RLY-2608 Plus Fulvestrant Demonstrates Efficacy in PIK3CA-Mutated, HR+/HER2– Advanced Breast Cancer

Sarah Sammons, MD

RLY-2608 in combination with fulvestrant (Faslodex) displayed a tolerable safety profile and preliminary activity in patients with PIK3CA-mutated, hormone receptor (HR)–positive, HER2-negative advanced breast cancer, paving the way for the combination to be examined in the phase 3 ReDiscover-2 study (NCT06982521), according to Sarah Sammons, MD.

During the 2025 ASCO Annual Meeting, Sammons presented data from the phase 1 ReDiscover trial (NCT05216432), which evaluated RLY-2608 plus fulvestrant in patients with PIK3CA-mutated, HR-positive/HER2-negative advanced breast cancer. At least 1 prior anti-estrogen therapy and a CDK4/6 inhibitor were required; no more than 1 prior line of chemotherapy in the metastatic setting was allowed.

At a median follow-up of 12.5 months, patients who received the combination (n = 52) achieved a median progression-free survival (PFS) of 10.3 months (95% CI, 7.2-18.4); the 6-month PFS rate was 69.3%. Response-evaluable patients (n = 31) experienced an overall response rate (ORR) of 38.7% (95% CI, 38.4%-88.2%) per RECIST 1.1 criteria.

Regarding safety, treatment-related adverse effects (TRAEs) of any grade occurred in 94.1% of patients treated at any dose level (n = 118) and 96.9% in those treated at the recommended phase 2 dose (RP2D) of 600 mg of RLY-2608 twice per day plus fulvestrant (n = 64). The rates of grade 3 or higher TRAEs were 27.1% and 35.9%, respectively. Most AEs were low grade and reversible; AEs led to treatment discontinuation in 2% of patients.

“The combination of RLY-2608 plus fulvestrant is very promising at this juncture in the post-CDK4/6 inhibitor setting, and we are excited to move it into a pivotal phase 3 trial,” Sammons said in an interview with OncLive^®.

Sammons is the associate director of the Metastatic Breast Cancer Program and a senior physician at Dana-Faber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

In the interview, Sammons discussed the design of ReDiscover, the findings presented during the ASCO Annual Meeting, and the potential role for RLY-2608 in the treatment of patients with HR-positive/HER2-negative breast cancer.

OncLive: What is the mechanism of action of RLY-2608 and the rationale for investigating it in this patient population?

Sammons: RLY-2608 is the first mutant-specific allosteric PIK3α inhibitor. It spares the wild-type PIK3CA receptor better than other approved drugs, [such as] alpelisib [Piqray] or inavolisib [Itovebi]. The hope is when you just target the mutation, you spare some of the adverse effects [AEs] that can occur when you also [target] the wild-type receptor.

PIK3CA mutations are a common mutation in metastatic breast cancer. They occur in approximately 40% of patients [with HR-positive, HER2-negative disease] and denote resistance to current endocrine therapies and CDK4/6 inhibitors. There is a need to be able to target PIK3CA mutations to delay resistance and provide therapies post–CDK4/6 inhibitor [disease] progression. ReDiscover was the first-in-human trial of RLY-2608. The dose-escalation phase was pan-tumor and included patients with PIK3CA [mutations].

What were the key design features of ReDiscover?

The expansion cohort examined RLY-2608 at the recommended phase 2 dose of 600 mg twice daily plus fulvestrant. We looked at the safety and efficacy in patients following [treatment with] a prior CDK4/6 inhibitor. Patients could only have received up to 1 line of chemotherapy in the advanced setting, and they could have had a number of lines of [prior] endocrine therapy. They were not permitted to have received a prior PIK3α , AKT, or mTOR inhibitor.

What were the notable efficacy findings from ReDiscover reported at ASCO?

The updated results excluded patients with concurrent PTEN or AKT alterations, and that was [approximately] 10% of the population. We believe that these mutant-specific inhibitors only work for patients with isolated PIK3CA mutations and not downstream alterations.

In the patients with isolated PIK3CA mutations, we saw an excellent ORR in the post-CDK4/6 [inhibitor] setting of 38.7%, and we saw tumor reduction in 80.6% of patients. In patients with kinase domain mutations [n = 15], we saw an ORR of 66.7% [95% CI, 38.4%-88.2%]. In patients who received prior fulvestrant [n = 15], the ORR was 40.0% [95% CI, 16.3%-67.7%], showing some monotherapy efficacy. We believe that [RLY-2608] is promising in that capacity.

In the overall population, the median PFS was 10.3 months. In the second-line population [n = 30], the median PFS was 11.0 months [95% CI, 7.3-22.0]. Among patients with kinase domain PIK3CA mutations [n = 29], we observed an impressive median PFS of 18.4 months [95% CI, 9.2-not reached].

Were there any safety concerns with this combination?

[PIK3α] inhibitors in this space that are already approved have problems with hyperglycemia, diarrhea, rash, mucositis, and oral sores, which can be challenging for our patients to tolerate. With RLY-2608, we are still seeing some hyperglycemia, but it is almost exclusively low grade. There was a 51.6% any-grade hyperglycemia rate [at the RP2D]; however, 31% [had] grade 1 [hyperglycemia] and required no intervention. There were a few grade 3 hyperglycemia events [at the RP2D (3.1%)].

We saw very little rash or mucositis, which is exciting compared with other drugs in this class. We did see some nausea and fatigue, which were generally manageable with supportive medications and, rarely, dose reductions. We also observed seeing some mild elevations in creatinine [levels], which we have to monitor.

Overall, the safety profile [of RLY-2608] compared with other inhibitors in its class is promising as we figure out how to best target this pathway so that our patients can stay on these drugs and benefit from them.

What are the next steps for the development of RLY-2608?

RLY-2608 plus fulvestrant is moving into a pivotal phase 3 trial that will open in 2025 [with] a comparator of capivasertib [Truqap] plus fulvestrant, which is the standard [of care] for patients with PIK3CA-mutated, HR-positive/HER2-negative breast cancer. This trial is exploring [the combination in] patients in the post–CDK4/6 inhibitor setting.

We hope [to see] improved efficacy and tolerability. That would be the holy grail of a compound in this space. As we move forward, it will be interesting to explore RLY-2608 and other mutant-selective inhibitors as triplets with CDK4/6 inhibitors and endocrine therapy.

Reference

Sammons SL, Manich CS, Italiano A, et al. Updated efficacy of mutant-selective PI3Kα inhibitor RLY-2608 in combination with fulvestrant in patients with PIK3CA-mutant HR+HER2- advanced breast cancer: ReDiscover trial. J Clin Oncol. 2025;43(suppl 16):1086. doi:10.1200/JCO.2025.43.16_suppl.1086