RLY-2608 Shows Preclinical Potential for Selective PI3K Inhibition, Decreased AEs in HR+, HER2– Breast Cancer

Increasingly mutant-targeted PI3K inhibitors, such as the investigational agent RLY-2608, may provide more potent efficacy in hormone receptor (HR)–positive, HER2-negative breast cancer, while decreasing the adverse effects (AEs) that are often associated with this class of agents, according to Julia E. McGuinness, MD.

RLY-2608 is the first known allosteric PI3Kα pan-mutant and isoform-selective inhibitor.¹ The safety and preliminary activity of this agent are being evaluated in a phase 1 first-in-human study (NCT05216432), which is investigating RLY-2608 as a single agent in adult patients with advanced solid tumors and in combination with fulvestrant (Faslodex) in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer.²

Eligible patients include those with at least 1 documented primary PIK3CA mutation per local assessment and no prior PI3K inhibitors. Patients in the breast cancer cohort must have received previous treatment with no more than 1 chemotherapy, at least 1 CDK4/6 inhibitor, and at least 1 anti-estrogen therapy. Recruitment for this trial is ongoing across 14 centers in the US and Spain.

“It’s getting increasingly complicated to figure out what the next therapy is for patients after they’ve progressed on CDK4/6 inhibitors. [Biomarker testing is] still crucial,” McGuinness said in an interview with OncLive^®.

In the interview, McGuinness discussed the rationale for combining this novel PI3K inhibitor with fulvestrant and emphasized the importance of developing increasingly mutant-specific PI3K inhibitors in HR-positive disease, including the need for therapies that don’t cause gastrointestinal (GI) AEs such as diarrhea.

McGuinness is an assistant professor of medicine in the Division of Hematology/Oncology at the Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York.

OncLive^®: What is the rationale for this phase 1 trial of RLY-2608?

McGuinness: Patients with HR-positive, HER2-negative metastatic breast cancer standardly receive first-line CDK4/6 inhibitors plus endocrine therapy. After they’ve progressed, we start talking about second-line therapies that are often guided by the mutational status of their tumors. About 40% of these patients have a PIK3CA mutation, [for which] the standard treatment option is alpelisib [Piqray], a PI3K inhibitor.

The problem with alpelisib is it can have dose-limiting toxicities, including hyperglycemia. That’s because the drug is not specific to the mutated PI3K, so it can also affect wild-type [PI3K], and that’s where the AEs come from.

This novel agent, developed by Relay Therapeutics, is a mutant-specific PI3K inhibitor. The rationale behind it is that its [properties may] potentially be more effective [at targeting mutant-specific PI3K, resulting in less toxicity]. This has been supported by [Relay’s previous] work in animal models.

What information from this study was shared at the 2022 San Antonio Breast Cancer Symposium?

[We shared] a trial-in-progress update. We don’t yet have published data on toxicity or preliminary efficacy from this study. That being said, we started enrolling to the combination arm about 8 months ago in the US, [and enrollment] is open at Columbia. Hopefully we’ll have updated results at a future meeting.

How does the impetus for this study speak to the importance of biomarker testing in breast cancer?

These potential targeted therapies that will hopefully show improved clinical benefit and improved toxicity highlight the importance of continuing to identify these patients through molecular testing, either at progression or initial diagnosis.

What is the importance of developing more selective inhibitors in breast cancer that don’t cause GI AEs?

Many current therapies cause GI toxicity, even among our first-line therapies like abemaciclib [Verzenio], and PI3K inhibitors like alpelisib. These can often limit doses and cause dose interruptions or even, in severe cases, lead patients to discontinue the drugs. Because of these severe toxicities, although our supportive management of them is improving, it’s increasingly important, since we want patients to benefit from these drugs, to find more selective agents to target the mutations of interest so they can potentially be on these drugs longer and have a better quality of life on these medications.

References

1. Varkaris A, Hamilton E, Henry J, et al. First-in human global multi-center study of RLY-2608, a pan mutant and isoform selective PI3Kα inhibitor, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract OT3-22-01.
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 November 21, 2022. Accessed December 13, 2022. https://clinicaltrials.gov/ct2/show/NCT05216432