KEYNOTE-B59: An open-label, multicenter, phase 1/2 study of efdelikofusp alfa (GI-101A; CD80-IgG4 Fc-IL2v2) in advanced solid tumors (part E & F of GII-101-P101).

2519 Background: Efdelikofusp alfa is a novel immunocytokine consisting of CD80 fused to an engineered IL-2 variant (IL-2v2) optimized to reduce IL-2Rα affinity. It blocks CTLA-4–mediated immune suppression while preferentially activating and expanding immune effector cells over regulatory T cells. Here, we report results from the dose-escalation phases of Part E (monotherapy) and Part F (combination with pembrolizumab) of the ongoing KEYNOTE-B59 study. Methods: KEYNOTE-B59 is an open-label, phase 1/2 study evaluating efdelikofusp alfa alone or in combination with pembrolizumab in patients (pts) with advanced solid tumors. In Part E, escalating doses of efdelikofusp alfa (0.05–0.3 mg/kg) were administered intravenously every 3 weeks (Q3W). In Part F, pts received efdelikofusp alfa (0.05–0.3 mg/kg) plus pembrolizumab (200 mg) Q3W. Primary objectives were to assess safety, tolerability, and to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose. Results: As of 29 December 2025, a total of 84 pts who had progressed on available therapies were enrolled, including 36 pts in Part E and 48 pts in Part F. In Part E, one dose-limiting toxicity (DLT) occurred at 0.1 mg/kg (grade 3 hypertension). However, MTD was not reached up to 0.3 mg/kg, and efdelikofusp alfa was generally well tolerated. At the biologically effective dose range (0.2–0.3 mg/kg), monotherapy demonstrated clinical activity in immunotherapy (IO)-experienced bladder cancer (confirmed CR; DoR 5.8 months; PFS 13.9 months) and mesothelioma (confirmed PR; DoR 5.6 months; PFS 6.7 months). In Part F, 48 pts were treated with efdelikofusp alfa in combination with pembrolizumab. Median age was 63 years and 45.8% of pts had received prior IO. The overall safety profile of the combination was comparable to monotherapy, with common treatment-related adverse events including pyrexia (89.6%), liver enzyme elevation (47.9%), chills (37.5%), and decreased platelet count (33.3%). Objective responses were observed across multiple tumor types, including ccRCC, urothelial cancer, squamous NSCLC, cutaneous squamous cell carcinoma, pancreatic adenocarcinoma, and cervical cancer, irrespective of prior IO exposure. In pts with ccRCC (n = 10), the most frequently enrolled indication (70.0% prior IO-treated), the objective response rate was 40.0% and the disease control rate was 70.0%, with durable responses observed from 5.5+ to 16.7+ months; median DoR was not reached. Efdelikofusp alfa induced robust peripheral lymphocyte expansion, mainly CD8 + T and NK cells, which correlated with longer median PFS. Conclusions: Efdelikofusp alfa was well tolerated as a monotherapy and in combination with pembrolizumab. Antitumor activity was observed with a favorable benefit–risk profile, supporting continued development in selected tumors, including ccRCC. Clinical trial information: NCT04977453 .