Abstract CT017: Pan-mutant and isoform selective PI3Kα inhibitor, RLY-2608, demonstrates selective targeting in a first-in-human study of PIK3CA-mutant solid tumor patients, ReDiscover trial
Authors: Varkaris Andreas , Jhaveri Komal , Perez Cesar A. , Kim Janice S. , Henry Jason T. , Subbiah Vivek , Spira Alexander I. , Gómez Lucía Sanz , Guerrero-Zotano Angel I. , Wisinski Kari B. , Li Xiaoyan , Tan Gege , Samadani Ramin , Hunter Tamieka Lauz , Guo Wei , Timm Alison , Karanovic Djuro , Wolf Beni B. , Hamilton Erika P. , Schram Alison M. 
Published: May 2023

Abstract
BACKGROUND: Oncogenic activation of PI3Kα via mutation of PIK3CA is the most common kinase driver event across solid tumors, particularly breast cancer (BC). Alpelisib, an orthosteric inhibitor, validated mutant-PI3Kα as a therapeutic target; however, toxicity from non-selective inhibition of WT PI3Kα (hyperglycemia) and other PI3K isoforms limits its clinical activity. RLY-2608, a novel oral allosteric PI3Kα inhibitor, is designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition. We initiated a first-in-human study (NCT05216432) to define the MTD, safety, pharmacokinetics (PK), and anti-tumor activity of RLY-2608 in PIK3CA-mutant solid tumor patients (pts) and of RLY-2608 plus fulvestrant (combo) in pts with PIK3CA-mutant, HR+HER2-BC, who had received prior CDK4/6 inhibitor and endocrine therapy.
METHODS: Adult pts with no prior PI3Ki/mTORi therapy received RLY-2608 QD or BID on a 4-week (wk) cycle following a Bayesian Optimal Interval dose escalation. Eligible BC pts received fulvestrant. PK, pharmacodynamics (ex vivo pAKT inhibition; tumor markers; ctDNAs), treatment emergent adverse events (TEAEs), and anti-tumor activity per RECIST 1.1 were assessed.
RESULTS: As of 31Jan23, 40 pts (21 BC combo pts) with PIK3CA mutations (12 kinase, 18 helical, 10 other) received RLY-2608 at doses of 100-1600 mg/day. Median number of prior treatments was 4 (1-11). An MTD has not been reached and dose escalation continues. RLY-2608 PK were favorable with BID dosing providing low steady-state peak-to-trough variability for mutant-selective inhibition. This enabled dose-dependent increase in exposure and target inhibition with doses ≥600 mg BID and pAKT suppression (≥80%) in the expected therapeutic range with minimal/no impact on glucose homeostasis. Across arms, safety was consistent: most frequent TEAEs (&gt;15%) were low grade (≤Gr 2) nausea (30%), fatigue (22.5%), headache (22.5%), hypokalemia (22.5%), and diarrhea (17.5%). No DLTs were observed, and no pts discontinued due to related AEs. Initial anti-tumor activity was observed in BC combo pts including declines in tumor markers, PIK3CA/ESR1 ctDNAs and radiographic tumor reduction in 7 of 10 RECIST measurable pts. At 600 mg BID, 6/6 BC combo pts had disease stabilization and remain on treatment, including all RECIST-measurable pts with tumor reduction. Overall, 17 (81%) BC combo pts remain on treatment with median duration of 12 (1-40) wks.
CONCLUSION: Across PIK3CA genotypes, RLY-2608 demonstrated target inhibition and anti-tumor activity with minimal impact on glucose homeostasis. These proof-of-mechanism data indicate that RLY-2608 is the first allosteric, pan-mutant selective PI3Kα inhibitor and that RLY-2608 has broad therapeutic potential in PIK3CA-driven cancers.
Citation Format: Andreas Varkaris, Komal Jhaveri, Cesar A. Perez, Janice S. Kim, Jason T. Henry, Vivek Subbiah, Alexander I. Spira, Lucía Sanz Gómez, Angel I. Guerrero-Zotano, Kari B. Wisinski, Xiaoyan Li, Gege Tan, Ramin Samadani, Tamieka Lauz Hunter, Wei Guo, Alison Timm, Djuro Karanovic, Beni B. Wolf, Erika P. Hamilton, Alison M. Schram. Pan-mutant and isoform selective PI3Kα inhibitor, RLY-2608, demonstrates selective targeting in a first-in-human study of PIK3CA-mutant solid tumor patients, ReDiscover trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT017.