Alpelisib (PI3Kα) benefit tracks with FGFR1/2 alterations and low TMB in SOLAR-1

Alpelisib is an oral PI3Kα-selective inhibitor combined with fulvestrant, an estrogen-receptor degrader, for HR+/HER2− advanced breast cancer with PIK3CA-altered disease. In this retrospective SOLAR-1 Phase 3 tissue-NGS analysis (NCT02437318; NGS cohort n=398; PIK3CA-altered cohort n=237), alpelisib+fulvestrant improved median PFS to 11.01 vs 5.55 months with placebo+fulvestrant (P=0.0004), consistent with the primary SOLAR-1 benchmark of ~11.0 vs 5.7 months in PIK3CA-mutant disease, while exploratory genomics suggested greater PFS benefit in FGFR1/2-altered and TMB-low tumors and weaker benefit with MYC/RAD21 alterations. Safety was not the focus of this correlative analysis, but the primary SOLAR-1 safety tradeoff remains important: grade 3/4 hyperglycemia and rash are materially higher than with newer endocrine-pathway options such as capivasertib+fulvestrant, which showed PFS benefit with lower AE-driven discontinuation in CAPItello-291.