Phase 2 Studies of Odronextamab Elicit High Overall Responses in DLBCL and FL

Andres Sirulnik

Findings from phase 2 trials (NCT02290951, NCT03888105) evaluating odronextamab (REGN1979) demonstrated high overall response rates (ORR) in 2 cohorts of patients, including those with relapsed/refractory (R/R) follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL), according to Regeneron Pharmaceuticals, Inc.

The investigational CD20xCD3 bispecific antibody odronextamab is designed to bridge CD20 on cancer cells with CD3-expressing T cells to facilitate local T-cell activation and cancer-cell killing.

According to findings of the 2 trials presented at the American Society of Hematology Annual Meeting 2022, in the DLBCL cohort, there was a 49% ORR in heavily pre-treated patients who were naïve prior to CAR T.¹ A total of 31% achieved a complete response (CR). In the FL cohort of the phase 2 trial, there was an 82% response rate in patients with grades I-IIIA disease, with 75% of the overall population achieving a CR.²

"The phase 1 and pivotal phase 2 odronextamab data demonstrated deep and durable responses that were consistent in patients who progress after CAR-T therapy, which is important as they have particularly difficult-to-treat disease and no effective treatment options. Coupled with its overall safety profile, these clinically important results reinforce the potential of odronextamab to treat this aggressive blood cancer," said Won Seog Kim, MD, PhD, Samsung Medical Center, and Division of Hematology-Oncology at Sungkyunkwan University, in Seoul, South Korea, and trial investigator, in the press release.

“We believe that the results [we shared] at ASH have set a new benchmark in terms of efficacy in this patient population. We are showing an overall response rate of 82%, and importantly, when you look at the response rate, we have observed a 75% complete response rate. This is remarkable and these responses are deep and durable,” added Andres Sirulnik, senior vice president, translational and clinical sciences, hematology, in an interview with Targeted OncologyTM.

In the ongoing, open-label, multicenter, phase 2 ELM-2 trial, over 500 patients are being assessed across 5 independent disease-specific cohorts, including DLBCL, FL, mantle cell lymphoma, marginal zone lymphoma, and other subtypes of B-cell non-Hodgkin lymphoma (B-NHL).¹

The primary end point of the trial is ORR with secondary end points of CR, progression free survival (PFS), overall survival (OS), duration of response, disease control rate, safety, and quality of life.

Then, ELM-1 is an ongoing, open-label, multicenter phase 1 trial where investigators are evaluating the safety and tolerability of odronextamab in patients with CD20+ B-cell malignancies. Patients were previously treated with CD20-directed antibody therapy. In 2 disease specific cohorts, subcutaneous administration is being evaluated.

In the cohort of patients with DLBCL, a total of 130 CAR-T naïve patients who had an opportunity for assessment at 12 weeks and had a median follow-up of 21 months (range, 3-30 months) were included. An additional 31 CAR-T experienced patients were also enrolled in the dose-expansion cohort of the phase 1 trial. These patients had a median follow-up of 24 months (range, 3-38.5 months).

Each patient enrolled had received at least 2 prior therapies, including a CD20 antibody and alkylating agent. Then, patients were administered a step-up regimen of odronextamab in the first cycle to help mitigate the risk of cytokine release syndrome (CRS) prior to receiving the full dose of 160 mg. The step-up regimen was modified part way through the trial to further mitigate CRS.

Findings showed that for patients who were CAR-T naïve, there was an ORR of 49% with 31% achieving a CR. Median duration of complete response (mDOCR) was 18 months (95% CI, 10 months-not evaluable [NE]).

Of the patients who were post-CAR T, there was a 48% ORR. Thirty-two percent of patients achieved a CR and the mDOCR was not reached (95% CI, 2 months-NE).

In the phase 2 cohort which assessed safety, including adverse events (AE), 79% of AEs were grade 3 or higher with the most common AEs in 20% of patients or more including CRS (55%), anemia (42%), pyrexia (39%), neutropenia (28%), and hypokalemia (20%).

For CRS, which was the most common AE, 64% of cases were grade 1 and mild with all cases resolved within a median time of 2 days (range, 1-133 days). No grade 4 or 5 CRS cases were observed.

A total of 10% of patients discontinued treatment due to an AE, and there were 5 deaths due to pneumonia (n = 3), COVID-19 (n = 1), and pseudomonas sepsis (n = 1).

Then for the R/R FL cohort of the trial, 121 patients were enrolled with a median follow-up of 22 months (range, 3-33 months).² In this cohort, all patients had also been given at least 2 previous therapies, including a CD20 antibody and alkylating agent. Patients were treated with a step-up regimen of odronextamab in the first cycle prior to receiving the full dose of 80 mg. This step-up regimen was also modified during the trial to mitigate the risk of CRS.

Results from this cohort revealed there to be an 82% ORR with 75% of patients achieving a CR. The mDOCR was 20.5 months (95% CI, 17 months-NE). The median PFS was 20 months (95% CI, 15 months-NE) and the median OS was not reached (95% CI, NE-NE).

“Importantly, we see the same response rates in both patient populations. We see very similar response rates and very similar complete responses in both patient populations,” added Sirulnik.

Regarding safety, AEs occurred in all patients, with 78% being grade 3 or greater in severity. The most common AEs which occurred in over 20% of patients consisted of CRS (56.5%), neutropenia (40%), pyrexia (31%), anemia (30%), infusion-related reaction (29%), arthralgia (21%), diarrhea (21%), and thrombocytopenia (20%). AEs led to discontinuations in 11.5% of patients. Three deaths were linked with pneumonia, progressive multifocal leukoencephalopathy and systemic mycosis.

In this cohort, CRS was also the most common AE. A total of 68% of cases were mild or grade 1 and all resolved within a median of 2 days (range, 1-51 days). No grade 4 or 5 cases of CRS were observed.

With these data, the phase 3 OLYMPIA development program investigating odronextamab in earlier stages of the disease is in the process of being initiated. The FDA has also granted odronextamab a fast track designation for DLBCL.

“Our overarching vision is not only to combine with standard of care in earlier lines of therapy, so moving into first-line follicular lymphoma, first-line diffuse large B-cell lymphoma and second-line, but also comparing monotherapy vs standard of care. We believe that the level of efficacy that we have observed is compelling enough, and we feel confident that we have a great opportunity to bring patients to have a chemo-free regimen in the future. Both combinations with standard of care and monotherapy will be explored in our phase 3 comprehensive program,” concluded Sirulnik.

REFERENCES:

1. Pivotal odronextamab (CD20XCD3) phase 2 data in patients with relapsed/refractory diffuse large B-cell lymphoma debut at ASH. News release. Regeneron Pharmaceuticals, Inc. December 11, 2022. Accessed January 4, 2023. https://bit.ly/3WYfntW

2. Odronextamab (CD20XCD3) demonstrates high and durable complete response rate among patients with relapsed/refractory follicular lymphoma in pivotal phase 2 trials. News release. Regeneron Pharmaceuticals, Inc. December 12, 2022. Accessed January 4, 2023. https://bit.ly/3QcqbCp