RLY-2608 in combination with fulvestrant has shown promising interim efficacy and a favorable safety profile in heavily pretreated patients with PI3Kα-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer. The data comes from the phase 1 ReDiscover trial (NCT05216432) and suggests a potential new treatment option for this patient population.
Interim Efficacy Data
As of the August 12, 2024, data cutoff, 118 patients were enrolled in the dose-escalation and -expansion portions of the ReDiscover trial, with 64 receiving the recommended phase 2 dose (RP2D) of RLY-2608 at 600 mg twice daily plus fulvestrant. All patients had received at least one prior CDK4/6 inhibitor and at least one prior line of endocrine therapy. According to Dr. Cynthia X. Ma, professor at Washington University School of Medicine in St. Louis, 45% of those treated at the RP2D had undergone at least two prior lines of therapy, 52% had received a prior selective estrogen receptor degrader, and 25% had been previously treated with chemotherapy or an antibody-drug conjugate.
At a median follow-up of 7.5 months, patients without PTEN or AKT co-mutations who received the RP2D (n = 52) achieved a median progression-free survival (PFS) of 9.2 months. The clinical benefit rate was 57% among 35 evaluable patients in the overall population. In patients with measurable disease at the RP2D (n = 30), the overall response rate (ORR) was 33%, and tumor reductions were observed in 73% of patients. In those with measurable disease and kinase mutations (n = 15), the ORR reached 53%.
Safety and Tolerability
RLY-2608 plus fulvestrant was generally well tolerated, with most adverse effects being low grade, treatment-related, and manageable. Hyperglycemia, a common concern with PI3K inhibitors, was rare and primarily low grade. Rates of diarrhea and rash were also much lower compared with historical data from other PI3K inhibitors, such as alpelisib (Piqray) and capivasertib (Truqap).
Clinical Implications
These early safety and efficacy data suggest that RLY-2608 could be a meaningful new treatment option for patients with PI3Kα-mutated, HR+/HER2- breast cancer. Further validation in randomized trials is warranted. The favorable safety profile, particularly the reduced incidence of hyperglycemia, diarrhea, and rash compared to other PI3K inhibitors, could make RLY-2608 a more tolerable option for patients. According to Dr. Ma, these data indicate that RLY-2608 could be a meaningful new treatment option for this patient population pending further validation in randomized trials.
