Bispecific antibodies targeting CD20 and CD3 led to response rates as high as 90% in patients with refractory B-cell non-Hodgkin lymphoma (B-NHL), including patients who had received CAR T-cell therapy, according to preliminary clinical results.
The data showed that 27 of 30 patients with follicular lymphoma (FL) responded to odronextamab, including complete responses (CRs) in 21 cases. Median duration of response had yet to be reached, and 22 of 27 responses lasted at least 3 months (and for as long as 41 months).
Additionally, six of 11 patients with diffuse large B-cell lymphoma (DLBCL) responded to the antibody (five CRs), as did a third of a cohort of patients with post-CAR T-cell DLBCL, reported Rajat Bannerji, MD, PhD, of Rutgers Cancer Institute of New Jersey in New Brunswick.
“Odronextamab is a CD20 by CD3 bispecific antibody, which offers an off-the-shelf, primarily outpatient treatment option for relapsed or refractory B-NHL,” Bannerji said at the American Society of Hematology virtual meeting. “In the first-in-human phase I trial, odronextamab has demonstrated compelling antitumor activity, including durable complete responses, in heavily pretreated patients with FL and DLBCL.
“In addition, odronextamab shows an acceptable benefit-risk profile, with the highest grade of CRS [cytokine release syndrome] of grade three and was mostly confined to initial and intermediate step-up doses,” he continued. “The highest grade of an ICANS [immune effector cell-associated neurotoxicity]-like event was grade three, and no tumor lysis syndrome was observed in these patients.”
In another study, subcutaneously administered epcoritamab reached the 90% response threshold in patients with DLBCL and FL, including patients previously treated with CAR T-cell therapy. The most common treatment-emergent adverse events (TEAEs) were pyrexia, disease progression, and pneumonia. One patient developed grade 3 tumor lysis syndrome, and four patients had transient neurologic symptoms (grade 3 in two cases), reported Martin Hutchings, MD, of Rigshospitalet and Copenhagen University Hospital in Denmark.
Bannerji reported findings for 136 patients with previously treated NHL. Most had relapsed/refractory DLBCL (57.4%) or grade 1-3 FL (27.9%). All patients had received at least one prior line of therapy (median of three) and as many as 11. A fourth of the patients had received prior CAR T-cell therapy, 80% were refractory to their most recent therapy, and two thirds were refractory to both an alkylating agent and an anti-CD20 antibody.
The antibody is administered intravenously on an outpatient basis with dexamethasone premedication and split step-up dosing to reduce the risk of CRS during the first 2 weeks, he explained. Treatment then continues weekly for 12 weeks, followed by every 2 weeks until disease progression.
The most common grade ≥3 TEAEs were anemia (24.3%), lymphopenia (20.6%), neutropenia (18.4%, febrile in 2.2%), and hypophosphatemia (18.4%). Nine patients discontinued odronextamab because of adverse events, but none because of CRS or neurotoxicity, he noted, adding that CRS occurred in 64% of patients but reached grade 3 severity in 6.6% and grade 4 in less than 1%.
In the FL subgroup, all patients had some degree of target-lesion regression across the dose range of 5-320 mg. Odronextamab achieved objective responses in six of 11 patients with DLBCL and no prior CAR T-cell therapy and eight of 24 patients with DLBCL and prior CAR T-cell exposure. Almost all of the CRs were durable in the DLBCL subgroups and persisted for as long as 21 months, Bannerji said.
He noted that enrollment has begun for a pivotal phase II trial of odronextamab in relapsed/refractory NHL, and studies of chemotherapy-free and chemotherapy-containing combinations (including earlier lines of treatment) have been planned.
Subcutaneous administration distinguishes epcoritamab from competing therapies in the class. Besides being more convenient and less time consuming, subcutaneous administration leads to more gradual increases in plasma cytokine levels and lower peak levels, Hutchings explained, noting that potency studies showed T cell-mediated killing at low levels of CD20 expression.
He reported findings from a phase I/II trial involving adults with relapsed/refractory CD20-positive B-cell NHL and prior treatment with an anti-CD20 antibody. Investigators enrolled a total of 68 patients, including 48 with DLBCL and 12 with FL. Almost all the patients had received anthracyclines and alkylating agents, about 10% had undergone autologous stem-cell transplants, and 10% had received prior CAR T-cell therapy.
Although a majority of patients developed CRS, no cases reached grade 3 severity, and most TEAEs, regardless of type, were grade 1/2 in severity, he said.
The investigators evaluated epcoritamab doses of 0.0128 to 60 mg. Response data included 23 patients from the DLBCL cohort treated with doses of 12-60 mg and 11 from the FL cohort treated with doses of 0.76-48 mg.
Hutchings reported that 15 of 22 (68%) of evaluable patients with DLBCL responded to the bispecific antibody, including CRs in 10 patients. Among 12 patients treated with the recommended phase II dose (48 mg) or higher, 11 responded (91%), including six CRs.
In the FL cohort, nine of 10 evaluable patients responded, including five CRs. Additionally four of five patients treated with 12-48 mg had objective responses, which were CRs in three of the four cases. Additionally, two of four patients with mantle cell lymphoma responded to epcoritamab.
“The recommended phase II dose was reached with no dose-limiting toxicities, and the maximum tolerated dose was not reached,” said Hutchings. “With longer follow-up, epcoritamab continues to demonstrate a favorable safety profile, and substantial single-agent activity was observed, including high overall response rates and complete responses in patients with diffuse large B-cell lymphoma, follicular lymphoma, and mantle-cell lymphoma.
“The route of epcoritamab administration, along with its great tolerability and distinct binding epitopes, supports the potential for outpatient administration, use in earlier lines, and as part of most drug combination regimens,” he said.
The odronextamab study was supported by Regeneron Pharmaceuticals.
Bannerji disclosed relationships with Regeneron, AbbVie, F. Hoffmann-La Roche/Genentech, Pharmacyclics, and Sanofi-Pasteur.
The epcoritamab study was supported by Genmab in collaboration with AbbVie.
Hutchings disclosed relationships with Genmab, Celgene, Roche, Takeda, Janssen, Novartis, and Sanofi.