step-up doses of odronextamab. Specifically in patients with follicular lymphoma or DLBCL, the highest grade of CRS was grade 3 (n = 1 follicular lymphoma). The CRS events did resolve within a median of 2 days (range, 1-41) with supportive care measures.

Regarding AEs of special interest, no grade 3 or higher TLS events were reported in either patients with follicular lymphoma or DLBCL; 2 grade 3 or higher TLS events were observed in other patients with B-cell NHL, but they were confined to initial and intermediate odronextamab step-up doses. Moreover, the highest grade of an ICANS-like event that was reported was grade 3 and occurred infrequently, and no patients discontinued odronextamab due to ICANS-like events.

An ongoing international phase 2 trial (NCT03888105) is evaluating the efficacy and safety of odronextamab in patients with relapsed/refractory B-cell lymphoma. Additional studies are planned to evaluate chemotherapy-free combinations with odronextamab, and those with chemotherapy in earlier lines of treatment.

References

1. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979) , a human CD20 x Cd3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 400.
2. Bannerji R, Allan JN, Arnason JE, et al. Clinical activity of REGN1979, a bispecific human, anti-CD20 x anti-CD3 antibody, in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Blood. 2019;134(suppl_1). doi:10.1182/blood-2019-122451.s