Related Experiment Video

Updated: Jan 14, 2026

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
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PI3Kα Inhibitor and Degrader Inavolisib Can Co-opt FGFR2 to Enhance Responses in Patients with PIK3CA-Mutated Solid

Dejan Juric1, Kyung Song2, Radia M Johnson2

  • 1Department of Medicine, Mass General Cancer Center, Harvard Medical School, Boston, Massachusetts.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 27, 2025
PubMed
Abstract

Insights

Inavolisib shows promise for PIK3CA-mutated cancers, especially breast cancer. Combining it with FGFR2 inhibitors may improve treatment outcomes for patients with co-occurring mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • PIK3CA mutations are key drivers in solid tumors, notably hormone receptor-positive breast cancer.
  • Inavolisib, a p110α inhibitor, targets these mutations and promotes p110α degradation.
  • Existing PI3K inhibitors have limitations in single-agent efficacy and safety.

Purpose of the Study:

  • To assess the safety and tolerability of inavolisib in a Phase 1 trial for patients with PIK3CA-mutated solid tumors.
  • To determine the maximum tolerated dose (MTD) of oral inavolisib.
  • To explore the drug's pharmacokinetic and pharmacodynamic effects, including correlations with ctDNA.

Main Methods:

  • A first-in-human Phase 1 study (NCT03006172) evaluated oral inavolisib.
  • Patients with PIK3CA-mutated solid tumors were enrolled.
  • Correlative analyses included circulating tumor DNA (ctDNA) and preclinical xenograft models.

Main Results:

  • The MTD was established at 9 mg daily, with manageable side effects like hyperglycemia and diarrhea.
  • Inavolisib demonstrated linear pharmacokinetics, pharmacodynamic modulation, and antitumor activity in HR+/PIK3CA-mutated breast cancer (26% ORR, 45% CBR).
  • FGFR2 mutations in ctDNA correlated with clinical benefit; preclinical data showed FGFR2 signaling enhances inavolisib sensitivity via HER3/RAS/p85β, promoting p110α degradation.

Conclusions:

  • A novel synergy exists between FGFR2 and p110α, enhancing inavolisib's efficacy.
  • Precision oncology should consider complex algorithms of co-occurring alterations, not just single biomarkers.
  • Combining inavolisib with FGFR2 inhibitors may yield superior and sustained responses in PIK3CA/FGFR2-altered tumors.

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