Abstract CT213: A phase I/II study to evaluate EP0031 (lunbotinib), a next-generation selective RET inhibitor, as monotherapy and in combination with chemotherapy, in patients with advanced RET-fusion-positive NSCLC

Abstract Background: EP0031 (lunbotinib, A400), a first-in-class, next-generation selective RET inhibitor (SRI), has broad potency against common RET alterations, including resistance mutations, and has greater potency, antitumor activity, and CNS penetration/activity compared with first-generation SRIs (1, 2). Clinical data indicates that EP0031 is active in patients who are SRI-naïve or have received prior SRI treatment, including those with brain metastases and/or on-target RET resistance mutations, and has acceptable tolerability (2, 3, 4). Resistance to first-generation SRIs is heterogeneous, characterized by RET-dependent and -independent pathways (4). SRI + chemotherapy may represent a promising strategy to address underlying disease heterogeneity. There is growing evidence that RET fusion-positive NSCLC is sensitive to pemetrexed-based chemotherapy and preclinical evidence confirms strong synergy between EP0031 and chemotherapy. This is the first study to evaluate this combination approach. Study Design and Methods: This is an ongoing phase I/II trial. A monotherapy RP2D of 90 mg daily was selected based on dose optimization data (4). Phase II expansion cohorts are recruiting patients with advanced RET fusion-positive NSCLC (NCT05443126) across three cohorts: (1) SRI-naïve patients receiving first-line therapy with EP0031 (N=25) ; (2) SRI-naïve patients receiving first-line therapy with EP0031 in combination with platinum-pemetrexed (N=25) ; and (3) Patients previously treated with a first-generation SRI, receiving second-line treatment with EP0031 in combination with platinum-pemetrexed (N=25). Key inclusion criteria include age ≥ 18 years, an Eastern Cooperative Oncology Group performance status ≤ 1, and RET fusion-positive NSCLC measurable by RECIST v1. 1, with or without asymptomatic, stable brain metastases. EP0031 is administered orally, continuously once daily. In combination cohorts, the chemotherapy doublet is administered every 21 days at standard doses for four cycles followed by pemetrexed maintenance. Each combination cohort has a 3+3 safety run-in before expansion in 25 patients at the combination RP2D. Endpoints include tumor response per RECIST v1. 1, progression-free survival, and overall survival. Other key endpoints include safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetic parameters. Circulating tumor DNA is collected to evaluate the emergence of on- and off-target mutations. The study is currently recruiting across the US, Europe, and the UAE. References 1. Zhou Q, et al. J Clin Oncol 2023: 41: 16ₛuppl, abstract 3007 2. Garralda E, et al. J Clin Oncol 2024: 42: 16ₛuppl, abstract 8556 3. Garralda E, et al. Ann Oncol 2024; 35: S824, abstract 1295P 4. Alonso G, et al. J Clin Oncol 2025: 43: 16ₛuppl, 8598 Citation Format: Jaime Rubio-Perez, Elena Garralda, Benjamin Besse, Mihaela Aldea, Yasir Elamin, Pilar Garrido, Saad Khan, Judy Wang, Luis Paz Ares, Daniel Morgensztern, Philippe Cassier, Salmon Punekar, Stephen V Liu, Matthew H Taylor, Liz Joseph, Andrew G Gianoukakis, Jacobi Hines, Javier Garcia-Corbacho, Pascale Tomasini, David Spigel, Matthew G Krebs, Antoine Italiano, Mohammad Al Masri, Geoff Fisher, Sonia Serrano, Hendrik-Tobias Arkenau, Alex Drilon. A phase I/II study to evaluate EP0031 (lunbotinib), a next-generation selective RET inhibitor, as monotherapy and in combination with chemotherapy, in patients with advanced RET-fusion-positive NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT213.