FDA Approves Inavolisib Plus Palbociclib/Fulvestrant for Endocrine-Resistant, PIK3CA-Mutated, HR+, HER2– Advanced Breast Cancer

The FDA has approved inavolisib (Itovebi) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) for use in adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.¹

The regulatory decision was supported by data from the phase 3 INAVO120 trial (NCT04191499), which showed that 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) compared with 7.3 months (95% CI, 5.6-9.3) for those treated with placebo plus palbociclib and fulvestrant (HR, 0.43; 95% CI, 0.32-0.59; P < .0001).

Additionally, patients in the experimental arm experienced an overall response rate (ORR) of 58% (95% CI, 50%-66%) vs 25% (95% CI, 19%-32%) for those in the placebo arm. The median duration of response (DOR) was 18.4 months (95% CI, 10.4-22.2) in the inavolisib group vs 9.6 months (95% CI, 7.4-16.6) in the placebo group.

A statistically significant difference was not reported for overall survival (OS); however, a trend favoring the inavolisib regimen was observed based on a 63% information fraction (HR, 0.64; 95% CI, 0.43-0.97).

The randomized, double-blind, placebo-controlled INAVO120 trial enrolled patients at least 18 years of age with confirmed hormone receptor–positive, HER2-negative breast cancer that was locally advanced or metastatic and not amenable to curative-intent therapy.² Disease progression during adjuvant endocrine therapy or within 12 months of completing adjuvant endocrine therapy was required. Confirmation of PIK3CA-mutation status was also necessary for inclusion.

Other key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria; an ECOG performance status of 0 or 1; a life expectancy of more than 6 months; and adequate hematologic and organ function.

Patients were excluded if they had metaplastic breast cancer; had a history of leptomeningeal disease or carcinomatous meningitis; received any prior systemic therapy for metastatic breast cancer; had prior treatment with fulvestrant or any selective estrogen receptor degrader, unless given as part of neoadjuvant therapy lasting no longer than 6 months; had active or known/untreated central nervous system metastases; and received any prior treatment with a PI3K, AKT, or mTOR inhibitor.

Patients were randomly assigned in a 1:1 fashion to receive 9 mg of inavolisib or placebo once per day on days 1 to 28 of each 28-day cycle in combination with palbociclib at 125 mg once per day on days 1 to 21 of each cycle and fulvestrant at 500 mg on days 1 and 15 of cycle 1, then on day 1 of subsequent cycles.¹ Treatment continued until disease progression or unacceptable toxicity.

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

PFS served as the trial's primary end point. Secondary end points included ORR, best overall response, DOR, clinical benefit rate, OS, quality of life, and safety.²

The most common adverse effects reported in at least 20% of patients in the experimental arm included decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased alanine aminotransferase, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.¹

Inavolisib has a recommended dose of 9 mg once per day taken with or without food, and treatment is intended to continue until disease progression or unacceptable toxicity.

References

1. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed October 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive
2. A study evaluating the efficacy and safety of inavolisib + palbociclib + fulvestrant vs placebo + palbociclib + fulvestrant in patients with PIK3CA-mutant, hormone receptor-positive, Her2-negative, locally advanced or metastatic breast cancer (INAVO120). ClinicalTrials.gov. Updated October 9, 2024. Accessed October 10, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04191499