Abstract B043: Preliminary results from a phase I/II study evaluating the safety, tolerability, and efficacy of EP0031, a next generation selective RET inhibitor, in patients with advanced RET-altered malignancies
Authors: Garralda Elena , Guzman Alonso , Garrido Pilar , Gianoukakis Andrew G , Taylor Matthew , Piha-Paul Sarina , Krebs Matthew G , Italiano Antoine , Clark Liz , Fisher Geoff , Arkenau Tobi , Subbiah Vivek 
Published: December 2023

Abstract
BACKGROUND Emergence of resistance to 1st generation (gen) selective RET inhibitors (SRIs, selpercatinib/pralsetinib) is an area of high unmet need. EP0031 (A400/KL590586) has promise as a next gen SRI. Clinical data was recently reported from an ongoing Phase I/II study in China that included 109 patients (pts) with RET-altered tumours (NCT05265091, Zhou et al. JCO 2023, 41:16, suppl. 3007). ORR was 80.8 and 69.7%, across 40-120 mg QD doses, in treatment-naïve or pre-treated metastatic NSCLC, respectively. Responses durable with longest 14.5 mo ongoing, median DoR not reached. Responses, including in the CNS, observed in 5/7 pts that previously received 1st gen SRI. EP0031 had an encouraging safety and tolerability profile. 90mg QD was selected as RP2D. Here we report initial data from the dose ranging and optimisation module of a parallel Phase I/II study in the US and Europe.
EXPERIMENTAL PROCEDURES This study (NCT05443126) is recruiting pts with RET-altered NSCLC, thyroid cancer or other solid tumours. Study includes male or female pts ≥ 18 years of age, PS 0 or 1 with/without asymptomatic, stable brain metastases. The first module is a dose escalation to investigate safety, tolerability, PK/PD and define the MTD and/or RP2D. This is based on rolling 6 design and is expected to recruit up to 40 pts.
RESULTS As of 10th July 2023, a total of 15 pts, 5 medullary thyroid cancer (MTC), 2 CRC and 8 NSCLC, have been included across dose cohorts of 20mg (N=3), 60mg (N=6) and 90mg (N=6). PK profile is comparable with Chinese pts and consistent with QD dosing. 60mg QD predicted to achieve IC50 for inhibition of RET fusions/mutations. No DLTs and no serious adverse events reported. No dose reductions, interruptions or discontinuations have been required. AEs have been mainly Grade 1 or 2. No neutropenia, hypertension, neurotoxicity or QTc prolongation observed. Three pts (all MTC) that received 20 mg QD had their dose escalated to 60mg (after 5-7 cycles at 20mg). 2 of those pts, both SRI naïve, have ongoing stable disease for &gt;23 weeks. 1 pt (prior SRI) with a new target lesion continues to derive clinical benefit and remains on treatment. Of 4 evaluable pts at 60 mg, 2 pts with NSCLC (prior SRI) have achieved a PR, treatment is ongoing and 2 pts with MTC (prior SRI) had PD, one of whom continues to derive clinical benefit and remains on treatment. The remaining pts at 60 or 90mg (potential RP2D) are not yet evaluable for efficacy. Genomic analyses for RET/non-RET resistance mechanisms are ongoing. Expansion of the 60mg and 90mg cohorts is planned for dose optimization. Expanded efficacy, safety and PK/PD data from dose ranging and optimization cohorts will be presented.
CONCLUSIONS These preliminary data are encouraging, consistent with that reported from a larger cohort of Chinese patients, with early evidence that EP0031 is active in pts that received prior 1st gen SRI. Once RP2D confirmed, the study will expand cohorts of both SRI-naïve and pre-treated pts with RET-altered NSCLC, thyroid and other solid tumours.
Citation Format: Elena Garralda, Alonso Guzman, Pilar Garrido, Andrew G Gianoukakis, Matthew Taylor, Sarina Piha-Paul, Matthew G Krebs, Antoine Italiano, Liz Clark, Geoff Fisher, Tobi Arkenau, Vivek Subbiah. Preliminary results from a phase I/II study evaluating the safety, tolerability, and efficacy of EP0031, a next generation selective RET inhibitor, in patients with advanced RET-altered malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B043.