Background: EP0031 (A400/KL590586) is a next generation SRI with greater potency against common RET alterations including resistance mutations, greater brain penetration, and produces deeper responses compared to 1^st gen SRIs in preclinical NSCLC models (EORTC-NCI-AACR 2023:B043). A Phase 1/2 study in China reported responses in RET fusion +ve NSCLC with prior SRI treatment, activity against brain metastases, a high ORR in SRI naïve RET fusion +ve NSCLC and encouraging tolerability. We report dose finding and optimization data from the first study of EP0031 in patients in the US and Europe. Methods: This Phase 1/2 study (NCT05443126) is recruiting patients with RET-altered NSCLC, medullary thyroid cancer (MTC) or other solid tumors and includes patients ≥ 18 years of age, PS 0 or 1, with/without asymptomatic, stable brain met. Results: As of 13^th Dec '23, a total of 27 patients (16 F, 11 M, median age 58 years), 14 NSCLC (12 SRI pre-treated), 8 MTC (5 SRI pretreated) and 5 patients with other tumors (3 SRI pre-treated) were enrolled across 4 cohorts: 20mg (n=3), 60mg (n=9), 90mg (n=9) and 120mg (n=6) QD. The 60 and 90mg cohorts were expanded for dose optimization. SRI pre-treated patients received 1-7 prior lines of therapy. 6 patients had stable brain metastases at enrollment. No DLTs were observed. Most frequent G1/2 TEAEs (≥15%) were constipation, headache, ALT/AST, anemia, blurred vision, and dizziness. G3 TEAEs were rare and included (≥5%): hyponatremia, anemia, hypertension and diarrhea. Dose interruptions, reductions and discontinuations were seen in 8, 3 and 1 patient, respectively. In 8 response evaluable NSCLC patients, 4 confirmed PRs (cPR) were observed in 7 SRI pre-treated patients, of which 2 patients had complete responses (cCR) in the brain, and 1 SRI naive pt had a cCR. In 8 response-evaluable MTC patients, 2 cPRs and 1 SD were observed in 3 SRI naïve patients, and 2 of 5 SRI pre-treated patients achieved SD. In 5 response evaluable patients with other tumors, 2 SDs were observed in patients with pancreatic and papillary thyroid cancer, both SRI pre-treated. Plasma exposures increased proportionately with doses up to 120mg QD. 90mg QD was selected as the RP2D, with plasma levels >IC₉₀ for all relevant RET fusions/mutations, including resistance mutations. This is consistent with the findings from the Phase 1/2 study in China. Expanded efficacy, safety, PK/PD and ctDNA data will be presented. Conclusions: These data add significantly to the large clinical data set reported for EP0031 from a trial of over 130 patients in China, most with advanced RET fusion +ve NSCLC. EP0031 has a manageable toxicity profile with promising activity in advanced NSCLC previously treated with or naïve to SRI, including those with brain metastases. This study is continuing at pace with Phase 2 expansion cohorts in SRI pre-treated and naïve patients. Clinical trial information: NCT05443126.