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<p>Hormone receptor–positive (HR+), HER2-negative breast cancer represents the most common breast cancer subtype, yet resistance to endocrine therapy and CDK4/6 inhibitors frequently limits long-term benefit. Aberrant activation of the PI3K/AKT/mTOR pathway, particularly through <i>PIK3CA</i> mutations, is a major driver of therapeutic resistance. Inavolisib (Itovebi™) is a next-generation PI3Kα inhibitor that combines catalytic inhibition with selective degradation of mutant PI3Kα protein, producing sustained suppression of oncogenic signaling. Preclinical studies confirmed its preferential activity against hotspot <i>PIK3CA</i> mutations (E542K, E545K, H1047R), favorable pharmacokinetic profile, and durable antitumor activity in xenograft models. Clinically, the pivotal INAVO120 trial demonstrated that adding inavolisib to palbociclib and fulvestrant significantly prolonged median progression-free survival (17.2 vs. 7.3 months; HR ≈ 0.45) and demonstrated a statistically significant improvement in overall survival, with median OS of 34.0 months compared with 27 months in the control group (<i>p</i> = 0.02), according to the updated results of the phase III INAVO120 trial and showed emerging overall survival benefit, establishing a new biomarker-driven standard of care for patients with <i>PIK3CA</i>-mutant HR+/HER2 − advanced breast cancer. The regimen’s safety profile was consistent with PI3K-class effects, with hyperglycemia as the most frequent but manageable adverse event. This review highlights the translational journey of inavolisib from mutational discovery to regulatory approval, underscoring its mechanistic innovations, clinical impact, and future directions in biomarker refinement, resistance management, and therapeutic sequencing within precision oncology.</p>

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Translational Medicine in Hormone Receptor–Positive Breast Cancer: The Journey of Inavolisib (Itovebi™) from Mutation to Clinical Success

  • 期刊论文

  • 发表日期：

    2026年4月21日

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  • Binoy Varghese Cheriyan,
  • Mahalakshmi Devaraji

摘要

Hormone receptor–positive (HR+), HER2-negative breast cancer represents the most common breast cancer subtype, yet resistance to endocrine therapy and CDK4/6 inhibitors frequently limits long-term benefit. Aberrant activation of the PI3K/AKT/mTOR pathway, particularly through PIK3CA mutations, is a major driver of therapeutic resistance. Inavolisib (Itovebi™) is a next-generation PI3Kα inhibitor that combines catalytic inhibition with selective degradation of mutant PI3Kα protein, producing sustained suppression of oncogenic signaling. Preclinical studies confirmed its preferential activity against hotspot PIK3CA mutations (E542K, E545K, H1047R), favorable pharmacokinetic profile, and durable antitumor activity in xenograft models. Clinically, the pivotal INAVO120 trial demonstrated that adding inavolisib to palbociclib and fulvestrant significantly prolonged median progression-free survival (17.2 vs. 7.3 months; HR ≈ 0.45) and demonstrated a statistically significant improvement in overall survival, with median OS of 34.0 months compared with 27 months in the control group (p = 0.02), according to the updated results of the phase III INAVO120 trial and showed emerging overall survival benefit, establishing a new biomarker-driven standard of care for patients with PIK3CA-mutant HR+/HER2 − advanced breast cancer. The regimen’s safety profile was consistent with PI3K-class effects, with hyperglycemia as the most frequent but manageable adverse event. This review highlights the translational journey of inavolisib from mutational discovery to regulatory approval, underscoring its mechanistic innovations, clinical impact, and future directions in biomarker refinement, resistance management, and therapeutic sequencing within precision oncology.