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

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Treatment with RLY-2608 plus fulvestrant appears well tolerated among patients with PI3Kα-mutated breast cancer in the ReDiscover trial.

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.

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
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