Odronextamab Exhibits Continued Clinical Activity and Tolerable Safety Profile in R/R DLBCL

Odronextamab (REGN1979) produced durable responses and a generally manageable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to the final results of the pivotal phase 2 ELM-2 trial (NCT03888105) that were presented during the 2023 ASH Annual Meeting.¹

Sabarish Ram Ayyappan, MD, medical director of hematologic malignancies, City of Hope Cancer Treatment Center, Atlanta, presented the final analysis at the meeting.

Median follow-up for efficacy data was 29.9 months (range, 20.4-32.6), and included 127 patients.

The ORR and complete response (CR) rates with odronextamab monotherapy were 52.0% and 31.5%, respectively, which were consistent across subgroups, Ayyappan said.

The median duration of response (DOR) was 10.2 months (95% CI, 5.0-17.9), with 12- and 24-month DOR rates of 48.1% (95% CI, 35.1%-59.9%) and 36.9% (95% CI, 24.2%-49.6%), respectively. Similarly, the median duration of complete response (DOCR) was 17.9 months (95% CI, 10.2-not evaluable [NE]), with 12- and 24-month DOCR rates of 61.5% (95% CI, 44.4%-74.8%) and 47.2% (95% CI, 29.7%-62.9%), respectively.

Ayyappan noted that response data for odronextamab were consistent with results from the phase 1 ELM-1 trial (NCT02290951) of the safety and efficacy of odronextamab in patients with relpased or refractory non-Hodgkin lymphoma.²

In the entire cohort of the phase 2 trial, median PFS was 4.4 months (95% CI, 3.6-5.9), while 12- and 24-month PFS rates were 29.6% (95% CI, 21.5%-38.2%) and 21.2% (95% CI, 13.7%-29.7%), respectively. When evaluating PFS by best overall response, the median PFS was 20.4 months (95% CI, 12.7-NE) in patients with a CR (n = 40), compared with 5.8 months (95% CI, 4.4-7.8) among those with a partial response (n = 26). Further, the 12- and 24-month PFS rates were 67.2% (95% CI, 50.3%-79.5%) and 47.5% (95% CI, 29.9%-63.1%), respectively, in complete responders, and were 25.2% (95% CI, 9.5%-44.7%) and 18.9% (95% CI, 5.4%-38.6%) in partial responders.

Median OS among the entire cohort was 9.2 months (95% CI, 6.5-12.7). The 12- and 24-month OS rates were 42.9% (95% CI, 33.7%-51.8%) and 31.6% (95% CI, 22.4%-41.4%), respectively. When stratified by best overall response, the median OS was not reached in complete responders, compared with 17.0 months (95% CI, 9.6-27.3) in partial responders. The 12- and 24-month PFS rates in complete responders was 75.0% (95% CI, 58.5%-85.7%) and 59.6% (95% CI, 41.7%-73.7%), respectively, and were 60.2% (95% CI, 37.2%-77.0%) and 30.5% (95% CI, 9.3%-55.3%) in partial responders.

Ayyappan noted that patient-reported outcome scores with odronextamab were maintained or improved from baseline through week 42, including the European Organization for Research of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 Pain score (change from baseline to week 42, –4.39; 95% CI, –7.92 to –0.85) and EORTC QLQ-C30 Emotional Functioning score (change from baseline to week 42, 6.06; 95% CI, 3.30-8.83).

Further, the investigators identified biomarkers of interest from their findings after cycle 4, day 15, which showed that patients who had circulating tumor DNA (ctDNA) detected, vs those who were cleared, demonstrated a reduced risk for disease progression by 73% (HR, 0.27; 95% CI, 0.12-0.61). Similarly, those with ctDNA detection with minimal residual disease (MRD) response who had no complete remission, compared with those with clear ctDNA results, also demonstrated a lower risk for disease progression (HR, 0.11; 95% CI, 0.025-0.49). Also of note, patients with EZB classification had reduced risk for disease progression, vs MCD or other LymphGen classification.

The safety profile of odronextamab was consistent with previous findings. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 84.3% of patients, while 64.6% experienced a serious TEAE. TEAEs led to treatment interruption in 72.4% of patients, reduction in 3.1%, discontinuation in 13.4%, and death in 15.7%).

TEAEs included cytokine release syndrome (CRS; 55.1%), pyrexia (43.3%), anemia (38.6%), neutropenia (30.7%), diarrhea (22.0%), cough (20.5%), thrombocytopenia (18.9%), hypokalemia (18.9%), infusion reaction (18.1%), fatigue (16.5%), COVID-19 (16.5%), and nausea (15.0%).

With the optimized step-up regimen initiated on the study, any grade CRS occurred in 53.3% of patients–including 24 patients with grade 1, 7 with grade 2, 1 with grade 3, and no patients with grade 4 CRS. The median time to onset was 18 hours (range, –3.41-221.0) and lasted for a median of 2 days (range, 1.0-7.0). Thirteen patients used systemic steroid for their CRS management compared with 15 patients treated with tocilizumab.

Ayyappan noted that CRS events were almost all low grade and were generally confined to cycle 1 of treatment with odronextamab. Further, no immune effector cell-associated neurotoxicity syndrome was reported.

Infections occurred more commonly among patients who were heavily pretreated, “given the expected mechanism of action of odronextamab,” he said. The most common infections were comprised of COVID-19 (16.5%), pneumonia (14.2%), upper respiratory tract infection (8.7%), urinary tract infection (8.7%), and Pneumocytis jirovecii pneumonia (6.3%). Treatment-related infections led to treatment discontinuation in 4.7% of patients.

ELM-2 Study

In the open-label, multicohort, multicenter, phase 2 study, patients with relapsed/refractory DLBCL were treated with weekly odronextamab administered in 21-day cycles as follows:

• Cycle 1: Odronextamob administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg.
• Cycle 2 through 4: 160 mg odronextamab on days 1, 8, and 15 of each cycle.
• Maintenance therapy: 320 mg odronextamab every 2 weeks.

Treatment was continued until disease progression or unacceptable toxicity.

Of note, to mitigate CRS, optimization of a step-up regimen was implemented. In total, 67 patients (52.8%) received the initial regimen of 1/20 mg, while 60 (47.2%) were given the optimized regimen.

Patients were eligible for the trial if they had DLBCL per WHO 2016 classification, had an ECOG performance status score of 0 or 1, and had disease that was refractory to or relapsed after 2 or more prior lines of therapy, including an anti-CD20 antibody and an alkylator.

ORR by independent committee review served as the study’s primary end point. Secondary end points included ORR by local investigator, CR, DOR, PFS, and OS. Safety and tolerability, as well as patient-reported outcomes were also evaluated, while MRD served as an exploratory end point.

The final analysis was performed when all patients with DLBCL had the opportunity for 36 weeks of follow-up or more.

Ayyappan highlighted that measures were taken to ensure the trial enrolled a diverse and inclusive patient population, including the utilization of diverse trial sites; translated consents for under-represented populations; extended screening windows for patients with access restraints; broad eligibility criteria to include patients with controlled HIV and hepatitis B and C; and lower thresholds for those with compromised organ function.

Of the 127 patients included in the DLBCL global cohort of the study, median age was 67 years (range, 24-88), including 23.6% who were aged 75 or older. Most patients were male (59.8%), reported with Ann Arbor stage III to IV disease (81.1%), and had an ECOG performance score of 1 (67.7%). In total, 48.0% of patients were White, and 41.7% were Asian, while 10.2% did not report their race.

The median number of prior lines of therapy was 2 (range, 2-8). Overall, 55.1% of patients had primary refractory disease, 86.6% were refractory to their last line of therapy, 78% were refractory to an anti-CD20 antibody agent in any line of therapy, and 64.6% were double refractory to alkylator/anti-CD20 antibody therapy in any line.

After a median follow-up of 32.8 months (range, 15.0-42.8), the median number of completed cycles in the trial was 7 (range, 0.3-82.1), with 91.3% of patients having completed cycle 1 and 63% completing 4 or more cycles.

FDA Implication

In September 2023, the FDA granted priority review to the biologics license application (BLA) that is seeking the approval of odronextamab to treat adult patients with relapsed/refractory follicular lymphoma or relapsed/refractory DLBCL who have progressed after at least 2 prior systemic therapies.³

“Despite advances in care, the outcomes in relapsed/refractory diffuse large B-cell lymphoma are poor and there is a need for novel therapies,” Ayyappan explained during the presentation, adding that odronextamab, an investigational CD20xCD3 bispecific antibody, has demonstrated encouraging efficacy and manageable safety in the EML-1 and ELM-2 trials, which were the basis for the BLA.

In ELM-1, designed to evaluate odronextamab in patients who previously received CAR T-cell therapy, the agent induced an ORR of 33.3% and CR rate of 26.7%, while median DOR was not reached. According to the interim analysis of the ELM-2 trial, ORR was 49.2%, with a CR rate of 30.8% and median DOR was 10.2 months.^1-2

According to a press release issued by Regeneron, the agent’s manufacturer, odronextamab, if approved, would be the first and only bispecific antibody approved in both follicular lymphoma and DLBCL.³

The FDA set a Prescription Drug User Fee Act decision date of March 31, 2024.

Further, based on these data, Ayyappan said that randomized phase 3 trials of odronextamab in earlier lines of therapy are underway, including the OLYMPIA-3 trial (NCT06091865) in patients with previously untreated DLBCL, and the OLYMPIA-4 trial in patients with relapsed/refractory disease.

References

1. Ayyappan S, Kim WS, Kim TM, et al. Final Analysis of the Phase 2 ELM-2 Study: Odronextamab in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL). Blood. 2023;142(1):436. doi:10.1182/blood-2023-179818.
2. Kim TM, Taszner M, Cho SG, et al. Odronextamab in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Grade 1-3a: Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2. Blood. 2022;140(1):2280–2282. doi:10.1182/blood-2022-158404.
3. Odronextamab BLA for treatment of relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) accepted for FDA priority review. News release. Regeneron Pharmaceuticals. September 29, 2023. Accessed September 29, 2023. https://tinyurl.com/23eru7am