The U.S. Food and Drug Administration (FDA) approved the PI3K inhibitor inavolisib (Itovebi) with the CDK4/6 inhibitor palbociclib and fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or completion of adjuvant endocrine therapy. The FDA also approved the FoundationOne Liquid CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with this combination therapy.
Efficacy and Safety
Efficacy was evaluated in INAVO120 (ClinicalTrials.gov identifier NCT04191499), a randomized, double-blind, placebo-controlled, multicenter trial in 325 patients with endocrine-resistant, PIK3CA-mutated HR-positive, HER2-negative locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who had not received prior systemic therapy for locally advanced or metastatic disease. Primary endocrine resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy; secondary endocrine resistance was defined as relapse while on adjuvant endocrine therapy after at least 2 years or relapse within 12 months of completing adjuvant endocrine therapy.
Patients were randomly assigned 1:1 to receive either inavolisib at 9 mg or placebo orally once daily, with palbociclib at 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days, and fulvestrant at 500 mg administered intramuscularly on cycle 1, days 1 and 15, and then on day 1 of every 28-day cycle. Patients received treatment until disease progression or unacceptable toxicity. Randomization was stratified by the presence of visceral disease (yes or no), endocrine resistance (primary or secondary), and geographic region (North America/Western Europe, Asia, other).
Median progression-free survival (the major efficacy outcome measure) was 15.0 months (95% confidence interval [CI] = 11.3–20.5 months) with inavolisib plus palbociclib and fulvestrant and 7.3 months (95% CI = 5.6–9.3 months) with placebo plus palbociclib and fulvestrant (hazard ratio = 0.43 [95% CI = 0.32–0.59] P < .0001). Objective response rate was 58% (95% CI = 50%–66%) with inavolisib and 25% (95% CI = 19%–32%) without inavolisib. Median duration of response was 18.4 months (95% CI: = 10.4–22.2 months) and 9.6 months (95% CI = 7.4–16.6 months), respectively. Interim analysis of overall survival based on 63% information fraction did not reach statistical significance but was supportive of the overall benefit risk assessment, with a hazard ratio of 0.64 (95% CI = 0.43–0.97).
The most common adverse reactions (≥ 20%), including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased alanine transaminase, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.
The recommended inavolisib dose is 9 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity. Refer to the prescribing information for palbociclib and fulvestrant dosing information.
For full prescribing information for inavolisib, see accessdata.fda.gov.
