Dr Ma on Interim Efficacy and Safety Data With RLY-2608 in PI3Kα-Mutant HR+/HER2– Breast Cancer

Cynthia X. Ma, MD, PhD, professor, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine in St. Louis, discusses positive interim data from the first-in-human, phase 1 ReDiscover trial (NCT05216432) evaluating RLY-2608 in combination with fulvestrant (Faslodex) in heavily pretreated patients with PI3Kα-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer.

As of the August 12, 2024, interim data cutoff, 118 patients were enrolled in the dose-escalation and -expansion portions of the trial, with 64 receiving the recommended phase 2 dose (RP2D) of RLY-2608 at 600 mg twice daily plus fulvestrant, Ma begins. The patient population was heavily pretreated, with all patients having received at least 1prior CDK4/6 inhibitor and at least 1 prior line of endocrine therapy, she details. Among those treated at the RP2D, 45% had undergone at least 2 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.

On September 9, 2024, a press release announced that RLY-2608 plus fulvestrant generated clinically meaningful progression-free survival (PFS) outcomes and a favorable safety profile in this patient population, Ma reports. 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 PFS of 9.2 months, and 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% regardless of kinase mutation status, and tumor reductions were observed in 73% of patients. In those with measurable disease and kinase mutations (n = 15), the ORR reached 53%.

RLY-2608 plus fulvestrant was generally well tolerated, with most adverse effects being low grade, treatment-related, and manageable, Ma continues. Hyperglycemia, a common concern with PI3K inhibitors, was rare and primarily low grade, she notes. Rates of diarrhea and rash were also much lower compared with historical data from other PI3K inhibitors, such as alpelisib (Piqray) and capivasertib (Truqap), Ma adds. These safety and efficacy data indicate that RLY-2608 could be a meaningful new treatment option for this patient population pending further validation in randomized trials, she concludes.