Abstract Introduction: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor, is approved in multiple countries for the treatment of RET fusion-positive lung or thyroid cancers. RET fusions are also implicated in the pathogenesis of other cancers. Selpercatinib's efficacy and safety were thus explored in patients (pts) with RET fusion-positive non-lung/non-thyroid cancers in a global, multicenter, registrational trial. Methods: Adults with locally advanced or metastatic RET fusion-positive non-lung/non-thyroid solid tumors enrolled in the phase 1/2 LIBRETTO-001 trial (NCT03157128) were included in this analysis (data cut-off: 19 March 2021). Following dose escalation, pts received the recommended dose of 160 mg orally, twice daily. Pts enrolled long enough to allow 6-month follow-up from their first dose comprised the efficacy-evaluable population. Response was assessed (RECIST 1.1) by investigators. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DoR), time to response, and safety. Results: Thirty-two pts with RET fusion-positive non-lung/non-thyroid cancers included 12 unique tumor types: 9 pancreatic, 9 colon, 2 each of breast, salivary, sarcoma, and unknown primary, and 1 each of carcinoid, rectal neuroendocrine, small intestine, xanthogranuloma, ovarian, and pulmonary carcinosarcoma. The median age was 48 years (range 22-85). Twenty-nine pts received prior systemic therapy (median prior lines: 2, range 0-9). The ORR was 47% (N=15/32, 95% CI: 29-65). Objective responses were observed in 9 unique cancer types including colon, pancreatic, carcinoid, small intestine, salivary, xanthogranuloma, breast, ovarian, and sarcoma, and 5 additional patients had stable disease lasting ≥ 16 weeks. Median time to response was 1.9 months (range 0.7-7.3). Median DoR was not reached (median follow-up time of 13 months). Responses were ongoing in 73% (11/15) of pts. Safety among this population was consistent with the overall selpercatinib safety database. No patients in this cohort discontinued due to treatment-related AEs. Conclusion: Selpercatinib demonstrated promising antitumor activity in RET fusion-positive non-lung/non-thyroid cancers, including multiple treatment-refractory GI malignancies. Broad-based genomic profiling is essential to identify actionable oncogenic drivers, including RET fusions. The safety and efficacy of selpercatinib will continue to be explored in pts with these cancers in the ongoing LIBRETTO-001 study. Citation Format: Vivek Subbiah, Bhavana Konda, Todd Bauer, Caroline McCoach, Gerald Falchook, Masayuki Takeda, Jyoti Patel, Jared Weiss, Nir Peled, Lyudmila Bazhenova, Victoria Soldatenkova, Pearl French, Nora Drove, Oliver Gautschi, Alexander Drilon. Efficacy and safety of selpercatinib in RET fusion-positive cancers other than lung or thyroid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT011.