Inavolisib Plus Palbociclib/Fulvestrant Shows OS Benefit in Endocrine-Resistant, PIK3CA-Mutated, HR+, HER2– Breast Cancer

Treatment with inavolisib (Itovebi) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) generated a statistically significant and clinically meaningful overall survival (OS) benefit vs palbociclib plus fulvestrant alone for patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer, meeting a key secondary end point of the phase 3 INAVO120 study (NCT04191499).1

These data reinforce the regimen’s efficacy in the frontline, as established by previously reported data from INAVO120. In the primary analysis, patients treated with inavolisib plus palbociclib and fulvestrant achieved a median progression-free survival (PFS) of 15.0 months (95% CI, 11.3-20.5) vs 7.3 months (95% CI, 5.6-9.3) with placebo plus palbociclib and fulvestrant.2This translated to a 57% reduction in the risk of disease worsening or death (HR, 0.43; 95% CI, 0.32-0.59; P < .001).1The overall response rate (ORR) in the experimental arm was 58% (95% CI, 50%-66%) vs 25% (95% CI, 19%-32%) in the placebo arm, and the median duration of response (DOR) was 18.4 months (95% CI, 10.4-22.2) vs 9.6 months (95% CI, 7.4-16.6) in these respective groups.2

Notably, although OS data were immature at the time of the primary analysis, a trend in favor of the inavolisib regimen was observed (HR, 0.64; 95% CI, 0.43-0.97; P = .0338).1

These results supported the FDA approval of inavolisib plus palbociclib and fulvestrant for patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, advanced or metastatic breast cancer in October 2024.2

“The INAVO120 OS results show that the [inavolisib]-based regimen not only delayed disease progression, but also helped people with advanced hormone receptor–positive, PIK3CA-mutated breast cancer live longer,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development, stated in a news release.1 “These findings underscore our ambition to improve survival rates for people with breast cancer. The [inavolisib]-based regimen has the potential to become the new standard of care for these patients.”

The company notes that complete OS results will be presented at an upcoming medical meeting. Data from INAVO120, which were published in the New England Journal of Medicine in October 2024, are also under review by global health authorities, such as the European Medicines Agency.

INAVO120 Overview

The randomized, double-blind, placebo-controlled trial enrolled 325 adult patients with endocrine resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative breast cancer that was locally advanced or metastatic.2 Patients were required to have experienced disease progression during or within 12 months of completing adjuvant endocrine therapy. Prior receipt of systemic therapy for locally advanced or metastatic disease was not permitted.

Upon enrollment, patients were randomly assigned 1:1 to receive either 9 mg of oral inavolisib or placebo once daily during a 28-day cycle. This was administered alongside 125 mg of daily palbociclib for 21 days per cycle and 500 mg of fulvestrant administered intramuscularly on days 1 and 15 of cycle 1, and day 1 of each subsequent cycle. Treatment continued until disease progression or unacceptable toxicity.

Stratification factors included the presence of visceral disease (yes vs no), endocrine resistance (primary vs secondary), and geographic region (North America/Western Europe vs Asia vs other).

The study’s primary end point was investigator-assessed PFS per RECIST 1.1 criteria. Secondary efficacy end points comprised OS, investigator-assessed ORR, and DOR.

The most common adverse effects reported in at least 20% of patients treated with the inavolisib-based regimen were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased alanine aminotransferase levels, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache. In the updated OS analysis, no new safety signals were observed.1

Ongoing Evaluation of Inavolisib

In addition to INAVO120, 3 phase 3 trials evaluating inavolisib-based combinations in patients with PIK3CA-mutated locally advanced or metastatic breast cancer are being conducted.1

These include the INAVO121 trial (NCT05646862), which is evaluating the agent in combination with fulvestrant vs alpelisib (Piqray) plus fulvestrant in hormone receptor–positive, HER2-negative breast cancer following progression on a CDK4/6 inhibitor and endocrine therapy; the INAVO122 study (NCT05894239) investigating inavolisib plus a subcutaneous fixed dose of pertuzumab (Perjeta) and trastuzumab (Herceptin) as maintenance therapy in HER2-positive disease; and the INAVO123 study (NCT06790693) evaluating first-line inavolisib plus a CDK4/6 inhibitor and letrozole in endocrine-sensitive, PIK3CA-mutated hormone receptor–positive, HER2-negative breast cancer.

Additional studies of inavolisib in breast cancer and other tumor types are planned, with the aim of extending the agent’s benefit to more people with PIK3CA-mutated cancers.

References

1. Roche’s Itovebi demonstrated statistically significant and clinically meaningful overall survival benefit in a certain type of HR-positive advanced breast cancer. News release. Roche. January 27, 2025. Accessed January 28, 2025. https://www.roche.com/media/releases/med-cor-2025-01-28
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 January 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive