The FDA has granted approval to inavolisib (Itovebi) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) for the treatment of adult patients with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer. This approval marks a significant advancement for patients who have experienced recurrence on or after completing adjuvant endocrine therapy.
The approval was primarily based on the results of the phase 3 INAVO120 trial (NCT04191499), a randomized, double-blind, placebo-controlled, multicenter study involving 325 patients. The study compared the efficacy of inavolisib plus palbociclib and fulvestrant against placebo plus palbociclib and fulvestrant in patients with endocrine-resistant, PIK3CA-mutated HR-positive, HER2-negative locally advanced or metastatic breast cancer.
Efficacy and Outcomes
The INAVO120 trial demonstrated a statistically significant improvement in progression-free survival (PFS) in the inavolisib arm. The median PFS was 15.0 months (95% CI: 11.3, 20.5) in the inavolisib plus palbociclib plus fulvestrant arm compared to 7.3 months (95% CI: 5.6, 9.3) in the placebo plus palbociclib plus fulvestrant arm (hazard ratio [HR] 0.43, 95% CI: 0.32, 0.59, p-value < 0.0001).
Furthermore, the objective response rate (ORR) was significantly higher in the inavolisib arm, with 58% (95% CI: 50, 66) compared to 25% (95% CI: 19, 32) in the placebo arm. The median duration of response (DoR) was 18.4 months (95% CI: 10.4, 22.2) and 9.6 months (95% CI: 7.4, 16.6), respectively.
Safety and Tolerability
The safety profile of inavolisib was deemed manageable in the trial, particularly in patients without pre-existing diabetes or glucose intolerance. Common adverse reactions (≥20%) included decreased neutrophils, decreased haemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhoea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.
Hope Rugo, MD, FASCO, highlighted the importance of this approval, noting that the manageable toxicity profile of inavolisib, combined with its efficacy, offers a valuable treatment option for patients with poor prognosis, hormone receptor-positive breast cancer. Careful monitoring of glucose levels and management of potential toxicities such as stomatitis, diarrhea, and rash are essential when using inavolisib.
Clinical Implications
This approval represents a significant step forward in the treatment of endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer. The combination of inavolisib, palbociclib, and fulvestrant provides a much-needed option for patients who have progressed on or after adjuvant endocrine therapy. The INAVO120 trial demonstrated a substantial improvement in PFS and ORR, offering hope for better outcomes in this patient population.
The recommended dose of inavolisib is 9 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity. The FDA also approved the FoundationOne Liquid CDx assay as a companion diagnostic device to identify patients with breast cancer for treatment with inavolisib with palbociclib and fulvestrant.
