Inavolisib Plus Palbociclib/Fulvestrant Earns Positive CHMP Opinion for PIK3CA-Mutated, ER+/HER2– Advanced Breast Cancer

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The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of inavolisib (Itovebi) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) for the treatment of adult patients with PIK3CA-mutated, estrogen receptor (ER)–positive, HER2-negative, locally advanced or metastatic breast cancer following recurrence on or within 12 months of completing adjuvant endocrine therapy.1

The recommendation was supported by data from the phase 3 INAVO120 trial (NCT04191499), findings from which showed that patients treated with inavolisib plus palbociclib and fulvestrant in the first-line setting experienced a median progression-free survival (PFS) of 15.0 months compared with 7.3 months for those who received palbociclib plus fulvestrant alone (HR, 0.43; 95% CI, 0.32-0.59; P < .001). The PFS benefit was consistent across all prespecified subgroups, and no new safety signals were reported with the combination.

“The positive CHMP recommendation for the [inavolisib]-based regimen represents a significant step towards providing people in the European Union with PIK3CA-mutated, ER-positive advanced breast cancer with a targeted therapy in the first-line setting,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a news release. “This recommendation is further enforced by the recent final overall survival [OS] results from the INAVO120 study, showing the regimen can meaningfully extend survival.”

At a press briefing ahead of the 2025 ASCO Annual Meeting, Nicholas C. Turner, MD, PhD, director of The Royal Marsden and Institute of Cancer and National Institute for Health and Care Research Biomedical Research Centre in London, United Kingdom, shared updated findings from INAVO120, which showed that at a median follow-up of 34.2 months, the median OS was 34.0 months (95% CI, 28.4-44.8) in the inavolisib arm (n = 161) vs 27.0 months (95% CI, 22.8-38.7) in the control arm (n = 164), producing a statistically significant improvement in OS in favor of the inavolisib arm (HR, 0.67; 95% CI, 0.48-0.94; P = .0190).2

In the inavolisib group, the 6-, 12-, 18-, 24, and 30-month OS rates were 96.8%, 87.0%, 74.3%, 65.8%, and 56.5%, respectively. These respective rates were 90.1%, 76.7%, 67.2%, 56.3%, and 46.3% in the control arm.

In October 2024, the FDA approved inavolisib in combination with palbociclib and fulvestrant for use in adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.3 This approval was based on data from INAVO120.

INAVO120 Overview

The double-blind, placebo-controlled study enrolled patients at least 18 years of age with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer that was not amendable to curative therapy.4 Disease progression during adjuvant endocrine therapy or within 12 months of completing adjuvant therapy with an aromatase inhibitor or tamoxifen was required. Confirmation of the presence of a PIK3CA mutation was also required.

Premenopausal patients were required to be receiving LHRH agonist therapy for at least 2 weeks before the first day of cycle 1. Other key eligibility criteria comprised measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of more than 6 months, and adequate hematologic and organ function.

Patients were excluded if they had metaplastic breast cancer; a history of leptomeningeal disease or carcinomatous meningitis; received any prior systemic therapy in the metastatic setting; or received prior treatment with fulvestrant or any selective estrogen-receptor degrader (SERD), unless patients received fulvestrant or a SERD during neoadjuvant therapy with treatment duration of 6 months or less. Prior treatment with a PI3K, AKT, or mTOR inhibitor was prohibited.

Investigators randomly assigned patients to receive inavolisib or placebo on days 1 to 28 of each 28-day cycle, palbociclib on days 1 to 21 of each cycle, and fulvestrant once every 4 weeks; or daily placebo plus the same dosing of palbociclib and fulvestrant.

PFS served as the trial’s primary end point. Secondary end points included objective response rate, duration of response, clinical benefit rate, OS, quality of life, safety, and pharmacokinetics.

References

1. CHMP recommends EU approval of Roche’s Itovebi for PIK3CA-mutated, ER-positive, HER2-negative, advanced breast cancer. News release. Roche. May 23, 2025. Accessed May 23, 2025. https://www.roche.com/media/releases/med-cor-2025-05-23c
2. Turner N, Im SA, Saura C, et al. INAVO120 phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC). Presented at: 2025 ASCO Annual Meeting; May 30-June 3, 2025; Chicago, IL. Abstract 1003.
3. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed May 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive
4. A 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. Updated April 24, 2025. Accessed May 23, 2025. https://clinicaltrials.gov/study/NCT04191499