Odronextamab Elicits Durable Responses in Heavily Pretreated R/R Follicular Lymphoma

Treatment with odronextamab elicited deep and durable responses in heavily pretreated patients with relapsed/refractory follicular lymphoma (FL), according to data from the phase 2 ELM-2 study (NCT03888105) presented at the 2024 EHA Congress.

Findings showed that at a median follow-up of 20 months (95% CI, 17.3-27.8), evaluable patients (n = 128) experienced an overall response rate (ORR) of 80% (95% CI, 72.5%-86.9%) and a complete response (CR) rate of 73% (95% CI, 64.9%-80.9%). The median duration of response (DOR) was 23 months (95% CI, 17.7–not evaluable [NE]), and the 12- and 24-month DOR rates were 72% (95% CI, 61.6%-79.8%) and 46% (95% CI, 33.2%-58.5%), respectively. The median duration of complete response (DOCR) was 25 months (95% CI, 20.5-NE), and the respective 12- and 24-month DOCR rates were 75% (95% CI, 64.5%-82.7%) and 50% (95% CI 36.1%-63.0%).

“Odronextamab could offer an important off-the-shelf treatment option for heavily pretreated patients with relapsed/refractory FL,” lead study author Michal Taszner, MD, of the Medical University of Gdańsk in Poland, said during a presentation of the data.

Odronextamab, an Fc-silenced human CD20×CD3 bispecific antibody, is currently being investigated in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, including FL, in the open-label, multicohort, multicenter ELM-2 study.

In the FL cohort, patients were eligible if they had grade 1 to 3a FL, an ECOG performance status of 0 or 1, and were relapsed or refractory following 2 or more prior lines of therapy, including an anti-CD20 antibody and an alkylator.

Enrolled patients in the FL cohort received intravenous (IV) odronextamab during 21-day cycles. Cycle 1 included step-up dosing with split infusion of 0.7 mg on days 1 and 2, 4 mg on days 8 and 9, and 20 mg on days 15 and 16. In cycles 2 to 4, odronextamab was given at 80 mg on days 1, 8, and 15; cycles 5 and beyond included maintenance therapy with odronextamab at 160 mg once every 2 weeks, or once every 4 weeks if a patient experienced a CR at least 9 months in duration.

Anti-infection prophylaxis recommendations included IV immunoglobulin supplementation, antivirals, and prophylaxis for pneumocystis jirovecii pneumonia. IV immunoglobulin supplementation was advised for patients with severe hypogammaglobulinemia (<400 mg/dL) or those with recurrent infections and immunoglobulin levels between 400 and 600 mg/dL.

Additionally, the primary end point of the study was ORR by independent central review. Secondary end points included investigator-assess ORR, CR rate, DOR, progression-free survival (PFS), overall survival (OS), safety, tolerability, and patient-reported outcomes.

Notably, 53% of the patients received a step-up regimen of 1 mg and 20 mg in cycle 1, and 47% of patients received the step-up regimen of 0.7 mg, 4mg, and 20 mg following a protocol amendment to further mitigate the risk of cytokine release syndrome (CRS). The median number of completed treatment cycles was 19 (range, 0.1-96.0); 95% of patients completed at least 1 cycle; and 85% completed 4 or more cycles.

Patients enrolled on the study had a median age of 61 years (range, 22-84), a majority of patients were younger than 65 years of age (62%), most patients were male (53%), and most patients were White (62%). Moreover, patients had an ECOG performance status of 0 (51%), 1 (48%), or 2 (1%). An Ann Arbor stage of III-IV was reported in 85% of patients. Regarding FL International Prognostic Index scores, patients had a score of 0 to 1 (16%), 2 (26%), or 3 to 5 (58%). Notably, bulky disease per investigator assessment was reported in 14% of patients.

Patients received a median of 3 prior lines of therapy (range, 2-13), and prior treatments included a PI3K inhibitor (14%), lenalidomide (Revlimid) plus rituximab (Rituxan; 13%), and autologous stem cell transplant (30%). Additionally, 72% of patients were refractory to their last line of therapy. Seventy-four percent of patients were refractory to an anti-CD20 antibody, 41% were double refractory to an alkylator and anti-CD20 antibody, and 49% of patients had progression of disease within 2 years (POD24).

“The subgroup analysis of achieved responses showed consistent efficacy across most high-risk subgroups, including patients with POD24, patients refractory to the last line of therapy, and [patients who were] double refractory,” Taszner added during the presentation.

Additional data showed the median PFS was 21 months (95% CI, 17.2-27.5). The 12-month PFS rate was 66% (95 % CI, 56.9%-74.0%), and the 24-month PFS rate was 46% (95% CI, 35.1%-56.3%).

Moreover, the median PFS was 28 months (95% CI, 23.0-NE) in patients who achieved a CR (n = 94) and 11 months (95% CI, 4.4-19.5) in patients who had a PR (n = 9). The 12-month PFS rate was 79% (95% CI, 68.9%-86.0%) in patients with a CR and 50% (95% CI, 15.2-77.5) in patients with a PR, whereas the respective 24-month PFS rates were 58% (95% CI, 44.5%-69.6%) and NE (95% CI, NE-NE).

"The exploratory analysis of PFS by minimal residual disease [MRD] as assessed by circulating tumor DNA at the time point of cycle 4, day 15, revealed that [patients who were] MRD negative had a better PFS than the patients with positive detectable disease [HR, 0.3; 95% CI, 0.1-0.7],” Taszner explained.

Furthermore, it was noted that patients with low or undetectable CD20 expression by immunohistochemistry or mRNA level could still achieve a CR with odronextamab.

The median OS was not reached (95% CI, 32.4-NE) in all patients. The 12-month OS rate in all patients was 86% (95% CI, 78.7%-91.2%), and the 24-month OS rate was 70% (95% CI, 59.7%-78.3%). The median OS was not reached (95% CI, 40.4-NE) in patients with a CR and 18 months (95% CI, 12.6-NE) in patients with a PR. The 12-month OS rate was 92% (95% CI, 84.8%-96.3%) in patients with a CR and 100% (95% CI, 100%-100%) in patients with a PR; the 24-month OS rates were 81% (95% CI, 69.3%-88.6%) and 19% (95% CI, 0.9%-55.4%) in these respective groups.

All patients experienced any treatment-emergent adverse effects (TEAEs), including 92% who had treatment-related TEAEs. Notably, 86% of patients experienced grade 3 and higher TEAEs, and 68% had serious TEAEs. Sixty-four percent of patients had grade 3 or higher treatment-related TEAEs, and 45% had serious treatment-related TEAEs.

TEAEs led to treatment interruption, dose reduction, and discontinuation, in 84%, 9%, and 16% of patients, respectively. Treatment-related TEAEs led to treatment interruption, dose reduction, and treatment discontinuation in 63%, 9%, and 8% of patients, respectively. TEAEs leading to death occurred in 14% of patients, and 3% of patients died due to treatment-related TEAEs.

The most common any-grade TEAEs reported in at least 15% of patients included CRS (56%), neutropenia (39%), pyrexia (38%), anemia (34%), COVID-19 (32%), infusion-related reaction (30%), diarrhea (28%), hypokalemia (22%), arthralgia (22%), nausea (20%), fatigue (19%), headache (19%), constipation (18%), increased alanine aminotransferase (18%), rash (18%), and cough (16%).

Regarding AEs of special interest, any-grade CRS occurred in 57% of patients treated with 0.7 mg, 4 mg, and 20 mg step-up dosing, including 45% with grade 1/2 CRS and 10% with grade 3 CRS. The median time to CRS onset was 20 hours (range, 0.7–159), and the median duration of CRS was 8 hours (range, 0.6-184). Thirty-three percent of patients received systemic steroids to manage CRS, and 17% were given tocilizumab.

Additional AEs of special interest were infections. Any-grade infection was reported in 80% of all patients. These included grade 1 (5%), grade 2 (32%), grade 3 (28%), grade 4 (3%), and grade 5 (11%) infections. Thirty-seven percent of patients had any-grade COVID-19, and the respective rates of grade 1 to 5 COVID-19 were 7%, 13%, 10%, 0%, and 6%.

“Rates of infection were consistent with those expected in heavily pretreated, immunosuppressed patients,” Taszner concluded.

Reference

Taszner M, Chong G, Novelli S, et al. Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients with relapsed/refractory follicular lymphoma. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract S232.