8-K: Relay Therapeutics Advances Zovegalisib to Phase 3 for Breast Cancer

Relay Therapeutics announced positive clinical data for its zovegalisib triplet combination, supporting advancement to Phase 3 development for frontline metastatic breast cancer.

Summary

• Relay Therapeutics is moving its drug zovegalisib, in combination with atirmociclib and fulvestrant, into Phase 3 development for patients with PI3K-mutated, HR+/HER2- metastatic breast cancer.
• The decision is based on preliminary data from the Phase 1/2 ReDiscover trial, which showed a 44% objective response rate (ORR) in heavily pre-treated patients.
• The triplet combination demonstrated a favorable safety profile, with only 3% of patients discontinuing zovegalisib due to treatment-related adverse events.
• A Phase 3 trial is planned to initiate in early 2027, subject to regulatory feedback, and will evaluate the triplet against a CDK4/6 inhibitor plus an aromatase inhibitor.
• Pfizer will supply atirmociclib for the experimental arm and palbociclib for the control arm of the Phase 3 trial.

Sentiment

Score: 7

Explanation: StockSavvy.ai views this as a positive development, with strong clinical data supporting advancement to Phase 3, though the ORR in heavily pre-treated patients still trails current frontline standards.

Positives

• The company is advancing zovegalisib plus atirmociclib into Phase 3 development for frontline metastatic breast cancer.
• The triplet combination (zovegalisib, atirmociclib, fulvestrant) achieved a 44% objective response rate (ORR) in heavily pre-treated patients (median third-line).
• The ORR in these pre-treated patients approaches that of current standard of care doublets in the frontline setting (53-55%).
• Nearly all patients (85%) experienced tumor reduction.
• The safety and tolerability profile of the triplet regimen is considered supportive for frontline use, with only 3% discontinuing zovegalisib due to TRAEs and 10% dose reducing.
• Grade 3 hyperglycemia was 0% despite 47% of patients being pre-diabetic.
• No instances of febrile neutropenia were observed.
• 77% of patients remain on study as of the data cut-off date, indicating good tolerability for longer-term treatment.

Negatives

• The data are not yet mature enough to estimate median progression-free survival.
• The overall grade 3+ TRAE rate in these median third-line patients is 40%, with neutropenia being the majority of these events.
• The ORR of 44% in heavily pre-treated patients is lower than the 53-55% ORR seen with current standard of care doublets in frontline patients.

Risks

• The preliminary or interim results of clinical trials may not be predictive of future or final results.
• There is a risk that interim and early clinical data may change as more patient data become available and are subject to audit and verification procedures.
• The company's ability to successfully demonstrate the safety and efficacy of its drug candidates is subject to risks.
• Timing and outcome of planned interactions with regulatory authorities are uncertain.
• Risks associated with global economic uncertainty, geopolitical instability, and public health epidemics could impact clinical trials and operations.
• Significant political, trade, or regulatory developments could affect the company's plans.
• There is a risk of delay or pause in current or planned clinical trials or development of drug candidates.
• Obtaining, maintaining, and protecting intellectual property presents ongoing risks.

Future Outlook

The company plans to initiate a randomized Phase 3 trial evaluating zovegalisib in combination with atirmociclib and an aromatase inhibitor in frontline endocrine-sensitive patients with PIK3CA-mutated, HR+/HER2- advanced or metastatic breast cancer, subject to regulatory feedback, with an aim to start in early 2027. Key endpoints for this trial will be median progression-free survival (primary) and overall survival (secondary).

Management Comments

• "We believe that combining the selective profiles of zovegalisib and atirmociclib with endocrine therapy has the potential to enable a well-tolerated, all-oral triplet regimen, and these initial data support advancing this combination into Phase 3 development for patients with frontline metastatic breast cancer."
• "While PI3K inhibition has demonstrated meaningful benefit in breast cancer, its use in the frontline setting has been limited by tolerability challenges with earlier agents."

Industry Context

StockSavvy.ai notes that Relay Therapeutics' advancement of zovegalisib into Phase 3 development for frontline metastatic breast cancer aligns with the industry trend of developing more targeted therapies for specific genetic mutations like PIK3CA. The focus on improving tolerability in combination regimens is crucial for achieving better patient outcomes and broader adoption in the frontline setting, where long-term treatment is common.

Comparison to Industry Standards

• The Objective Response Rate (ORR) of 44% in heavily pre-treated patients (median third-line) for the zovegalisib triplet approaches the ORR of 53-55% seen with current standard of care doublets in frontline (1L) patients.
• The Grade 3+ TRAE rate of 40% in median third-line patients is compared to higher rates (50-90%) seen with some other triplet regimens in 1L breast cancer, suggesting a potentially more favorable tolerability profile for long-term use.
• The company references capivasertib + fulvestrant in 2L breast cancer, which showed a median Progression-Free Survival (mPFS) of 5.5 months, as a benchmark, while its own doublet data showed 11.1 months mPFS.
• The company also references Inavolisib + palbociclib + fulvestrant in 1L endocrine resistant breast cancer, which showed a Hazard Ratio for PFS of 0.42 (17.2mo vs. 7.3mo) and OS of 0.67 (34.0mo vs. 27.0mo), but notes its high Grade 3+ AE rate (91%) limits its use.

Stakeholder Impact

• Shareholders: Positive outlook due to advancement of a key pipeline asset towards potential commercialization, contingent on successful Phase 3 trials and regulatory approvals.
• Patients: Potential for a new, well-tolerated, all-oral triplet regimen for frontline metastatic breast cancer, particularly those with PIK3CA mutations.
• Healthcare Providers: Will have a new treatment option to consider for their patients, with data suggesting a favorable efficacy and tolerability profile.
• Pfizer: Continues its role as a supplier of atirmociclib, supporting Relay Therapeutics' development efforts.

Next Steps

• Conduct regulatory interactions to finalize Phase 3 design and dose.
• Initiate the Phase 3 trial in early 2027, subject to regulatory feedback.
• Continue execution of Phase 1/2 dose finding and expansion in the ReDiscover study.
• Continue execution of the ReDiscover-2 Phase 3 trial in second-line breast cancer.
• Present initial data for zovegalisib in vascular anomalies at ISSVA 2026.

Key Dates

Recommendation

The advancement to Phase 3 is a significant positive step, but the ORR in heavily pre-treated patients still lags behind current frontline standards, and the ultimate success hinges on Phase 3 outcomes and regulatory approval. While promising, it warrants a 'hold' pending further data and de-risking.

Keywords

zovegalisib, atirmociclib, metastatic breast cancer, PI3K mutation, HR+/HER2-, Phase 3 trial, clinical data, oncology