Exploring Bispecific Antibodies and Targeted Approaches in Follicular Lymphoma

Recent advances in the treatment of patients with follicular lymphoma (FL) have included the development of novel immunotherapies in relapsed and refractory disease and long-term follow-up of pivotal trials. A number of clinical studies presented during the 2024 American Society of Clinical Oncology Annual Meeting (ASCO 2024) further delineated effective approaches in this clinical space.

“Overall, a number of trials are combining bispecific antibodies with chemotherapy or chemoimmunotherapy for upfront settings, as well as focusing on dose-limiting or time-limiting therapy in follicular lymphoma,” Julie M. Vose, MD, MBA, the Neumann M. and Mildred E. Harris Professor and chief of the Division of Hematology and Oncology at the University of Nebraska Medical Center/Nebraska Medicine in Omaha, told Targeted Therapies in Oncology during an interview.

At ASCO 2024, Vose and colleagues¹ presented data demonstrating the ability to reduce the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that patients experience when given the bispecific antibody epcoritamab (Epkinly). Improving the safety of epcoritamab may improve accessibility and reduce health care resource use, the investigators postulated.

The FDA granted approval to epcoritamab based on findings from the pivotal phase 1/2 EPCORE NHL-1 study (NCT03625037) in which 128 patients with relapsed/refractory FL who had received at least 2 prior lines of therapy were given epcoritamab in 3 step-up doses of 0.16 mg (day 1), 0.8 mg (day 8), and 48 mg (day 15) during cycle 1.² Hospitalization was required for 24 hours following the first full dose, and patients were given prednisolone for CRS prophylaxis.

"We were trying to see if we could reduce hospitalizations and toxicity by including an additional step-up dose of 3 mg on day 15 of the cycle 1 optimization (OPT; n = 86) cohort," Vose said. This subsequently shifted the first full dose of 48 mg to day 22. In addition, patients received 15 mg of dexamethasone prior to each step-up dose, as well as intravenous hydration. “In our study, hospitalization was not mandated, it was optional,” Vose added. The data cutoff was January 8, 2024, and the median follow-up was 5.7 months.¹

Baseline characteristics were similar between the study cohorts. Similar to the pivotal cohort, the OPT cohort included patients with high-risk relapsed/refractory disease. The median age in the pivotal cohort was 65 years (range, 39-84), and in the OPT cohort, it was 63.5 years (range, 33-90). Eighty-five percent of patients had stage III to IV disease in the pivotal study compared with 92% of patients in the OPT trial. In the pivotal trial, 61% had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5 compared with 51% of patients in the OPT trial. All patients had 2 or more prior lines of therapy, including a regimen containing an anti-CD20 monoclonal antibody. Further, 31% of patients in the pivotal cohort received 4 or more lines of therapy compared with 20% in the OPT cohort.¹

Prior treatments that OPT participants received included alkylating agents (98%), anthracyclines (76%), bendamustine (60%), and nucleotides (38%).¹

In the pivotal trial, 37% of patients had ongoing treatment compared with 74% in the OPT trial. Sixty-three percent of patients in the pivotal cohort discontinued treatment compared with 26% in the OPT trial.¹

When the incidence and severity of CRS and ICANS were compared between the 2 trials, grade 1 CRS for both cohorts was the same (40%), but grade 2 and 3 cohorts diverged. Grade 2 CRS in the pivotal trial was 25% vs 9% in the OPT trial. Grade 3 CRS was 2% in the pivotal trial vs 0% in the OPT trial. In both cohorts, most CRS occurred after the first full dose and was conf ined to cycle 1.¹

“Regarding ICANS, there was a small percentage reported in the pivotal trial [6%] compared with 0% in the optimization trial,” Vose said.

Vose then turned to IL-6 levels. “Consistent with the lower rates of CRS, in cycle 1, the IL-6 levels 24 hours after the first full dose were lower in the OPT cohort as compared with the pivotal study,” she said.¹ In both cohorts, high rates of complete response and minimal residual disease (MRD) negativity were present, Vose said. The MRD negative rate at C3D1 was 63% and the MRD negative rate at any point was 66%, which correlated with a marked improvement in PFS.

In both cohorts, median time to response was 1.4 months and median time to complete response was 1.5 months.¹ The step-up drug regimen, prophylactic dexamethasone administration, and hydration substantially reduced the incidence and severity of CRS and ICANS with epcoritamab, Vose said. The MRD negative rate at C3D1 was 63% and the MRD negative rate at any point was 66%, which correlated with a marked improvement in PFS. In both cohorts, median time to response was 1.4 months and median time to complete response was 1.5 months.

The step-up drug regimen, prophylactic dexamethasone administration, and hydration substantially reduced the incidence and severity of CRS and ICANS with epcoritamab, Vose said.

“Patients were able to be [treated] as outpatients with the appropriate step-up dosing and supportive care,” Vose said. “It’s huge for the patients to be able to do that without having to be admitted to the hospital.” The data support the feasibility and safety of epcoritamab as a potential outpatient treatment for patients with relapsed/ refractory FL, she concluded.

Epcoritamab Plus Rituximab and Lenalidomide

Also presented at ASCO 2024 were results from the phase 1/2 EPCORE NHL-2 trial (NCT04663347; arms 6 and 7).³ The trial explored adding rituximab (Rituxan) and lenalidomide (Revlimid) to epcoritamab. Investigators assessed the long-term safety and efficacy of the 3-drug combination in frontline FL therapy (updated data from arm 6) and epcoritamab monotherapy as maintenance treatment after standard of care (SOC) in FL (arm 7).³

The triplet therapy demonstrated an objective response rate (ORR) of 95% and a complete response rate of 85%. At 18 months, an estimated 90% of patients remained progression free. CRS was low grade and consistent with prior safety reports, and its onset was predictable and confined to cycle 1. Investigators reported no ICANS or clinical lysis syndrome.³

For patients in arm 7 of the study, Lori et al reported no new safety signals in epcoritamab maintenance after SOC. Common treatment-emergent adverse effects (TEAEs) were low grade, and the most common TEAEs that led to discontinuation were myelodysplastic syndrome (MDS) and respiratory failure (n = 1 for each). However, the investigators did not deem the MDS to be related to the epcoritamab.³

Similar to arm 6, for patients in arm 7, CRS timing was predictable with events occurring primarily during cycle 1. All CRS events were low grade and resolved, and no cases of ICANS or tumor lysis syndrome were reported.³

Abexinostat

Also at ASCO 2024, the oral histone deacetylase inhibitor abexinostat was evaluated in a phase 2 study (NCT03934567) in patients with relapsed/refractory FL.⁴ A total of 90 patients received 80 mg of abexinostat twice a day, 4 hours apart, in a 1-week-on, 1-week-off schedule (days 1-7 and 15-21 on a 28-day cycle).

The primary end point was ORR as determined by an independent review committee. Secondary end points included duration of response, progression-free survival, overall survival (OS), and safety.⁴

Median age was 55 years (range, 27-79), and 57.8% were men. Forty-one patients were classified as intermediate/high risk per FLIPI-2 criteria. The majority of patients (35.6%) had 2 prior lines of treatment, and 27.8% had received prior PI3K inhibitor treatment.⁴

Of the 90 patients evaluable for safety, the most common treatment-related adverse events (TRAEs) reported were thrombocytopenia (85.6%), neutropenia (58.9%), leukopenia (52.2%), and nausea (44.4%). Grade 3 or higher TRAEs included thrombocytopenia (36.7%), neutropenia (23.3%), and leukopenia (7.8%). TEAEs led to dose reductions and discontinuations in 30.0% and 3.3% of all patients, respectively.⁴ The most common (≥ 40%) treatment-emergent adverse events (TEAEs) were thrombocytopenia (85.6%), neutropenia (58.9%), and leukopenia (52.2%).⁴

With a median follow-up of 20.8 months, of the 82 patients evaluable for efficacy, ORR was 67.1%. The median PFS was 13.77 months, and the median duration of response (DOR) was 13.96 months.⁴

The investigators concluded that single- agent abexinostat was well tolerated at a dose of 80 mg and demonstrated a significant response in patients with heavily pretreated relapsed/refractory FL.

A randomized phase 3 confirmatory trial will determine the benefit of the agent with combinations in patients with relapsed/ refractory FL after 1 or more prior therapies, reported investigators.

Odronextamab

The ongoing phase 3 OLYMPIA-5 trial (NCT06149286)5 determined whether the combination of odronextamab plus lenalidomide could show a deeper response in patients compared with patients treated with rituximab plus lenalidomide. OLYMPIA-5 is a 2-part trial, with part 1 evaluating how safe and tolerable the agent is when used in combination with lenalidomide in patients with FL or marginal zone lymphoma (MZL). The aim of part 2 is to compare the combination of odronextamab and lenalidomide with rituximab and lenalidomide.⁵

Patients were eligible for enrollment if they had FL grade 1 to 3a, refractory or relapsed disease, and an ECOG performance status of 0,1, or 2.⁵

For part 2, 422 patients with relapsed/ refractory FL or MZL were randomly assigned to receive either odronextamab or lenalidomide for up to twelve 28-day cycles. Investigators report that step-up dosing of odronextamab will be implemented during cycle 1 to help mitigate the risk of CRS. The full dose was administered from cycle 1, day 22, forward.⁵

Another ongoing trial featuring odronextamab is the phase 3 OLYMPIA-2 trial (NCT06097364), which is evaluating odronextamab plus chemotherapy vs the current first-line SOC, rituximab plus chemotherapy.⁶ Investigators report that the effect of odronextamab maintenance on improving efficacy outcomes will also be determined.

OLYMPIA-2 is also a 2-part trial with an initial dose escalation and optimization portion followed by part 2 involving a 3-arm randomization.

Patients in arm A will receive odronextamab plus chemotherapy, arm B will receive odronextamab plus chemotherapy plus odronextamab maintenance, and arm C will receive rituximab plus chemotherapy plus rituximab maintenance.

FDA Approvals

Two FDA approvals in 2024 have expanded the clinical landscape of FL as well: the combination of zanubrutinib (Brukinsa) and obinutuzumab (Gazyva),⁷ and the targeted subcutaneous agent epcoritamab.²

The FDA granted accelerated approval to the combination of zanubrutinib and obinutuzumab on March 7, 2024, supported by findings from the phase 2 ROSEWOOD trial (NCT03332017),⁷ an open-label, multicenter, randomized trial that enrolled 217 adult patients with relapsed or refractory FL after at least 2 prior systemic treatments. Patients were randomly assigned 2:1 to receive either zanubrutinib 160 mg orally twice daily plus obinutuzumab (ZO) until disease progression or unacceptable toxicity, or obinutuzumab alone.⁷

Investigators reported that ORR was 69% (95% CI, 61%-76%) in the ZO arm and 46% (95% CI, 34%-58%) in the obinutuzumab arm (2-sided P = .0012). With a median follow-up of 19.0 months, the median DOR was not reached in the ZO arm (95% CI, 25.3-not evaluable) and was 14.0 months (95% CI, 9.2-25.1) in the obinutuzumab arm. The estimated DOR rate at 18 months was 69% (95% CI, 58%-78%) in the ZO arm.⁷

Looking Ahead

Vose is encouraged about the opportunities that bispecific antibodies will offer to patients who are not candidates for cellular therapy.

“A lot of these bispecific antibodies are becoming more available, especially in the community setting. I think we’ll see a lot more use of these agents for older patients or for patients who are not candidates for CAR [chimeric antigen receptor] T-cell therapy,” Vose said.

She notes that the use of less- intensive therapy for patients has garnered more interest. “There is some evidence that decreasing the amount of treatment in some patients will still result in a cure or long-term survival. Our study, which decreased toxicity, adds to that, but there is still a lot of work to be done,” Vose concluded.

REFERENCES:

1. Vose JM, Vitolo U, Lugtenburg PJ, et al. EPCORE NHL-1 follicular lymphoma (FL) cycle (c) 1 Optimization (OPT) cohort: expanding the clinical utility of epcortimab in relapsed or refractory FL. J Clin Oncol. 2024;42(suppl 16):70157015. doi:10.1200/JCO.2024.42.16_suppl.7015

2. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. News release. Accessed August 1, 2024. https://tinyurl.com/ye5jna9w

3. Lori LA, Falchi L, Vermaat JSP, et al. Epcoritamab with rituximab + lenalidomide (R2) in previously untreated (1L) follicular lymphoma (FL) and epcoritamab maintenance in FL: EPCORE NHL-2 arms 6 and 7. J Clin Oncol. 2024;42(suppl 16):7014-7014. doi:10.1200/JCO.2024.42.16_suppl.7014

4. Shi Y, Gui L, Cheng Y, et al. A phase II multicenter study of abexinostat, an oral histone deacetylase inhibitor, in patients with relapsed/refractory follicular lymphoma. J Clin Oncol. 2024;42(suppl 16):7059-7059. doi:10.1200/JCO.2024.42.16_ suppl.7059

5. Vitolo U, Merli M, Norasetthada L, et al. Phase 3 trial of odronextamab plus lenalidomide versus rituximab plus lenalidomide in relapsed/refractory (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL; OLYMPIA-5). J Clin Oncol. 2024;42(suppl 16):TPS7094-TPS7094. doi:10.1200/ JCO.2024.42.16_suppl.TPS7094

6. Hardin C, Gray C, Novelli S, et al. Phase 3 trial evaluating the efficacy and safety of odronextamab plus chemotherapy versus rituximab plus chemotherapy in previously untreated follicular lymphoma (OLYMPIA-2). J Clin Oncol. 2024; 42 (suppl 16):TPS7099-TPS7099. doi:10.1200/JCO.2024.42.16_ suppl.TPS7099

7. FDA grants accelerated approval to zanubrutinib for relapsed or refractory follicular lymphoma. News release. Accessed August 1, 2024. https://tinyurl.com/mvppetxu