Novel PI3Kα Inhibitor Combo Shows Meaningful PFS in HR+/HER2– Breast Cancer

Developers designed RLY-2608 to function as the first known allosteric, pan-mutant, and isoform-selective inhibitor of PI3Kα. Investigators hypothesize that the agent’s pan-mutant design may overcome the limitations associated with other PI3Kα inhibitors that focus on the active or orthosteric site, which have lacked clinically meaningful selectivity for mutant vs wild-type PI3Kα and off-isoform activity.

Combining the investigational PI3Kα inhibitor RLY-2608 with fulvestrant (Faslodex) conferred a clinically meaningful progression-free survival (PFS) benefit in patients with heavily pretreated, PI3Kα-mutated, hormone receptor (HR)–positive, HER2-negative locally advanced or metastatic breast cancer, according to interim data from the ReDiscover trial (NCT05216432).¹

Among 52 evaluable patients who received the recommended phase 2 dose (RP2D) of RLY-2608 at 600 mg twice daily and did not have PTEN or AKT co-mutations, treatment yielded a median PFS of 9.2 months across all mutations and 10.3 months for those with kinase mutations. Additionally, the clinical benefit rate (CBR) was 57% (n = 20/35), and the objective response rate (ORR) among 30 patients with measurable disease was 33%, which consisted of 9 confirmed partial responses (PRs) and 1 unconfirmed PR.

Data also showed that 73% (n = 22) of patients had tumor size reductions. Of the evaluable patients with kinase mutations, the ORR was 53% (n = 8/15), which included 7 confirmed PRs and 1 confirmed PR following the data cutoff date.

In general, treatment with RLY-2608 plus fulvestrant appeared to be well tolerated among 118 patients across all evaluated doses, as most treatment-related adverse effects (TRAEs) were low-grade, manageable, and reversible. Investigators reported that 2 patients discontinued study treatment due to a TRAE, which included grade 1 pruritus (n = 1) and grade 1 nausea plus loss of appetite (n = 1). Reports of hyperglycemia were typically grade 1, with only 1 patient having a grade 3 event. Grade 3 TRAEs occurred in 25% of patients; treatment resulted in no grade 4/5 TRAEs.

“These interim data suggest that by selectively targeting mutant PI3Kα, 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,” Don Bergstrom, MD, PhD, president of Research & Development at Relay Therapeutics, the developers of RLY-2608, said in the press release.¹

“We are very encouraged to see that RLY-2608 [plus] fulvestrant led to clinically meaningful [PFS] in heavily pretreated patients with PI3Kα-mutated, [HR-positive, HER2-negative] metastatic breast cancer. We will move quickly to share these data with regulators and align on the design of a pivotal study, which we anticipate starting in 2025,” he added.

Developers designed RLY-2608 to function as the first known allosteric, pan-mutant, and isoform-selective inhibitor of PI3Kα. Investigators hypothesize that the agent’s pan-mutant design may overcome the limitations associated with other PI3Kα inhibitors that focus on the active or orthosteric site, which have lacked clinically meaningful selectivity for mutant vs wild-type PI3Kα and off-isoform activity.

Investigators are also currently evaluating biologically active doses of RLY-2608 in combination with ribociclib (Kisqali) and fulvestrant in the dose-escalation portion of the ReDiscover study. Initial safety data from this cohort are anticipated in the fourth quarter of 2024, and the dose-expansion cohorts are expected to launch in the first half of 2025. Developers also plan to begin assessing a triplet regimen consisting of RLY-2608, atirmociclib, and fulvestrant by the end of 2024.

The primary end points of the ReDiscover trial include the maximum-tolerated dose and/or RP2D as well as safety in terms of AEs and serious AEs.² Secondary end points include pharmacokinetics, ORR, duration of response, DCR, CBR, and quality of life. Patients 18 years and older with an ECOG performance status of 0 or 1 and at least 1 documented primary oncogenic PI3Kα mutation per local assessment are eligible for enrollment on the trial.

References

1. Relay Therapeutics announces positive interim data for RLY-2608 demonstrating clinically meaningful progression free survival. News release. Relay Therapeutics, Inc. September 9, 2024. Accessed September 10, 2024. https://tinyurl.com/tfj357an
2. First-in-human study of mutant-selective PI3Kα inhibitor, RLY-2608, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer. ClinicalTrials.gov. Updated June 6, 2024. Accessed September 10, 2024. https://tinyurl.com/bdhft396