Inavolisib Combo Significantly Extends Survival in PIK3CA+ Breast Cancer

"This is the first time OS has been significantly improved by a PI3K pathway targeted drug,” according to lead study author, Nicholas C. Turner, MD, PhD.

A statistically significant overall survival (OS) improvement occurred among patients with hormone receptor–positive, HER2-negative, endocrine-resistant advanced breast cancer harboring PIK3CA mutations following treatment with inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex), according to final OS analysis data from the phase 3 INAVO120 trial (NCT04191499) presented in a press briefing in advance of the 2025 American Society of Clinical Oncology Annual Meeting (ASCO).¹

At a median follow-up of 34.2 months, the median OS was 34.0 months (95% CI, 28.4-44.8) with inavolisib (n = 161) vs 27.0 months (95% CI, 22.8-38.7) with placebo (n = 164; stratified HR, 0.67; 95% CI, 0.48-0.94; P = .0190). The 6-, 12-, 18-, 24, and 30-month OS rates in the inavolisib arm were 96.8%, 87.0%, 74.3%, 65.8%, and 56.5%. The respective rates in the placebo arm were 90.1%, 76.7%, 67.2%, 56.3%, and 46.3%.

“This is the first time OS has been significantly improved by a PI3K pathway targeted drug,” Nicholas C. Turner, MD, PhD, lead study author and director of The Royal Marsden and Institute of Cancer and National Institute for Health and Care Research Biomedical Research Centre in London, United Kingdom, said in the press briefing.

INAVO120 Trial Background and Grounds for Approval

Mutations in the PIK3CA gene are present in approximately 40% of advanced hormone receptor–positive, HER2-negative breast cancers and confer poor prognosis and response to PI3K inhibitors. Key components of tumor growth involve the estrogen receptor, CDK4/6, and PI3K signaling pathways. As such, inhibition of all three pathways can augment treatment response and prolong the time to resistance. However, previous attempts to combine PI3K inhibitors and CDK4/6 inhibitors have been futile because of toxicity.

Inavolisib is an oral, highly potent, selective PI3K inhibitor that causes degradation of the mutated PI3Kα, p110α, and can be safely combined with palbociclib and fulvestrant at full dose.

This triplet regimen has been approved by the FDA since October 2024, based on earlier findings from INAVO120 showing a more than doubling in the median progression-free survival (PFS) and overall response rate (ORR) vs palbociclib and fulvestrant alone.²

INAVO120 was a double-blind trial that enrolled patients with PIK3CA-mutant, hormone receptor–positive, HER2-negative advanced breast cancer by central circulating tumor DNA (ctDNA) or local tissue/ctDNA confirmation.¹ To be eligible for enrollment, patients also needed to have measurable disease and disease progression during or within 12 months of completing adjuvant endocrine therapy. Prior therapy for advanced disease was not permitted, nor was fasting glucose levels above 126 mg/dL and hemoglobin A1C levels above 6%.

Enrollment took place between January 2020 and September 2023, during which 325 patients were randomly assigned 1:1 to the inavolisib or placebo arm. In the investigational arm, patients received 9 mg of oral inavolisib daily plus 125 mg of oral palbociclib on days 1 through 21 and 500 mg of fulvestrant on days 1 and 15 of cycle 1 and every 4 weeks thereafter. In the control arm, patients received placebo in place of inavolisib plus the same dose and schedule of palbociclib and fulvestrant. Treatment was continued until progressive disease or toxicity.

Patients were stratified by 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 were OS, investigator-assessed ORR, best overall response, clinical benefit rate, duration of response, and patient-reported outcomes.

Inavolisib Shines With Maintained PFS Benefit, Time to Subsequent Therapy

With an additional 12.8 months of follow-up investigators showed that the PFS benefit with inavolisib was upheld.^1,3 The median PFS was 17.2 months (95% CI, 11.6-22.2) with inavolisib vs 7.3 months (95% CI, 5.9-9.2) with placebo (stratified HR, 0.42; 95% CI, 0.32-0.55).¹ The 6-, 12-, 18-, and 24-month PFS rates with inavolisib were 83.4%, 58.0%, 49.7%, and 41.8%, respectively. The respective rates in the placebo arm were 57.9%, 31.3%, 20.5%, and 16.7%.

Additional efficacy data revealed that the time to first subsequent chemotherapy was substantially delayed with the addition of inavolisib. The median time to first subsequent chemotherapy was 35.6 months (95% CI, 25.4-not reached) with inavolisib vs 12.6 months (95% CI, 10.4-16.1) with placebo (stratified HR, 0.43; 95% CI, 0.30-0.60).

“I’m impressed with this study by the almost 2-year prolongation in the delay in going on chemotherapy from 12.6 months to 35.6 months. Delaying the need in the metastatic setting to go on chemotherapy by almost 2 years is certainly an outcome that matters to patients,” Julie Gralow, MD, chief medical officer and executive vice president at ASCO, remarked during the briefing.

Breaking Down the Safety Data

With respect to safety, all patients in both arms experienced an adverse effect (AE). The rates of grade 3/4 AEs in the inavolisib and placebo arms were 90.7% and 84.7%, respectively. Six patients (3.7%) in the inavolisib arm and 2 (1.2%) in the placebo arm had grade 5 events, none of which were deemed treatment related by investigators. Serious AEs occurred in 27.3% and 13.5% of patients in the inavolisib and placebo arms, respectively.

AEs leading to discontinuation in the inavolisib and placebo arms, respectively, occurred with inavolisib/placebo (6.8%; 0.6%), palbociclib (6.2%; 0%), and fulvestrant (3.7%; 0%).

AEs leading to dose reduction in the inavolisib and placebo arms, respectively, occurred with inavolisib/placebo (14.9%; 3.7%), and palbociclib (40.4%; 34.4%).

Turner noted that the AEs were similar to prior reports and that inavolisib had a low treatment-related discontinuation rate.

“Inavolisib plus palbociclib and fulvestrant significantly improved OS compared with placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative, endocrine-resistant advanced breast cancer,” Turner said in conclusion.

Disclosures: Turner listed no disclosures.

References

1. 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.
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 May 21, 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. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584-1596. doi:10.1056/NEJMoa2404625