Phase 1b study of immunocytokine simlukafusp alfa (FAP-IL2v) combined with pembrolizumab for treatment of advanced and/or metastatic melanoma

This study explored the combination of FAP-IL2v, a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma. This open-label, multicenter, phase 1b clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics (PK), 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 -experienced. Patients received 10 mg FAP-IL2v either continuously once every three 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. 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 PK 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 AEs 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 in 2 of 8 CPI-naïve patients (one complete, one partial response). The median progression-free survival was 3.1 months. 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 melanoma patients with prior CPI due to the lack of clinical activity.