Patients with advanced, hormone receptor (HR)-positive, HER2-negative, endocrine-resistant breast cancer, who also have a PIK3CA gene mutation, had a statistically significant improvement in overall survival (OS) when treated with Itovebi (inavolisib) plus Ibrance (palbociclib) and Faslodex (fulvestrant) compared with placebo plus Ibrance and Faslodex.
Notably, these results were a part of the final OS analysis of the phase 3 INAVO120 study and were shared during a press event ahead of the 2025 ASCO Annual Meeting.
At a median follow-up of 34.2 months, the median OS was 34.0 months in the Itovebi treatment group (161 patients) versus 27.0 months in the placebo treatment group (164 patients). The six-, 12-, 18-, 24- and 30-month OS rates in the Itovebi group were 96.8%, 87.0%, 74.3%, 65.8% and 56.5%. The respective rates in the placebo group 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,” Dr. Nicholas C. Turner, 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.
Itovebi is an oral, highly potent, selective PI3K inhibitor that causes degradation of the mutated PI3Kα, p110α, and can be safely combined with Ibrance and Faslodex 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) versus Ibrance and Faslodex alone.
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. 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 to the Itovebi or placebo group. In the investigational arm, patients received 9 mg of oral Itovebi daily plus 125 mg of oral Ibrance on days one through 21 and 500 mg of Faslodex on days ones and 15 of cycle ones and every four weeks thereafter. In the control arm, patients received placebo in place of Itovebi plus the same dose and schedule of Ibrance and Faslodex. Treatment was continued until progressive disease or toxicity.
Patients were stratified by visceral disease (yes versus no), endocrine resistance (primary versus secondary) and region (North America/Western Europe versus Asia versus 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.
Itovebi 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 Itovebi was upheld. The median PFS was 17.2 with Itovebi versus 7.3 months with placebo. The six-, 12-, 18- and 24-month PFS rates with Itovebi 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 Itovebi. The median time to first subsequent chemotherapy was 35.6 months with Itovebi versus 12.6 months with placebo.
“I’m impressed with this study by the almost two-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 two years is certainly an outcome that matters to patients,” Dr. Julie Gralow, 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 a side effect. The rates of grade 3 (serious; interferes with a person's ability to do basic things) and 4 (severe; require's hospitalization) side effects in the Itovebi and placebo groups were 90.7% and 84.7%, respectively. Six patients (3.7%) in the Itovebi arm and two (1.2%) in the placebo group had grade 5 events (death), none of which were deemed treatment related by investigators. Serious side effects occurred in 27.3% and 13.5% of patients in the Itovebi and placebo groups, respectively.
Side effects leading to discontinuation in the Itovebi and placebo arms, respectively, occurred with Itovebi/placebo (6.8%; 0.6%), Ibrance (6.2%; 0%) and Faslodex (3.7%; 0%).
Side effects leading to dose reduction in the Itovebi and placebo arms, respectively, occurred with Itovebi/placebo (14.9%; 3.7%) and Ibrance (40.4%; 34.4%).
Turner noted that the side effects were similar to prior reports and that Itovebi had a low treatment-related discontinuation rate.
“Itovebi plus Ibrance and Faslodex significantly improved OS compared with placebo plus Ibrance and Faslodex in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative, endocrine-resistant advanced breast cancer,” Turner said in conclusion.
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