Final Results of a Phase 1 Study of EP0031, a Next Generation Selective RET Inhibitor (SRI) in Patients with SRI Naïve or Pretreated Advanced RET-altered Tumors.

8598 Background: EP0031 (A400/KL590586), a first in class next gen selective RET inhibitor (SRI) with FDA Fast Track Designation, has broad potency against common RET alterations, including resistance mutations. It has greater potency, antitumor activity, and CNS penetration/activity compared with 1 st gen SRIs (Garralda et al. JCO 2024; 42:16; abstr 8556; Zhou et al. JCO 2023; 41:16, abstr 3007). We report final data from the dose finding and optimization Phase 1 trial in the US and Europe. Methods: The study recruited pts with RET-altered NSCLC, medullary thyroid cancer (MTC) and other solid tumors and included pts ≥ 18 years, PS 0 or 1, with/without asymptomatic, stable brain mets, who received EP0031 QD in 28 days’ cycles. Results: A total of 40 pts (23 F, 17 M, median age 59 y), 22 NSCLC (20 SRI pre-treated, 1-6 prior lines), 12 MTC (7 SRI pre-treated, 1-4 prior lines) and 6 pts with other tumors (4 SRI pre-treated) were enrolled across 4 cohorts: 20 (n=3), 60 (n=10), 90 (n=16) and 120 (n=11) mg QD. The 60, 90 and 120mg cohorts were expanded for dose optimization. 9 pts had stable brain mets at baseline. No DLTs were observed. Most frequent G1/2 TEAEs (≥20%) were headache, anemia, ALT/AST increase, constipation, dizziness, hyperphosphatemia, blurred vision, keratitis, blood creatinine increased, dry mouth, dyspnea and fatigue. G3 TEAEs were rare and included (≥5%): hyponatremia, hypertension, anemia, AST/ALT increase, headache, diarrhea and ulcerative keratitis. Interruptions, reductions and discontinuations related to study drug were seen in 16 (40%), 8 (20%) and 1 (2.5%) pt. 25 pts with prior SRI were response evaluable. 5 PRs and 6 SDs reported in 15 NSCLC pts, with complete resolution of brain mets in 3/5 pts. Median DoR was 7.3mo (range 5.4-16.3). In 7 MTC pts, 2 PRs (DoR 6.6 – 9.2mo) and 2 SDs seen. Of 3 pts with other tumors, a pancreatic cancer pt had SD for 3.5 mo, and a pt with papillary thyroid cancer was clinically stable for 9 mo. In pts who were SRI naïve, 1 CR and 1 PR were reported in 2 NSCLC pts; and 5 PRs (1 uPR) were reported in all MTC pts. Baseline on-target RET resistance mutations were detected in 6/31 prior SRI pts (19.4%) with evidence of activity in 3, and sustained reduction and clearance of ctDNA (including RET resistant mutations: G810R solvent front and L730V, L730I roof mutations). Plasma exposures increased proportionately with dose. 90mg QD was selected as RP2D, with plasma levels >IC 90 for all relevant RET fusions/mutations. Conclusions: There is a need for new treatments for pts that progress on 1 st gen SRIs. EP0031 was associated with durable responses in advanced RET altered solid tumors previously treated with SRI, including pts with brain mets, with a manageable safety profile. These data confirm that the first in class next gen SRI EP0031 has the potential to address a high unmet need. Phase 2 trials are evaluating EP0031/KL590586 in US, Europe, UAE and China. Clinical trial information: NCT05443126 .