Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma
- Author(s)
- Munoz-Couselo, E; Teichgräber, V; Soria Rivas, A; Sandhu, S; Long, GV; Sanmamed, MF; Spreafico, A; Buchbinder, E; Sznol, M; Prenen, H; Fedenko, A; Milhem, M; Arance Fernandez, AM; Grob, JJ; Demidov, L; Robert, C; Habigt, C; Evers, S; Sleiman, N; Dejardin, D; Ardeshir, C; Martin, N; Boetsch, C; Charo, J; Kraxner, A; Keshelava, N; Bechter, O;
- Details
- Publication Year 2025-02-24,Volume 5,Issue #2,Page 358-368
- Journal Title
- Cancer Research Communications
- Publication Type
- Research article
- Abstract
- PURPOSE: This study explored the combination of fibroblast activation protein (FAP) IL2 variant (FAP-IL2v), a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma. PATIENTS AND METHODS: This open-label, multicenter, phase Ib clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of FAP-IL2v (simlukafusp alfa, RO6874281) in combination with pembrolizumab. Patients with advanced and/or metastatic melanoma were either checkpoint inhibitor (CPI)-naïve or CPI-experienced. Patients received 10 mg FAP-IL2v either continuously once every 3 weeks (Q3W) or in an induction/maintenance setting consisting of a 3-week induction phase with weekly (QW) dosing followed by continuous Q3W dosing. Pembrolizumab was dosed Q3W at 200 mg. RESULTS: Eighty-three patients were treated: 16 patients in two safety run-in cohorts and 67 patients in two extension cohorts; 75 (90.4%) patients were CPI-experienced. The pharmacokinetics of FAP-IL2v in combination with pembrolizumab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded NK and CD8 T cells. The most common FAP-IL2v-related grade 3/4 adverse events were lymphopenia (23%), elevated γ-glutamyltransferase (8%), elevated alanine aminotransferase (6%), and infusion-related reaction (6%). A response was observed in 5 of 75 (6.7%) CPI-experienced patients (all partial responses) and 2 of 8 CPI-naïve patients (one complete response and one partial response). The median progression-free survival was 3.1 months. CONCLUSIONS: The safety profile of FAP-IL2v in combination with pembrolizumab was manageable and consistent with the known safety profile. However, further exploration of FAP-IL2v and pembrolizumab was precluded in patients with melanoma with prior CPI due to the lack of clinical activity. SIGNIFICANCE: In this phase Ib study, the combination of FAP-IL2v, an immune-cytokine developed to overcome the limitations of wild-type IL2, with the CPI pembrolizumab did not show meaningful antitumor activity in patients who had progressed on prior CPI therapy, suggesting that FAP-IL2v alone cannot overcome CPI resistance or unresponsiveness.
- Keywords
- Humans; *Melanoma/drug therapy/pathology/genetics/mortality; Male; *Antibodies, Monoclonal, Humanized/therapeutic; use/pharmacokinetics/pharmacology/administration & dosage/adverse effects; Female; Middle Aged; Aged; Adult; Antineoplastic Combined Chemotherapy Protocols/therapeutic; use/pharmacokinetics/adverse effects/pharmacology; Interleukin-2/administration & dosage/genetics/pharmacokinetics/therapeutic; use/adverse effects; Aged, 80 and over; Skin Neoplasms/drug therapy/pathology/genetics; Endopeptidases; Membrane Proteins/genetics
- Department(s)
- Medical Oncology
- Publisher's Version
- https://doi.org/10.1158/2767-9764.Crc-24-0601
- Open Access at Publisher's Site
https://doi.org/10.1158/2767-9764.Crc-24-0601- Terms of Use/Rights Notice
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Creation Date: 2025-02-04 07:05:31
Last Modified: 2025-03-21 04:38:02