Relay Therapeutics Unveils Zovegalisib Triplet Data, Signs Pfizer Supply Deal for Phase III Plan

Key Points

• ORR 44% in a heavily pretreated cohort: relay reported a 44% overall response rate in 62 patients treated with the zovegalisib+atirmociclib+fulvestrant triplet (median follow-up 7.4 months), with median PFS not yet reached and 77% of patients still on therapy; 40% experienced Grade ≥3 treatment-related AEs (mainly neutropenia) but <10% had zovegalisib dose reductions and hyperglycemia was low.
• Phase III plan and Pfizer supply agreement: Relay aims to start a frontline phase III in early 2027 for endocrine‑sensitive, HR+/HER2‑, PIK3CA‑mutated patients comparing the triplet versus standard CDK4/6+AI therapy, with Pfizer supplying atirmociclib (and palbociclib for part of the control arm) while Relay sponsors the trial and retains global rights to zovegalisib.
• Selective‑agent rationale and dosing: Relay is prioritizing a next‑generation selective triplet (mutant‑selective PI3Kα zovegalisib plus CDK4‑selective atirmociclib) to improve long‑term tolerability versus non‑selective combinations; atirmociclib raises zovegalisib exposure ~2.5×, prompting a planned phase III dose of 150 mg zovegalisib with 300 mg atirmociclib pending regulatory feedback.

Relay Therapeutics NASDAQ: RLAY outlined new data and development plans for its lead oncology program, zovegalisib, during a “frontline breast cancer update” conference call, highlighting encouraging activity and tolerability from a triplet regimen in heavily pretreated metastatic breast cancer patients and announcing a phase III supply agreement with Pfizer for the CDK4 inhibitor atirmociclib.

Program focus and three targeted opportunities

CEO Sanjiv Patel said the company’s “lead program, zovegalisib…a pan-mutant selective PI3Kα inhibitor,” is being positioned across three “very large commercial opportunities”: second-line hormone receptor (HR)-positive, HER2-negative metastatic breast cancer; frontline HR-positive, HER2-negative metastatic breast cancer; and vascular anomalies.

Patel said Relay is “laser-focused” on executing its ongoing pivotal trial in second-line disease, ReDiscover-2, which is “recruiting patients globally.” The call’s main focus was frontline development, where Patel said Relay has selected Pfizer’s CDK4-selective inhibitor atirmociclib as the combination partner for a next-generation triplet with endocrine therapy.

Rationale: selective triplet to improve tolerability

Patel pointed to the recent Roche INAVO120 trial and approval, which showed that adding a PI3Kα inhibitor to a CDK4/6 inhibitor plus endocrine therapy in PIK3CA-mutated frontline patients improved outcomes, including progression-free survival (PFS) and overall survival. However, he said tolerability can be problematic when “stacking a non-selective PI3K inhibitor with a non-selective CDK inhibitor,” noting that safety issues have led to “Dear Doctor letters…due to potentially life-threatening safety events.”

Relay’s goal, Patel said, is to preserve the efficacy benefits of adding PI3K inhibition while improving long-term tolerability by combining selective agents: zovegalisib (mutant-selective PI3Kα) and atirmociclib (CDK4-selective). The company “deprioritized” other triplet cohorts it had been testing after observing what Patel called a “step change” in safety and tolerability with the atirmociclib triplet.

Triplet dataset: 62 patients, median third-line, ORR 44%

President of R&D Don Bergstrom presented results from 62 patients treated with zovegalisib plus atirmociclib plus fulvestrant, with median follow-up of 7.4 months. Patients received zovegalisib 100–200 mg twice daily and atirmociclib 100–300 mg twice daily, plus standard-dose fulvestrant. Bergstrom emphasized this was a heavily pretreated population: all had at least one prior CDK4/6 inhibitor; more than half had received a SERD; more than a quarter had received chemotherapy or an antibody-drug conjugate; and 10 patients had received prior PI3K pathway-directed therapy. Nearly half were pre-diabetic at baseline, more than 60% had visceral disease, and over 40% had a co-occurring ESR1 mutation.

Bergstrom said atirmociclib increases zovegalisib blood concentrations by about 2.5-fold, with 150 mg zovegalisib in the triplet approximating exposure seen with 400 mg zovegalisib in the zovegalisib/fulvestrant doublet being tested in ReDiscover-2. Relay plans to prioritize 300 mg atirmociclib (the dose Pfizer studied in FOURLIGHT-1 and is studying in FOURLIGHT-3) and intends to bring 150 mg zovegalisib forward as the phase III dose, pending regulatory feedback. The company did not report data from the 200 mg zovegalisib plus 300 mg atirmociclib dose level, stating that while it was “not a formal MTD,” its safety profile did not meet the target for chronic frontline use.

Despite unoptimized dosing, Bergstrom reported an overall response rate (ORR) of 44% among patients with RECIST-measurable disease. He said responses were comparable in kinase and non-kinase domain PIK3CA mutations and were observed in patients previously treated with a SERD and/or a PI3K pathway inhibitor. One patient converted from a confirmed partial response to an unconfirmed complete response.

Safety and durability signals

On tolerability, Bergstrom said 40% of patients experienced Grade 3 or higher treatment-related adverse events, with most higher-grade events being neutropenia and “no cases of febrile neutropenia.” He added that hyperglycemia rates were low, with “no Grade 3 or higher hyperglycemia,” despite many patients being pre-diabetic at entry. Less than 10% of patients dose reduced zovegalisib, 16% dose reduced atirmociclib, and the combined rate of dose reduction for either drug was 23%. Discontinuations due to treatment-related adverse events were limited to two patients for zovegalisib and four for atirmociclib, and two patients who discontinued the triplet remained on study receiving the zovegalisib/fulvestrant doublet.

Regarding durability, Bergstrom said that after 7.4 months median follow-up, 77% of patients (48 of 62) remained on therapy, and median PFS was not yet reached.

In Q&A, Bergstrom said rash observed in the triplet has been “primarily low grade,” managed with antihistamines, and that Relay is evaluating whether atirmociclib or prior PI3K-pathway therapies may contribute.

Frontline phase III plan and Pfizer supply agreement

Relay plans to initiate a phase III frontline trial in endocrine-sensitive, HR-positive, HER2-negative, PIK3CA-mutated patients in early 2027, “subject to regulatory feedback,” according to Patel and Bergstrom. The proposed trial would randomize patients to zovegalisib plus atirmociclib plus an aromatase inhibitor versus investigator’s choice of ribociclib, abemaciclib, or palbociclib plus an aromatase inhibitor. Bergstrom said Relay expects it may need to account for “contribution of components” because both zovegalisib and atirmociclib are investigational in the experimental arm and plans to discuss the design with health authorities.

Rahmer said Relay has extended its prior collaboration with Pfizer into a phase III supply agreement. Under the agreement, Relay will sponsor, operationalize, and fund the frontline phase III trial and retain full global rights to zovegalisib, while Pfizer will supply atirmociclib for the experimental arm and palbociclib for part of the control arm.

On timing, Rahmer said the company expects to return later in the year “on the other side of a regulatory interaction” to confirm trial design and dose before starting the study. He also said Relay’s current cash guidance contemplates starting the study, though “over time, to fund the entirety of the study, we will need more cash.”

Patel closed by reiterating Relay’s focus on a selective, all-oral regimen aimed at improving tolerability for multi-year treatment in frontline PIK3CA-mutated metastatic breast cancer, and he noted the company expects to share initial vascular anomalies data at the ISSVA conference in Philadelphia on May 20.

About Relay Therapeutics NASDAQ: RLAY

Relay Therapeutics, Inc is a clinical-stage biotechnology company focused on the discovery and development of precision therapies for oncology. Headquartered in Cambridge, Massachusetts, the company was founded in 2016 with the goal of targeting dynamic protein motion using an integrated scientific platform. Relay Therapeutics leverages computational modeling, structural biology, and experimental validation to identify small-molecule drug candidates that modulate the behavior of disease-associated proteins.

The company's core business activity centers on its proprietary drug-discovery engine, which combines high-performance computing—including molecular dynamics simulations—with advanced experimental techniques such as cryo-electron microscopy and biophysical screening.

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