PI3Kα Inhibitor and Degrader Inavolisib Can Co-opt FGFR2 to Enhance Responses in Patients with PIK3CA-Mutated Solid Tumors and in Preclinical Models.
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Juric Dejan, Song Kyung, Johnson Radia M, Accordino Melissa K, Bedard Philippe L, Cervantes Andrés, Gambardella Valentina, Hamilton Erika, Italiano Antoine, Kalinsky Kevin, Krop Ian E, Oliveira Mafalda, Saura Cristina, Schmid Peter, Turner Nicholas C, Varga Andreea, Gendreau Steven, Hwang Michael S, Kuang Zheng, Lau Jeffrey T, Lin Eva, Pham Trang, Maddalo Danilo, Rees Matthew G, Ronan Melissa M, Roth Jennifer A, Martin Scott, Sodir Nicole M, Sokol Ethan S, Whitfield Zachary J, Wong Alice, Yauch Robert L, Aimi Junko, Cheeti Sravanthi, Fredrickson Jill, Hilz Stephanie, Hafner Marc, Hutchinson Katherine E, Jin Yanling, Peters Ubong, Zingg Daniel, Royer-Joo Stephanie, Shankar Noopur, Schutzman Jennifer L, Jhaveri Komal L, Dey Anwesha
Аннотация
PATIENTS AND METHODS: A first-in-human phase 1 study (NCT03006172) evaluated oral inavolisib in patients with PIK3CA-mutated solid tumors to determine the maximum tolerated dose and safety. Correlative analyses included ctDNA. Preclinical studies in cell lines and xenografts elucidated the role of FGFR2.
RESULTS: The maximum tolerated dose was 9 mg daily, with a manageable safety profile (e.g., hyperglycemia and diarrhea). Inavolisib showed linear pharmacokinetics, consistent pharmacodynamic modulation, and antitumor activity in hormone receptor-positive PIK3CA-mutated breast cancer (26% objective response rate and 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 nondegrading inhibitors. Combination therapy with FGFR2 inhibitors showed synergy and delayed resistance.
CONCLUSIONS: 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, suggesting that combining inavolisib with FGFR2 inhibitors may offer enhanced and more durable responses in PIK3CA/FGFR2-altered tumors.