Abstract P3-08-19: Preliminary results from PIKture-01, a First-in-Human Study of OKI-219, a mutant selective inhibitor of PI3Kα-H1047R, in mutant selected solid tumors including breast cancer

Abstract Background: Aberrant activation of the PI3Ka pathway contributes to tumorigenesis and is associated with resistance to anticancer therapies, making this pathway an attractive target for new therapies[1]. PI3Kα is one of the most commonly mutated oncogenes, found in approximately 13% of human cancers and 29% of breast cancer [2]. There are three predominate mutations in PI3Kα important in cancer. The H1047R mutation in the kinase domain is the most common of the three, found in 40% of HR+/HER2– breast cancers and 10-15% of HER2+ breast cancers [3]. The currently approved PI3Kα inhibitors such as alpelisib target both wild-type and mutant forms, leading to significant on-target toxicities, including hyperglycemia, rash, and diarrhea [4,5]. OKI-219, a mutant-selective PI3Kα inhibitor, has shown preclinical efficacy in PI3Kα-H1047R-mutated models, without the metabolic dysfunction associated with wild-type inhibition, supporting a potential improved therapeutic profile. We hypothesize OKI-219 may achieve greater mutant target coverage with a wider therapeutic window compared to other non-selective PI3Kα inhibitors. Methods: PIKture-01 is a global, multi-center, first-in-human phase 1a/1b study evaluating OKI-219 as monotherapy and in combination with fulvestrant or trastuzumab in subjects with advanced solid tumors including breast cancer harboring a PI3Kα-H1047R mutation. In Phase 1a, subjects receive escalating oral doses of OKI-219 starting at 300 mg BID continuously. Phase 1b will assess OKI-219 in combination with fulvestrant in patients with HR+ breast cancer, or with trastuzumab in patients with HER2+ breast cancer. The study also includes a dose optimization phase to evaluate the optimal combination doses of OKI-219 with fulvestrant or trastuzumab. Results: As of 30 September 2024, OKI-219 has been dosed at three dose levels as a single agent: 300 mg BID, 600 mg BID, and 900 mg BID, continuously. Across all dose levels to date, a total of ten subjects have been dosed: six subjects with HR+/HER2- breast cancer, two with HER2+ positive breast cancer, and two with colorectal cancer in the single agent dose escalation. Eight of the ten subjects remain on study. OKI-219 has been very well tolerated, with no dose-limiting toxicities, dose interruptions, or dose reductions required. The most common treatment-emergent adverse events (TEAE) that occurred in >15% of subjects were urinary tract infection, upper extremity cellulitis and pruritus. The most common treatment-related adverse events (TRAE) were grade 1 pruritus. Single-dose pharmacokinetic (PK) results of OKI-219 are consistent with predicted human exposures. At steady state, the exposures of OKI-219 exceed exposures associated with robust antitumor activity in preclinical models. Conclusion: OKI-219 has been very well tolerated with a favorable safety profile, and only Grade 1 TRAEs observed at exposures that are consistent with preclinical activity, even at the lowest dose level. As a single agent, OKI-219 has shown favorable PK that support pharmacologically relevant exposures, even at the lowest assessed dose levels, with a safety profile that suggests little or no inhibition of WT PI3Kα. We anticipate near completion of enrollment of the single agent portion of the study as well as the initiation of combination expansion of OKI-219 with fulvestrant by the end of the year. Data will be updated accordingly. References: 1. Martini, M., et al., PI3K/AKT signaling pathway and cancer: an updated review. Ann Med, 2014. 46(6): p. 372-83. 2. Millis, S.Z., et al., Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors. JAMA Oncol, 2016. 2(12): p. 1565-1573. 3. COSMIC database https://cancer.sanger.ac.uk/cosmic/gene/analysis?all_data=&coords=AA%3AAA&dr=&end=1069&gd=&id=276592&ln=PIK3CA&seqlen=1069&sn=breast&start=1#ts 4. Narayan, P., et al., FDA approval summary: alpelisib plus fulvestrant for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. Clin Cancer Res, 2021. 27(7): p. 1842-1849. 5. Shields, M., et al., A systematic review and meta-analysis of selected toxicity endpoints of alpelisib. Oncotarget, 2020. 11(42): p. 3793-3799. Citation Format: Samuel Agresta, Alexander Spira, Andreas Varkaris, Seock-Ah Im, Peter Kabos, Ramon Yarza, Yeon Hee Park, Kevin Litwiler, Guy Gammon, Amy Heim, Brian Tunquist, Robbie Alton, Duncan Walker. Preliminary results from PIKture-01, a First-in-Human Study of OKI-219, a mutant selective inhibitor of PI3Kα-H1047R, in mutant selected solid tumors including breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-19.