Abstract CT075: Phase 1a/1b dose-escalation study of efbalropendekin alfa (XmAb24306) as single-agent and with atezolizumab in solid tumors

Abstract Background: Efbalropendekin alfa (EBA) is an engineered IL-15/IL-15Rα-Fc fusion protein with optimized potency, designed to improve systemic exposure and pharmacodynamics (PD) while decreasing acute toxicity. It aims to enhance anti-tumor immunity via IL-15-mediated signaling on NK cells and CD8+ T cells. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), PD, and activity of EBA ± atezolizumab (ATZ) in Phase 1a (Ph 1a) and Ph 1b. Methods: Patients (pts) aged ≥18 years with histologically confirmed, locally advanced, recurrent or metastatic incurable solid tumors, measurable disease by RECIST v1.1, ECOG 0/1, and a life expectancy of ≥12 weeks were enrolled in Ph 1a (EBA doses 0.01-0.12 mg/kg Q2W and 0.12 mg/kg Q4W) and Ph 1b (EBA doses 0.01-0.12 mg/kg + 840 mg ATZ Q2W, and 0.06-0.18 mg/kg + 1680 mg ATZ Q4W). Crossover from Ph 1a to 1b was permitted. Treatment (tx) continued until disease progression or unacceptable toxicity. Results: As of July 2024, 91 pts enrolled in dose-escalation and backfill cohorts (Ph 1a, N=24; Ph 1b, N=67). One pt experienced a dose-limiting toxicity of Gr3 rash maculo-papular (RMP) at EBA 0.18 mg/kg + 1680 mg ATZ Q4W. The maximum tolerated dose was not reached; the recommended dose for expansion (RDE) for EBA was set at 0.12 mg/kg Q4W based on overall data. In Ph 1a, all 24 pts experienced tx-emergent adverse events (TEAEs) and 20 (83%) had tx-related AEs (TRAEs). TRAEs in ≥20% of pts were fatigue, infusion-related reaction (IRR), decreased appetite, and RMP. EBA dose was reduced in 3 (13%) pts due to TRAEs. Pts (n=9, 38%) had Gr3-4 TRAEs, with AST increased in 4 pts. There were no deaths or tx withdrawals due to AEs. At the RDE, evaluable Ph 1a pts had stable (n=3, 38%) and progressive (n=4, 50%) disease. In Ph 1b, all 67 pts experienced TEAEs and 57 (85%) had TRAEs. TRAEs in ≥20% of pts were pyrexia, fatigue, IRR, ALT/AST increased, nausea, decreased appetite, and RMP. Pts (n=25, 37%) had Gr3-4 TRAEs; the most common were anemia (n=7), IRR and neutropenia (n=4 each). EBA dose was reduced in 4 (6%) pts and study txs were withdrawn in 7 (10%) due to AEs. There were no tx-related deaths. At the RDE, evaluable Ph 1b pts had complete response (n=1, 6%), partial response (n=4, 24%), stable (n=5, 29%) and progressive (n=7, 41%) disease. PK were similar between tx arms, with no apparent anti-drug antibody impact. PD in peripheral blood showed EBA-driven dose-dependent expansion of NK cells in both Ph 1a and 1b, and effects within T cell subsets were largely driven by CD122 (IL-2/IL-15Rβ) expression. Total CD8+ T cell expansion at RDE for EBA was comparable between Ph 1a and 1b. The RDE for EBA + ATZ demonstrated cyclical proliferation of peripheral CD8+ effector T cells, without inducing CD4+ Treg expansion. Conclusions: Based on the totality of the data, the RDE for EBA was 0.12 mg/kg Q4W and supported the enrollment of dose-expansion to further assess safety and activity. Citation Format: Ben Tran, Anna Spreafico, Daan G. Knapen, Do-Youn Oh, Erika Hamilton, Bridget P. Keenan, Saad A. Khan, Patricia LoRusso, Marwan Fakih, Michael Gordon, Jing Jing, Yanqiu Liu, Patrick Holder, Pranay Dogra, Whitney Kirschbrown, Vittal Shivva, Samuel Tracy, Sharareh Monemi, Shomyseh Sanjabi, Alexander Ungewickell, Caroline McCoach, Tae Won Kim. Phase 1a/1b dose-escalation study of efbalropendekin alfa (XmAb24306) as single-agent and with atezolizumab in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT075.