Dr Sammons on the Efficacy of RLY-2608 Plus Fulvestrant in PIK3CA-Mutant HR+/HER2– Breast Cancer

"We think that the combination of RLY-2608 and fulvestrant is very promising at this juncture in the post–CDK4/6 [inhibitor] setting, and we are excited to move it into a pivotal phase 3 trial."

Sarah Sammons, MD, assistant professor of medicine at Harvard Medical School, and associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute, shared updated efficacy data from the phase 1 ReDiscover study (NCT05216432) of the PI3Kα inhibitor RLY-2608 in combination with fulvestrant (Faslodex) in patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer.

Sammons began by noting that the updated analysis excluded patients with concurrent PTEN or AKT alterations, which accounted for approximately 10% of the total population, because PI3Kα-specific inhibitors may be less effective in patients with downstream alterations.

Findings presented at the 2025 ASCO Annual Meeting showed that, among patients with isolated PIK3CA mutations (n = 31), the overall response rate (ORR) with RLY-2608 was 38.7% (95% CI, 21.8%-57.8%) in the post–CDK4/6 inhibitor setting. Moreover, tumor reductions were observed in 80.6% of patients, Sammons stated.

In the subgroup of patients with kinase domain mutations (n = 15), the ORR with RLY-2608 was 66.7% (95% CI, 38.4%-88.2%). Furthermore, patients who had received prior fulvestrant (n = 15) exhibited a 40% (95% CI, 16.3%-67.7%) ORR, indicating some monotherapy activity of RLY-2608. Sammons emphasized that these findings support the potential utility of RLY-2608 in combination with fulvestrant in this clinical context.

Regarding progression-free survival (PFS), Sammons stated that the median PFS with RLY-2608 in the overall population post–CDK4/6 inhibitor progression (n = 52) was 10.3 months (95% CI, 7.2-18.4) across mutation types. In the second-line setting, the median PFS reached 11 months (95% CI, 7.3-22.0). Notably, patients with PIK3CA kinase domain mutations achieved a median PFS of 18.4 months (95% CI, 9.2-not reached), Sammons added.

Overall, the combination of RLY-2608 and fulvestrant demonstrated clinical activity in patients withPIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer following CDK4/6 inhibition, supporting the planned pivotal phase 3 trial evaluating this agent, Sammons concluded.