RLY-2608/Fulvestrant Yields Early Clinical Activity in PI3Kα-Mutated, HR+/HER2–Breast Cancer

Don Bergstrom, MD, PhD

RLY-2608 in combination with fulvestrant (Faslodex) generated clinically meaningful progression-free survival (PFS) outcomes and a favorable safety profile in heavily pretreated patients with PI3Kα-mutated, hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer, according to findings from the first-in-human, phase 1 ReDiscover trial (NCT05216432).¹

At a median follow-up of 7.5 months, patients with PI3Kα-mutated, HR-positive, HER2-negative metastatic disease without PTEN or AKT co-mutations who received RLY-2608 at the recommended phase 2 dose (RP2D) of 600 mg twice daily plus fulvestrant (n = 52) achieved a median PFS of 9.2 months regardless of kinase mutation status. Among those with kinase mutations, the median PFS was 10.3 months. The clinical benefit rate was 57% across all 35 patients evaluable for clinical benefit in the overall population.

Among patients with measurable disease who received RLY-2608 at the RP2D (n = 30), the overall response rate (ORR) was 33% (n = 10) in the entire population regardless of kinase mutation status. All responses were partial responses (PRs); 8 were confirmed, 1 was confirmed after the data cutoff date, and 1 was unconfirmed in an ongoing patient. In the entire population, 73% of patients experienced tumor reductions. Treatment with RLY-2608 at the RP2D produced an ORR of 53% in patients with measurable disease and a kinase mutation (n = 8). All responses were PRs; 7 were confirmed, and 1 was confirmed after the data cutoff date.

“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 and Development at Relay Therapeutics, stated in a news release. “We are very encouraged to see that RLY-2608 [plus] fulvestrant led to clinically meaningful progression-free survival 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.”

The ReDiscover Trial

The ongoing ReDiscover trial is investigating the safety, tolerability, pharmacodynamics, pharmacokinetics, and preliminary antitumor activity of RLY-2608 as monotherapy in patients with advanced solid tumors, as well as in combination with fulvestrant with or without ribociclib (Kisqali) or atirmociclib (PF-07220060) in patients with advanced breast cancer.2 At an interim data cutoff date of August 12, 2024, 118 patients were enrolled in the dose-escalation and -expansion portions of the RLY-2608 plus fulvestrant arm across all dose levels. This included 64 patients at the RP2D (dose-escalation, n = 17; dose-expansion, n = 47).1 Of those patients, 31 harbored a kinase mutation, and 33 harbored a non-kinase mutation. In total, 12 patients displayed AKT or PTEN co-mutations and were excluded from the efficacy analysis to align with the currently proposed pivotal population.

All patients across dose levels had received at least 1 prior CDK4/6 inhibitor and at least 1 prior endocrine therapy. Of the patients who received the RP2D, 45% had received at least 2 prior lines of therapy, 52% had received a prior selective estrogen receptor degrader, and 25% had received prior chemotherapy or an antibody-drug conjugate. Furthermore, 59% of patients had visceral metastases and 34% of patients had a body mass index of at least 30 and/or hemoglobin A1c levels of at least 5.7%.

The news release noted that RLY-2608 plus fulvestrant was generally well tolerated across dose levels and that most adverse effects (AEs) were low grade, treatment-related, manageable, and reversible. At the RP2D, the median dose intensity was 95%; 2 patients discontinued treatment due to AEs (grade 1 pruritus, n = 1; grade 1 nausea and loss of appetite, n = 1). Most instances of hyperglycemia were grade 1; 1 patient had grade 3 hyperglycemia, and no instances of grade 4 or 5 hyperglycemia were reported. Overall, 25% of patients had a grade 3 treatment-related AE (TRAE), and no grade 4 or 5 TRAEs were observed.

The dose-escalation portion of the ReDiscover arm is currently testing biologically active doses of RLY-2608 plus fulvestrant and ribociclib and is on track to identify a dose of the agent that can be combined with a full dose of ribociclib. Initial safety data from this arm are expected to read out in the fourth quarter of 2024, and investigators plan to initiate dose-expansion cohorts in this arm in the first half of 2025. Additionally, initiation of the ReDiscover arm investigating RLY-2608 plus fulvestrant and atirmociclib is expected by the end of 2024.

An abstract with data from ReDiscover has been submitted for presentation at the 2024 San Antonio Breast Cancer Symposium.

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 9, 2024. https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-positive-interim-data-rly-2608
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 9, 2024. https://clinicaltrials.gov/study/NCT05216432