FDA Approves Inavolisib Plus Standard Therapy in PIK3CA-Mutant Breast Cancer

• The FDA granted approval to inavolisib (Itovebi, previously GDC-0077) plus palbociclib (Ibrance) and fulvestrant for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2–), PIK3CA-mutated breast cancer.
• This designation is supported by data from the phase 3 INAVO120 study (NCT04191499).
• The PIK3CA mutation occurs in approximately 40% of HR+ metastatic breast cancers, highlighting the need for targeted therapy.

The regimen of inavolisib, palbociclib, and fulvestrant has been approved by the FDA for the treatment of patients with HR+, HER2–, PIK3CA-mutated breast cancer.¹

The approval is supported by findings from the phase 3 INAVO120 study. Initial findings were presented at the 2023 San Antonio Breast Cancer Symposium, and additional data were presented at the 2024 American Society of Clinical Oncology Annual Meeting. With a median follow-up of 21.3 months, the addition of inavolisib to palbociclib and fulvestrant reduced the risk of disease progression or death by 57% (HR, 0.43; 95% CI, 0.32-0.59; P <.0001). The median progression-free survival (PFS) was 15.0 months with inavolisib vs 7.3 months in the placebo plus palbociclib and fulvestrant arm. The 6-month, 12-month, and 18-month PFS rates in the inavolisib arm were 82.9%, 55.9%, and 46.2%, respectively, vs 55.9%, 32.6%, and 21.1% in the placebo arm.^2,3

An interim analysis of overall survival (OS) showed a reduction in the risk of death of 36% (HR, 0.64; 95% CI, 0.43-0.97; P =.0338). The 6-month, 12-month, and 18-month OS rates were 97.3%, 85.9%, and 73.7%, respectively, with inavolisib vs 89.9%, 74.9%, and 67.5% with placebo. Inavolisib also delivered an overall response rate of 58.4% vs 25.0% with placebo and a clinical benefit rate of 75.2% vs 47.0% with placebo.

“[Inavolisib] is unique…This agent is that does not just inhibit the target. In certain cells or contexts, it promotes the degradation of the target. You go after the target inhibited, and then you destroy it. The cells have no way to adapt and reactivate the same target because it's destroyed,” said Dejan Juric, MD, lead investigator of INAVO120, medicine-hematology and medical oncology at Massachusetts General Hospital Cancer Center, in an interview with Targeted Oncology^TM.

In the study, 325 patients were randomized to receive inavolisib at 9 mg daily (n = 161) or placebo (n = 164). Both groups received palbociclib at 125 mg daily on day 1 to 21 of each cycle and fulvestrant at 500 mg on day 1 and 15 in cycle 1 followed by once every 4 weeks. In both arms, about two-thirds of patients had an ECOG performance status of 0 and the remainder had 1.

Nearly half of patients in each group had 3 or more organ sites involved, and nearly half had liver involvement, with approximately 40% having lung involvement. Approximately 82% of patients received prior neoadjuvant or adjuvant chemotherapy, and nearly all had received prior neoadjuvant or adjuvant endocrine therapy. A minority of patients had received a prior CDK4/6 inhibitor (1.9% in the inavolisib group and 0.6% in the placebo group).

REFERENCES:

1. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. News release. FDA. October 10, 2024. Accessed October 10, 2024. https://tinyurl.com/ynkka5ta

2. Jhaveri KL, Im S-A, Saura C, et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: Phase III INAVO120 primary analysis. Presented at San Antonio Breast Cancer Symposium®; December 5–9, 2023; San Antonio, TX. Abstract GS03-13.

3. Juric D, Kalinsky K, Turner N, et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2‑negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 phase III randomized trial additional analyses. J Clin Oncol. 2024;42 (suppl 16):1003. doi:10.1200/JCO.2024.42.16_suppl.1003.