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BACKGROUND: PIK3CA mutations frequently drive solid tumors, particularly hormone receptor-positive (HR+) breast cancer. Inavolisib, an ATP-competitive p110α inhibitor, also promotes the degradation of mutated p110α. PI3K inhibitors have generally shown modest single-agent activity and have safety concerns.METHOD: A first-in-human Phase 1 study (NCT03006172) evaluated oral inavolisib in patients with PIK3CA-mutated solid tumors, to determine the maximum tolerated dose (MTD) and safety. Correlative analyses included circulating tumor DNA (ctDNA). Preclinical studies in cell lines and xenografts elucidated the role of FGFR2.RESULTS: The MTD was 9 mg daily, with a manageable safety profile (e.g., hyperglycemia, diarrhea). Inavolisib showed linear pharmacokinetics, consistent pharmacodynamic modulation, and antitumor activity in HR+ PIK3CA-mutated breast cancer (26% objective response rate, 45% clinical benefit rate). FGFR2 hotspot mutations in ctDNA were strongly associated with clinical benefit. Preclinically, oncogenic FGFR2 signaling enhanced inavolisib sensitivity by engaging HER3, RAS, and p85β, that facilitated mutated p110α degradation, surpassing non-degrading inhibitors. Combination therapy with FGFR2 inhibitors showed synergy and delayed resistance.CONCLUSION: These findings highlight a novel cooperativity between FGFR2 and p110α that boosts the effectiveness of inavolisib. The data support advancing precision oncology beyond single biomarkers to complex algorithms utilizing co-occurring alterations, particularly suggesting that combining inavolisib with FGFR2 inhibitors may offer enhanced and more durable responses in PIK3CA/FGFR2-altered tumors.