Inavolisib

• The FDA approved Rezdiffra (resmetirom) as the first specific treatment for nonalcoholic steatohepatitis (NASH), addressing a critical unmet need for patients with liver damage. • Duvyzat (givinostat) gained approval as the first nonsteroidal treatment for all genetic variants of Duchenne muscular dystrophy (DMD), offering a new option for patients aged 6 and older. • Cobenfy (xanomeline and trospium) was approved for schizophrenia, representing the first new class of antipsychotic medication in 35 years, with a novel mechanism of action. • Itovebi (inavolisib) received approval in combination with palbociclib and fulvestrant for certain types of breast cancer, demonstrating a 57% reduction in disease progression or death.

• RLY-2608, an oral, mutant-selective PI3Kα inhibitor developed by Relay Therapeutics, is currently undergoing Phase I clinical trials. • The drug is being evaluated both as a single agent and in combination with fulvestrant for the treatment of HR+/HER2- breast cancer. • RLY-2608 aims to overcome toxicities associated with wild-type PI3Kα inhibition, a limitation of existing PI3Kα modulators like alpelisib and inavolisib. • This innovative molecule targets specific PI3Kα mutations, potentially reducing side effects such as hyperglycemia and rash observed with less selective inhibitors.

• Next-generation sequencing (NGS) is crucial for personalizing treatment decisions in hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, identifying actionable mutations like PIK3CA, AKT, and P10. • The phase 3 INAVO120 trial demonstrated that inavolisib, a PI3K kinase inhibitor, combined with palbociclib and fulvestrant, significantly improved progression-free survival in patients with PIK3CA-mutated HR-positive, HER2-negative breast cancer. • The CAPItello-291 trial showed that capivasertib plus fulvestrant led to longer progression-free survival, especially in patients with PI3K, AKT, or P10 alterations, with manageable adverse events. • Antibody-drug conjugates like fam-trastuzumab deruxtecan-nxki and sacituzumab govitecan-hziy are promising for HER2-low breast cancer, necessitating further research to optimize their sequencing for maximum patient benefit.

• Ribociclib's approval for adjuvant use in high-risk HR+/HER2- early breast cancer marks a significant advancement, potentially benefiting a broader patient population. • Inavolisib, combined with palbociclib and fulvestrant, gains FDA approval for endocrine-resistant, PIK3CA-mutated HR+/HER2- advanced breast cancer, improving progression-free survival. • The FDA emphasizes the need for increased diversity in clinical trials and post-marketing studies to ensure the safety and efficacy of new drugs across all patient populations. • Dose optimization strategies, like those promoted by Project Optimus, are crucial for balancing efficacy and toxicity in novel targeted therapies for breast cancer.

• The Phase III INAVO120 trial demonstrates that adding inavolisib to standard endocrine plus CDK4/6 inhibitor therapy improves outcomes in advanced-stage, PIK3CA-mutant, HR+ breast cancer. • The study included patients with metastatic recurrence of PIK3CA-mutant HR+, HER2- breast cancer who relapsed during or within 12 months of adjuvant endocrine therapy. • The addition of inavolisib to palbociclib and fulvestrant showed increased efficacy, suggesting a potential new first-line treatment option for this patient population.