Evaluating Inavolisib vs Alpelisib Plus Fulvestrant for Hormone Receptor-Positive, HER2-Negative, PIK3CA-Mutated Advanced Breast Cancer

Among patients with hormone receptor-positive, HER2-negative breast cancer, dysregulating mutations in PIK3CA occur in approximately 40%. These mutations are also a common mechanism of resistant to CDK4/6 inhibitor and endocrine therapy combinations, the standard of care for patients with high-risk, early breast cancer.

The selective PI3Kα inhibitor alpelisib is approved in combination with fulvestrant for patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer. There are concerns, however, about “clinically relevant” adverse events associated with this regimen, as Misty Shields, MD, Moffitt Cancer center and Research Institute, Tampa, Florida, and coauthors wrote in a meta-analysis, notably a high rate of hyperglycemia, “that can lead to treatment discontinuation.” As Dejan Juric, MD, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, and coauthors wrote, “there is a significant need to develop PI3Kα inhibitors with a better therapeutic index.”

Inavolisib is a highly potent and selective PI3Kα inhibitor that has demonstrated manageable safety and tolerability both along and in combination with the standard-of-care treatments for this patient population. In 2021, results from a phase 1 trial found inavolisib plus fulvestrant demonstrated encouraging preliminary antitumor activity among patients in this population who had been heavily pretreated, including those who had been treated with a prior CDK4/6 inhibitor-based regimen.

Additionally, the phase 3 INAVO120 trial reported sustained benefits in survival, delay of next-line therapy, and patient-reported outcomes with inavolisib plus palbociclib and fulvestrant compared with placebo among patients with hormone receptor-positive, HER2-negative, PIK3KA-mutated locally advanced or metastatic breast cancer who had relapsed during or within 12 months of adjuvant endocrine therapy.

The randomized, open-label, phase 3 INVAO121 study seeks to evaluate inavolisib plus fulvestrant compared with alpelisib plus fulvestrant, among patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer, as confirmed by circulating tumor DNA or tumor tissue, who have progressed during or after treatment with a CDK4/6-based regimen. Patients are randomized on a 1-to-1 basis to receive either 9 mg inavolisib daily plus 500 mg fulvestrant on days 1 and 15 of cycle 1, then day 1 of subsequent cycles, or 300 mg daily plus fulvestrant. Randomization is stratified by presence of visceral disease and prior CDK4/6 inhibitor therapy in adjuvant vs metastatic setting.

The primary end point of this study is progression-free survival by blinded independent central review (BICR). Secondary end points include overall survival, objective response rate by BICR, best overall response by BICR, duration of response by BICR, clinical benefit rate by BICR, safety, tolerability, patient-reported outcomes, and pharmacokinetics.

This trial is currently open for enrollment. In June of 2024, when this trial in progress was presented at the 2024 American Society of Clinical Oncology Annual Meeting, there had been 159 patients randomized, with a target enrollment of 400 patients.

Sources:

Shields M, Mo Q, Armitage M, et al. A systematic review and meta-analysis of selected toxicity endpoints of alpelisib. Oncotarget. 2020;11:3793-3799. doi:10.18632/oncotarget.27770

Juric D, Kalinsky K, Im S-A, et al. INAVO121: Phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2–), PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC). J Clin Oncol. 2024;42(16_suppl). doi:10.1200/JCO.2024.42.16_suppl.TPS1136.

Juric D, Bedard PL, Cervantes A, et al. A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2–) metastatic breast cancer [abstract]. Presented at San Antonio Breast Cancer Symposium. December 7-10, 2021; San Antonio, TX. Abstract P5-17-05.

Juric D, Kalinsky D, Turner NC, 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 trail additional analyses. Presented at ASCO Annual Meeting. May 31-June 4, 2024; Chicago, IL. Abstract #1003.