LOXO-783 + fulvestrant

LOXO-783 + fulvestrant is an investigational combination therapy being evaluated for the treatment of advanced breast cancer and other solid tumors harboring PIK3CA mutations, particularly the H1047R mutation. LOXO-783 is an oral, brain-penetrant, highly selective, allosteric inhibitor of the phosphoinositide 3-kinase alpha (PI3Kα) H1047R variant. Fulvestrant is an established estrogen receptor antagonist that promotes degradation of the estrogen receptor. The combination is designed to target both key oncogenic pathways: PI3Kα-mediated signaling and estrogen receptor-driven tumor proliferation. This combination is under investigation in phase 1 clinical trials, demonstrating proof of concept for selective PI3Kα inhibition with reduced risk of hyperglycemia compared to earlier PI3K inhibitors, though gastrointestinal side effects, particularly diarrhea, remain notable. The regimen targets estrogen receptor-positive, HER2-negative, PIK3CA-mutant advanced breast cancers.