Inavolisib Plus Palbociclib/Fulvestrant Gains European Approval in PIK3CA-Mutant, HR+/HER2– Advanced Breast Cancer

The combination of inavolisib (Itovebi) with palbociclib (Ibrance) and fulvestrant (Faslodex) won European approval for the treatment of patients with PIK3CA-mutated, estrogen receptor (ER)–positive, HER2-negative, locally advanced or metastatic breast cancer after recurrence on or within 12 months of completing adjuvant endocrine therapy.¹

In October 2024, the FDA approved inavolisib plus palbociclib and fulvestrant for the treatment of patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer, detected by an FDA-approved test, after recurrence on or after adjuvant endocrine therapy.²

“[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, the developer of inavolisib, stated in a news release.¹ “Therefore, the [inavolisib]-based regimen may help address an important unmet need for people with this subtype of breast cancer.”

Of note, both approvals were supported by data from the phase 3 INAVO120 trial (NCT04191499).^1,2 Updated study data presented at the 2025 ASCO Annual Meeting demonstrated a median progression-free survival (PFS) of 17.2 months (95% CI, 11.6-22.2) in the inavolisib arm (n = 161) compared with 7.3 months (95% CI, 5.9-9.2) with palbociclib plus fulvestrant alone (n = 164; stratified HR, 0.42; 95% CI, 0.32-0.55).³ Notably, the PFS benefit was consistent among all prespecified subgroups, and the inavolisib-based regimen was well tolerated without new safety signals observed.¹ Furthermore, at a median follow-up of 34.2 months, the median overall survival (OS) was 34.0 months (95% CI, 28.4-44.8) compared with 27.0 months (95% CI, 22.8-38.7) in the respective arms (stratified HR, 0.67; 95% CI, 0.48-0.94; P = .0190).³

Diving Into the INAVO120 Trial Design

The randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of inavolisib plus palbociclib and fulvestrant for the treatment of patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer by central circulating tumor DNA (ctDNA) or local tissue or ctDNA test. Patients included on the trial were also required to have measurable disease, experience disease progression during or within 12 months of adjuvant endocrine therapy completion, have received no prior therapy for advanced breast cancer, and have fasting glucose of 126 mg/dL or less and glycated hemoglobin of 6.0% or less. Patients were stratified based on visceral disease (yes vs no), endocrine resistance (primary vs secondary), and region (North America/Western Europe vs Asia vs other). The primary end point was investigator-assessed PFS. Secondary end points included OS, investigator-assessed overall response rate (ORR), best overall response, clinical benefit rate, duration of response (DOR), and patient-reported outcomes. Following these factors, patients (n = 325) were randomly assigned 1:1 to receive either the inavolisib-based regimen or placebo plus palbociclib and fulvestrant.

Those in the inavolisib arm received inavolisib at a dose level of 9 mg once daily plus palbociclib at 125 mg once daily on days 1 to 21 and fulvestrant at 500 mg on days 1 and 15 of cycle 1 and once every 4 weeks thereafter. Conversely, patients in the placebo arm were treated at the same dose levels and schedules of palbociclib and fulvestrant as the investigational arm.

Additional Efficacy and Safety Data

Regarding ORR, patients in the inavolisib arm achieved an ORR of 62.7% compared with 28.0% in the placebo arm (delta, 34.7%; 95% CI, 24.5%-44.8%; P < .0001). The median DOR was 19.2 months (95% CI, 14.7-28.3) vs 11.1 months (95% CI, 8.5-20.2) in the respective arms. Of note, the median time to first subsequent chemotherapy was 35.6 months (95% CI, 25.4-not reached) and 12.6 months (95% CI, 10.4-16.1) in the inavolisib vs placebo arms (stratified HR, 0.43; 95% CI, 0.30-0.60).

Of note, any-grade adverse effects (AEs) were observed in 100% of patients from both the inavolisib and placebo arms, with 90.7% and 84.7% comprising grade 3/4 AEs. Grade 5 AEs were observed in 6 and 2 patients from the respective arms. AEs leading to discontinuation of treatment were reported in 11 patients and 1 patient from the respective arms.

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://www.roche.com/media/releases/med-cor-2025-07-23
2. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed July 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive
3. Turner NC, 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). J Clin Oncol. 2025;43(suppl 16):1003. doi:10.1200/JCO.2025.43.16_suppl.100