Set to start in 2025, Relay Therapeutics is moving toward a pivotal study of experimental treatment RLY-2608 in heavily pretreated locally advanced or metastatic breast cancer.
Relay Therapeutics on Monday unveiled interim Phase I/II data for its investigational PI3Kα inhibitor RLY-2608, which elicited “clinically meaningful” progression-free survival in heavily pretreated patients with certain types of breast cancer.
The study, dubbed ReDiscover, focused on patients with PI3Kα-mutated, HR-positive and HER2-negative locally advanced or metastatic breast cancer. RLY-2608 was administered at its recommended Phase II dose of 600 mg twice-daily and was given in four arms: as a monotherapy, with AstraZeneca’s hormone therapy Truqap (fulvestrant), with fulvestrant plus ribociclib or with fulvestrant plus atirmociclib. Both ribociclib and atirmociclib are CDK4/6 inhibitors.
Results showed that at this dose, RLY-2608 led to a median progression-free survival (PFS) of 9.2 months regardless of mutations. PFS was slightly longer at 10.3 month in patients harboring kinase mutations. Clinical benefit rate—defined as the percentage of evaluable patients who achieved complete or partial response or stable disease at 24 weeks—was 57%.
In addition, 30 patients had measurable disease at the time of the analysis, of whom 10 achieved a partial response, yielding an objective response rate (ORR) of 33%. In the 15 patients with measurable disease and kinase mutations, ORR was 53%.
RLY-2608 also showed a “meaningfully differentiated tolerability profile” in ReDiscover, according to Relay. Side effects were mostly low-grade and were manageable and reversible. Two patients dropped out because of treatment-emergent adverse events, while only 25% of the toxicities were deemed grade 3 in severity.
Don Bergstrom, Relay’s president of R&D, said in a statement that these findings suggest that RLY-2608 “has the potential to offer a level of benefit to patients that has not previously been possible with existing non-selective medicines, while also having significantly less toxicity.” Encouraged by these early data, Relay will “move quickly” to engage with regulators and arrive at a design for a pivotal trial, which the biotech aims to start next year.
Relay expects to report initial safety findings for RLY-2608, when combined with ribociclib and fulvestrant, in the fourth quarter of 2024, followed by a dose-expansion cohort for this regimen in the first half of 2025. The atirmociclib triplet cohort with RLY-2608 is set to start by the end of this year.
RLY-2608 is a mutant-selective blocker of the PI3Kα, which under healthy conditions is involved in many different important cellular functions. According to Relay, PI3Kα is “the most frequently mutated kinase in all cancers,” accounting for 14% of oncogenic mutations in solid tumors.
AstraZeneca’s Truqap targets AKT, a different protein in the PIK3CA pathway.
If approved, RLY-2608 could potentially help treat over 300,000 patients per year in the U.S., according to Relay.
