RLY-2608 Uses PI3Kα Mutant–Specific Inhibition to More Safely Treat Breast Cancer and Other Solid Tumors

In the phase 1 ReDiscover trial (NCT05216432), the first-in-human study of the mutant-selective PI3Kα inhibitor RLY-2608, investigators are aiming to leverage the agent’s mechanism of action to decrease the frequency of adverse effects (AEs) observed with PI3K inhibitors and offer an additional treatment option for patients with advanced solid tumors including breast cancer.¹

“RLY-2608 is a mutant-selective PI3K inhibitor,” Komal Jhaveri, MD, FACP, explained in an interview with OncologyLive. “When we think about targeting PI3K, we can think about targeting PI3Kα, which is the oncogenic driver, but we target both the mutant and the wild-type [forms] with the currently approved drugs. It is the wild-type inhibition [that] leads to the on-target hyperglycemia, which is the major challenge that we face for patients in clinic with these currently approved drugs. The next wave of inhibitors, such as RLY-2608, [is] being developed to only inhibit the mutant PI3Kα and spare the wild-type inhibition. Hopefully [this] will overcome the issue of hyperglycemia, which we see with this class of drugs.”

Jhaveri is section head of the Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

In past preclinical work, RLY-2608 displayed tumor growth inhibition with maintained glucose homeostasis in hormone receptor (HR)–positive mouse xenograft models harboring PIK3CA kinase and helical mutations. Additionally, the agent displayed minimal disruption of insulin levels in preclinical study.²

“The preclinical work with this compound in cell line models and mouse models [has displayed] activity as monotherapy,” Cristina Saura Manich, PhD, head of the Breast Cancer Unit of the Service of Medical Oncology and principal investigator of the research group on breast cancer and melanoma at Vall d’Hebron University Hospital in Barcelona, Spain, said in an interview with OncologyLive. “This activity has been shown in mouse models with [kinase and helical domain] mutations. It’s interesting to see that with this compound, there is minimal perturbation of insulin levels that may be translated into less hyperglycemia in patients in the clinic.”

ReDiscover Study Design

ReDiscover is a global, open-label, dose-escalation and expansion study that is evaluating RLY-2608 as monotherapy in patients with advanced solid tumors and in combination with fulvestrant (Faslodex) with or without a CDK4/6 inhibitor in patients with HR-positive/HER2-negative metastatic breast cancer. The triplet arms will evaluate RLY-2608 and fulvestrant with either ribociclib (Kisqali) or palbociclib (Ibrance; Figure).¹

To be eligible for the study, patients must have at least 1 documented PI3KCA mutation and an ECOG performance status of 1 or less. In the monotherapy arm, patients are required to have measurable disease per RECIST 1.1 criteria and be refractory, intolerant to, or decline standard therapy. The monotherapy arm includes patients with clear cell ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, other solid tumors, and unresectable or metastatic solid tumors with PIK3CA double mutations.

In the combination arms, patients must have HR-positive/HER2-negative unresectable or metastatic breast cancer that is not amenable to curative therapy and is measurable per RECIST 1.1 criteria. Patients must have received a maximum of 1 prior line of chemotherapy in the metastatic setting, at least 1 CDK4/6 inhibitor in the adjuvant or metastatic setting, at least 1 antiestrogen therapy in the adjuvant or metastatic setting, and at least 1 PARP inhibitor if a germline BRCA1/2 mutation is present.

In part 1 of the monotherapy arm, patients received multiple ascending doses of RLY-2608; in part 2, they were treated with the recommended phase 2 dose (RP2D). In the doublet arm, patients received multiple ascending doses of RLY-2608 in part 1 and the RP2D in part 2 in combination with intramuscular fulvestrant 500 mg on day 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle. In the triplet arms, patients received RLY-2608 and fulvestrant in the same manner as the other arms in combination with either palbociclib 125 mg once daily for 21 days on and 7 days off or ribociclib at a dose of 400 mg or 600 mg daily for 21 days on and 7 days off.¹

The primary end points are the RP2D and the maximum-tolerated dose (MTD) of RLY-2608 as monotherapy and as a combination component as well as safety. Secondary end points include objective response rate, duration of response, disease control rate, quality of life, and pharmacokinetics.

“We are recruiting very well. Patients with HR-positive metastatic breast cancer have PIK3CA mutations,” Saura Manich said. “In Europe and the United States, it’s a good opportunity [for patients]. The safety and toxicity profile and efficacy results we have already seen have encouraged investigators to offer this trial to patients.”

RLY-2608 Displays Preliminary Activity in Breast Cancer

Early findings from ReDiscover have been encouraging, with investigators being particularly excited about the safety profile of RLY-2608, Jhaveri said. In June 2024, Relay Therapeutics, Inc, the developer of the agent, announced new data from the study that updated preliminary efficacy and safety findings presented during the 2023 American Association for Cancer Research Annual Meeting.³

At a data cutoff of July 24, 2023, the dose-escalation portion had been completed in the RLY-2608 plus fulvestrant arm, with 43 patients with HR-positive/HER2-negative locally advanced or metastatic breast cancer having received the combination at any dose level, including 17 at 600 mg twice daily and 5 at 400 mg twice daily. Additionally, 4 patients had been treated in the RLY-2608 monotherapy arm.³

The median age of patients who received RLY-2608 plus fulvestrant at any dose and at the 600-mg dose was 59 years (range, 40-82) and 60 years (range, 49-80), respectively, and all patients in both groups were female. Most patents in both groups were White (67% and 59%, respectively) and had a median body mass index of less than 30 kg/m2 (74% and 82%). The median number of prior treatment regimens in the metastatic setting was 1 (range, 1-6) and 2 (range, 1-6), respectively.

Among patients with breast cancer with measurable disease per RECIST (n = 24), 4 patients experienced a partial response, including 1 who received RLY-2608 monotherapy, across dose levels and PI3Kα genotypes. Sixty-three percent (n = 15/24) of patients exhibited radiographic tumor reductions, 13 of which are ongoing. Most patients (80%) treated with the combination of RLY-2608 600 mg plus fulvestrant achieved radiographic tumor regression, including 1 with a partial response who remains on treatment.³

Across all dose levels, 28 of 43 treated patients remain on treatment, with a median treatment duration of 15 weeks (range, 1-64). In patients with at least 6 months of follow-up who received RLY-2608 600 mg plus fulvestrant (n = 7), the interim clinical benefit rate was 86%, and the median treatment duration among all patients in this arm was 12 weeks (range, 1-41). Fifteen of 17 patients in this arm were still on treatment at the data cutoff.³

“It’s early days for efficacy; as a phase 1 study, this is designed to look at the safety and the tolerability [profile of the agent],” Jhaveri noted. “We’re seeing manageable, low-grade, and low-incidence hyperglycemia and diarrhea with the agent so far. We look forward to additional results and more follow-up data with combination therapy with an endocrine backbone in combination with RLY-2608 and a larger data set to see the efficacy—now that we’re at least getting excited about the safety.”

In terms of safety, patients with breast cancer across arms experienced any-grade treatment-emergent AEs (TEAEs) including nausea (44%), hyperglycemia (37%), increased blood creatine (33%), fatigue (28%), diarrhea (23%), hypokalemia (23%), headache (21%), decreased appetite (16%), and vomiting (16%). Grade 3 TEAEs consisted of fatigue (7%), hypokalemia (9%) and headache (2%).³ 

In the 600-mg combination group, patients experienced any-grade nausea (41%), hyperglycemia (35%), increased blood creatine (35%), fatigue (12%), diarrhea (24%), hypokalemia (24%), headache (29%), decreased appetite (29%), and vomiting (18%). Grade 3 fatigue and hypokalemia were both reported at a rate of 6%.³

Relay Therapeutics noted that there were no dose-limiting toxicities and that the MTD had not been defined. By the end of 2024, the company expects to disclose updated data from more than 100 safety-evaluable patients who received the doublet at all doses, more than 60 safety-evaluable patients treated at the 600-mg dose level, and findings from the landmark progression-free survival analysis of more than 40 patients with at least 6 months of follow-up. Early safety and tolerability data from the triplet arms are also expected by this time. ReDiscover is continuing to enroll patients at approximately 25 sites across 4 countries.³

References

1. 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 July 8, 2024. https://clinicaltrials.gov/study/NCT05216432
2. Saura C, Sanz L, Kim J, et al. First-in-human study of RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, as a single agent in patients (pts) with advanced solid tumors and in combination with fulvestrant in pts with advanced breast cancer. J Clin Oncol. 2024;42(suppl 16):TPS1128. doi:10.1200/JCO.2024.42.16_suppl.TPS1128
3. Corporate presentation. Relay Therapeutics Inc. June 2024. Accessed July 8, 2024. bit.ly/4bIpmuk