Relay Therapeutics' RLY-2608, a novel oral and mutant-selective PI3Kα inhibitor, has entered Phase I clinical trials for the treatment of HR+/HER2- breast cancer. The drug is being investigated both as a monotherapy and in combination with fulvestrant, addressing a critical need for more targeted and tolerable therapies in this patient population.
Overcoming Limitations of Current PI3Kα Inhibitors
Existing PI3Kα modulators, such as alpelisib (approved by the FDA) and inavolisib, face challenges due to off-target toxicities stemming from the inhibition of wild-type PI3Kα. These toxicities often manifest as hyperglycemia and rash, limiting the drugs' clinical utility and patient adherence. RLY-2608 is designed to selectively inhibit mutant PI3Kα, potentially mitigating these adverse effects.
Mechanism of Action and Mutant Selectivity
RLY-2608's mechanism of action focuses on targeting specific PI3Kα mutations commonly found in HR+/HER2- breast cancer. By selectively inhibiting these mutant forms, the drug aims to disrupt cancer cell growth and proliferation while sparing normal cells expressing wild-type PI3Kα. This selectivity is crucial for reducing the incidence and severity of treatment-related toxicities.
Clinical Development and Trial Design
The ongoing Phase I trial is evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of RLY-2608. Patients with HR+/HER2- breast cancer harboring PI3Kα mutations are being enrolled. The trial includes both single-agent and combination arms, with fulvestrant being the chosen combination partner due to its established efficacy in HR+ breast cancer. Key endpoints include objective response rate, progression-free survival, and overall survival, as well as detailed assessments of adverse events and pharmacokinetic parameters.
