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The FDA granted fast track to EO2463, an OncoMimics immunotherapy, for low–tumor burden follicular lymphoma in the watch-and-wait setting.
The FDA has awarded fast track designation to the OncoMimics immunotherapy EO2463 for use as a potential therapeutic option in patients with follicular lymphoma and low tumor burden who are in the “watch-and-wait” setting, according to an announcement from Enterome.1
“The FDA’s decision is an important validation of the unique potential of Enterome’s OncoMimics™ program,” Pierre Belichard, chief executive officer of Enterome, stated in the news release. “It will expedite the clinical development and the regulatory pathways for EO2463, which is ready to enter registrational testing as early as next year after this fast track designation and a recent positive type C meeting with the FDA.”
Interim data from cohort 2 of the phase 2 SIDNEY trial (NCT04669171) presented during the 2024 ASH Annual Meeting showed that EO2463 monotherapy elicited an objective response rate (ORR) of 46% in the first 13 patients; this included a complete response (CR) rate of 15% and a partial response rate of 31%; 31% of patients had stable disease and 23% had indeterminate response.2,3 The approach was found to have acceptable tolerability with no severe toxicities reported.
“These data provide encouraging indications that EO2463 can safely induce meaningful responses in patients with newly diagnosed follicular lymphoma typically managed with observation alone, addressing an important unmet need,” Jan Fagerberg, chief medical officer of Enterome, stated in a news release around the time of data presentation.2 “Additionally, our biomarker findings open up possibilities for precision immunotherapy by identifying patients most likely to benefit early in their treatment course.”
The off-the-shelf immunotherapy combines four synthetic peptides, which correspond with CD8 HLA-A2 epitopes that display molecular mimicry with the markers CD20, CD22, CD37, and CD268.1 The product also comprises CD4-positive epitope and universal cancer peptide 2. The design allows for selective targeting of several B-cell markers and allows for the elimination of B lymphocytes that are malignant.
Cohort 2 of the trial included patients with newly diagnosed, previously untreated follicular and marginal zone lymphoma that was grade 1 to 3A, HLA-A2, and did not require treatment.3 Patients had an ECOG performance status no higher than 1, low tumor burden by GELF criteria, Ann Arbor stage III or IV, or stage I or II disease when not eligible for definitive radiotherapy. Patients also had measurable disease and had not received dexamethasone at a dose higher than 2 mg per day or equivalent within 2 weeks before administration of EO2463.
Participants were given EO2463 at 300 µg subcutaneously with adjuvant Montanide ISA 51 VG every 2 weeks for 4 cycles and then every 4 weeks for a total of 12 doses. Treatment was continued until completion, intolerable toxicity, or disease progression by Lymphoma Response to Immunomodulatory Therapy Criteria.
At the time of the data cutoff date of October 10, 2024, 9 of 15 patients were still receiving treatment, 2 had completed treatment, 2 had discontinued because of disease progression, 1 withdrew consent, and 1 discontinued because of physician decision. The median follow-up was 30 weeks (range, 19-44).
The most common treatment-related toxicities included local administration site reactions such as erythema, pruritus, induration, and pain; these effects occurred in 13 of 15 patients. However, most reactions were grade 1. Only 5 patients experienced grade 2 events, and no grade 3 or higher local administration site reactions were observed.
Other treatment-related adverse effects (TRAEs) included fatigue (n = 2; grade 1 and 2), headache (n = 2; grade 1), and myalgia (n = 2; grade 1 and 2). The only grade 3 TRAE was asthenia, and the effect persisted for 2 days. Infections were reported in 7 patients, with a total of 13 events. Specifically, patients experienced colds, asymptomatic pneumonia, asymptomatic bacteriuria, urinary tract infection, skin infection, upper respiratory infection, herpes zoster, sinusitis, diverticulitis, groin abscess, and tinea cruris.
This portion of the study included patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma who previously received at least 1 line of systemic treatment.4 Patients received EO2463 every 2 weeks for 4 cycles then every 4 weeks subcutaneously with adjuvant Montanide ISA 51 VG up to 15 doses. After 6 weeks of single-agent treatment with the immunotherapy, lenalidomide was given at a daily dose of 20 mg for 21/28 days up to 12 cycles. If no complete remission was achieved by week 19, rituximab was given at a weekly dose of 375 mg/m2 for 4 cycles followed by every-4-week infusions for 4 cycles.
Leveraging a 3-by-3 safety design, EO2463 was evaluated at a starting dose of 150 µg/peptide, with a max escalation to 300 µg/peptide. Patients received treatment until completion, intolerable toxicity, or disease progression. The primary objective of this portion was to identify the recommended phase 2 dose of the agent and to better understand the safety of the agent as a monotherapy and in combination with lenalidomide and rituximab.
Data showed that the approach was well tolerated in these populations, and the immunotherapy provided on-target immune activation while expanding certain cytotoxic T cells that were able to eliminate malignant HLA-A2 B cells in vitro. Early activity was also reported with the single agent, with 44% of patients (n = 4/9) experiencing metabolic or size reduction by 6 weeks. When subsequent combination therapy was added, 78% of patients (n = 7/9) achieved a CR. The radiologic CR rate was 56%.
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