Inavolisib Combo Receives EU Approval in PIK3CA+ ER+/HER2– Breast Cancer

Previously, the FDA approved inavolisib plus palbociclib/fulvestrant for patients with endocrine-resistant, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer harboring PIK3CA mutations in October 2024 based on data from the INAVO120 trial.

The European Commission has approved inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant for adults with estrogen receptor (ER)–positive, HER2-negative locally advanced or metastatic breast cancer harboring PIK3CA mutations following recurrence on or after adjuvant endocrine therapy, according to a press release from the developer, Roche.¹

Supporting findings for the approval came from the phase 3 INAVO120 trial (NCT04191499) assessing inavolisib plus palbociclib/fulvestrant vs placebo plus palbociclib/fulvestrant among those with PIK3CA-mutated, ER-positive, HER2-negative breast cancer. Findings published in New England Journal of Medicine showed a median progression-free survival (PFS) of 15.0 months in the inavolisib arm vs 7.3 months in the placebo arm (HR, 0.43; 95% CI, 0.32-0.59; P <.001).² Inavolisib-based treatment produced a PFS benefit across all prespecified subgroups, and the combination was found to be well tolerated.

Additional data presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting showed a median overall survival (OS) of 34.0 months (95% CI, 28.4-44.8) with the inavolisib combination vs 27.0 months (95% CI, 22.8-38.7) with the placebo regimen (HR, 0.67; 95% CI, 0.48-0.94; P = .0190).³ The observed OS benefit with the inavolisib regimen appeared to be consistent across key patient subgroups. Additionally, the objective response rate (ORR) was 62.7% vs 28.0% in the experimental and placebo arms, respectively, and the median duration of response (DOR) was 19.2 months (95% CI, 14.7-28.3) vs 11.1 months (95% CI, 8.5-20.2) after a median follow-up of 34.2 months.

“[Inavolisib] is the first treatment of its kind to improve survival outcomes for those living with PIK3CA-mutated, ER-positive advanced breast cancer,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in the press release.¹ “Therefore, the [inavolisib]-based regimen may help address an important unmet need for people with this subtype of breast cancer.”

In the double-blind phase 3 INAVO120 study, 325 patients were randomly assigned 1:1 to receive inavolisib (n = 161) or matched placebo (n = 164) in combination with palbociclib and fulvestrant. Investigators administered inavolisib at 9 mg orally once daily, palbociclib at 125 mg orally on days 1 to 21 of each cycle, and fulvestrant at 500 mg on days 1 and 15 of cycle 1 and every 4 weeks. The study treatment continued until progressive disease or toxicity.

The trial’s primary end point was investigator-assessed PFS. Secondary end points included OS, ORR, clinical benefit rate, DOR, and patient-reported outcomes.

Patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer per central circulating tumor DNA (ctDNA) or local tissue or ctDNA testing were eligible for enrollment on the trial. Other eligibility criteria included having measurable disease, progression on or after 12 months of completing adjuvant endocrine therapy, and no prior treatment for advanced disease.

Data from ASCO showed that 100% of patients in the inavolisib and placebo arms experienced adverse effects (AEs) of any grade. Of note, serious AEs affected 27.3% and 13.5% in each arm, and 6.8% and 0.6% of patients experienced toxicity leading to the discontinuation of inavolisib and placebo, respectively.

The most common toxicities of any grade in the inavolisib and placebo arms, respectively, included neutropenia (91.3% vs 90.8%), hyperglycemia (63.4% vs 13.5%), stomatitis or mucosal inflammation (55.3% vs 28.8%), and thrombocytopenia (49.7% vs 46.0%). The most common grade 3/4 AE in both arms was neutropenia (82.6% vs 80.4%).

The FDA approved inavolisib plus palbociclib/fulvestrant for patients with endocrine-resistant, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer harboring PIK3CA mutations in October 2024 based on data from the INAVO120 trial.⁴

References

1. European Commission approves Roche’s Itovebi for people with ER-positive, HER2-negative, advanced breast cancer with a PIK3CA mutation. News release. Roche. July 22, 2025. Accessed July 23, 2025. https://tinyurl.com/u47bw9b4
2. Turner NC, Im S-A, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584-1596. doi:10.1056/NEJMoa2404625
3. Turner N, Im S-A, 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). J Clin Oncol. 2025;43(suppl 16):1003. doi:10.1200/JCO.2025.43.16_suppl.1003
4. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. News release. FDA. October 10, 2024. Accessed July 23, 2025. https://tinyurl.com/2rydf6b4