FDA Grants Breakthrough Therapy Designation to Inavolisib for PIK3CA-Mutated Breast Cancer


Inavolisib was submitted to the FDA for review as a first-line treatment for advanced HR-positive, HER2-negative PIK3CA-mutated breast cancer.

The FDA has granted the investigational oral therapy inavolisib (Roche), in combination with palbociclib (Ibrance; Pfizer) and fulvestrant (Faslodex; AstraZeneca), breakthrough therapy designation for the treatment of advanced hormone receptor (HR)-positive, HER2-negative breast cancer with a PIK3CA mutation. The decision is based on results from the phase 3 INAVO120 trial, which demonstrated inavolisib more than doubled progression free survival when used in combination with palbociclib and fulvestrant.1 The FDA’s decision marks the beginning of significant clinical expansion opportunities aimed at meeting care needs and improving treatment outcomes for patients with HR-positive, PIK3CA-mutated breast cancer.

breast cancer therapy

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HR-positive breast cancer accounts for nearly 70% of all breast cancer cases, and approximately 40% of patients have a PIK3CA mutation. In HR+ breast cancer with a PIK3CA mutation, the phosphoinositide 3-kinase (PI3K) pathway is altered, leading to metastatic growth, endocrine resistance, and progression of disease.4 Research has shown that activating PIK3CA mutations disrupt the PI3K signaling pathway, resulting in treatment resistance and poorer patient outcomes.1

Inavolisib is an investigational, oral targeted treatment designed to minimize the adverse effects of endocrine therapy (ET) and provide improved responses for patients with HR-positive, PIK3CA-mutated breast cancer. Due to its high in vitro potency and unique mechanism, inavolisib is different from other currently available PI3K inhibitors and is effective in breaking down mutated PI3K alpha.1,2

The success of inavolisib was identified through a randomized, double-blind, placebo-controlled phase 3 study, INAVO120, evaluating the effectiveness of the treatment in combination with palbociclib and fulvestrant compared to placebo plus palbociclib and fulvestrant. Eligible patients were required to have metastatic or locally advanced HR-positive breast cancer with a PIK3CA mutation that could not be treated curatively. Alternatively, patients could have experienced disease progression either during treatment or within 12 months after completing adjuvant ET, administered in the form of either an aromatase inhibitor or tamoxifen (Soltamox; Mayne Pharma Group Limited).1,3

The study evaluated 325 patients who were randomly assigned to either the investigational treatment or placebo trial, receiving inavolisib 1 to 28 of each 28-day cycle or placebo plus oral palbociclib on days 1 to 21 of each 28-day cycle and intramuscular fulvestrant about every 4 weeks.5 The primary end point of the study included investigator-assessed progression free survival (PFS) with a secondary outcome measuring overall survival (OS).2

The study findings showed that the inavolisib-based regimen reduced the risk of disease progression or death by 57% compared to palbociclib and fulvestrant alone (15.0 months vs 7.3 months; hazard ratio=0.43, 95% CI: 0.32-0.59, p<0.0001). Researchers observed a positive trend in OS data (stratified hazard ratio=0.64, 95% CI: 0.43-0.97, p=0.0338 [boundary of 0.0098]), although further investigations are needed in future analyses.1

Inavolisib is included in 2 additional phase 3 clinical trials for patients with PIK3CA-mutated breast cancer. The phase 3 trial INAVO121 (NCT05646862) will investigate use of inavolisib in combination with fulvestrant vs alpelisib plus fulvestrant in HR-positive/HER2-negative breast cancer post cyclin-dependent kinase 4/6 inhibitor and endocrine combination therapy, while INAVO122 (NCT05894239) explores use in combination with pertuzumab plus trastuzumab for subcutaneous injection (SC) vs pertuzumab plus trastuzumab for SC and optional physician's choice of ET as a maintenance treatment in HER2-positive disease.1

“We are pleased that the FDA granted breakthrough therapy designation for inavolisib in recognition of the substantial clinical benefit observed with this regimen,” said Levi Garraway, MD, PhD, Roche’s chief medical officer and head of global product development, in a press release. “This promising inavolisib-based regimen could transform the PI3K inhibitor class, potentially becoming the standard of care for this patient population in the first-line setting.”1

  1. FDA grants Breakthrough Therapy Designation to Roche’s inavolisib for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. Roche. May 21, 2024. Accessed May 21, 2024.
  2. Study Finds Inavolisib Combination Treatment Improved PFS in Patients With Breast Cancer. Pharmacy Times. Published December 5, 2023. Accessed May 21, 2024. https://www.pharmacytimes.com/view/study-finds-inavolisib-combination-treatment-improved-pfs-in-patients-with-breast-cancer
  3. Inavolisib Plus Palbociclib and Fulvestrant Improves PFS in PIK3CA-Mutated HR+ Breast Cancer. OncLive. Published December 7, 2023. Accessed May 21, 2024. https://www.onclive.com/view/inavolisib-plus-palbociclib-and-fulvestrant-improves-pfs-in-pik3ca--mutated-hr-breast-cancer
  4. Anderson EJ, Mollon LE, Dean JL, et al. A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer. Int J Breast Cancer. 2020;2020:3759179. Published 2020 Jun 20. doi:10.1155/2020/3759179
  5. Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120). ClinicalTrials.gov identifier: NCT04191499. Updated April 26, 2024. Accessed May 21, 2024. https://www.clinicaltrials.gov/study/NCT04191499?cond=PIK3CA-Mutant,%20Hormone%20Receptor-Positive,%20Her2-Negative,%20Locally%20Advanced%20or%20Metastatic%20Breast%20Cancer%20&rank=1
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