Dr Manich on the ReDiscover Study of RLY-2608 in PIK3CA-Mutant Advanced Solid Tumors

Cristina Saura Manich, MD, PhD, head, Breast Cancer Unit, the Service of Medical Oncology, Vall d’Hebron University Hospital; principal investigator, Breast Cancer and Melanoma Research Group, Vall d’Hebron Institute of Oncology, discusses the ongoing phase 1 ReDiscover study (NCT05216432) which investigated the PI3Kα inhibitor RLY-2608 in patients with advanced breast cancer and other solid tumors. 

The first-in-human, global, multi-center, dose escalation/expansion study is evaluating RLY-2608 as a single agent for adults with previously treated, PIK3CA-mutated advanced solid tumors who are refractory, intolerant, or have declined standard therapy. The study is also assessing RLY-2608 in combination with fulvestrant (Faslodex) for previously treated patients with PIK3CA-mutated, hormone receptor (HR)–positive, HER2-negative metastatic breast cancer. The monotherapy arm began treating patients in December 2021, and the RLY-2608 plus fulvestrant combination arm started in April 2022.

Initially, the trial tested RLY-2608 monotherapy in a dose escalation format, which yielded a favorable safety and efficacy profile. Prior data reported at the 2023 AACR Annual Meeting demonstrated clinical proof of mechanism, showing that RLY-2608 achieved selective target engagement at multiple predicted efficacious doses with a good safety and tolerability profile. Notably, 1 heavily pretreated patient with breast cancer achieved a partial response (PR) at the 400-mg twice daily dosing level, and initial anti-tumor activity was observed with the agent across a range of doses.

Overall, early data indicate that RLY-2608 may have broad therapeutic potential in PIK3CA-driven tumors. Based on these promising initial efficacy and safety results, the trial has expanded to evaluate RLY-2608 in combination with fulvestrant and either ribociclib (Kisqali) or palbociclib (Ibrance) in patients with PIK3CA-mutated HR-positive, HER2-negative advanced or metastatic breast cancer. The trial has been amended to reflect the good results achieved, highlighting both the efficacy and favorable toxicity profile. Currently, the trial is enrolling patients onto the doublet and triplet combination arms.