Inavolisib Plus Palbociclib/Fulvestrant Earns FDA Priority Review for Advanced HR+/HER2–, PIK3CA+ Breast Cancer

The FDA has granted priority review to the new drug application (NDA) seeking the approval of inavolisib (GDC-0077) in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) for the treatment of adult patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer harboring PIK3CA mutations, following recurrence on or within 12 months of completing adjuvant endocrine therapy.¹

The NDA is supported by data from the phase 3 INAVO120 trial (NCT04191499), which demonstrated that treatment with inavolisib plus palbociclib and fulvestrant led to a 57% reduction in the risk of progression or death in the first-line setting compared with palbociclib plus fulvestrant alone (HR, 0.43; 95% CI, 0.32-0.59; P<.0001). The median progression-free survival (PFS) was 15.0 months for the inavolisib arm vs 7.3 months for the control arm.

Although overall survival (OS) data were immature at the time of the trial’s primary analysis, a trend was observed favoring the inavolisib-based combination (stratified HR, 0.64; 95% CI, 0.43-0.97; P = .0338).

The FDA has set a target action date of November 27, 2024, under the Prescription Drug User Fee Act.

“The addition of inavolisib to standard of care treatment significantly delayed disease progression in the first-line setting and has the potential to extend survival for people with metastatic breast cancers that harbor PIK3CA mutations,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, stated in a news release. “We welcome the FDA’s priority review designation for inavolisib, which underscores the urgency to bring this potential best-in-class treatment option to patients as quickly as possible.”

On May 21, 2024, the FDA granted breakthrough therapy designation to inavolisib plus palbociclib and fulvestrant for the treatment of patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer harboring a PIK3CA mutation following recurrence on or within 12 months of completing adjuvant endocrine therapy. That regulatory decision was also supported by data from INAVO120.²

INAVO120 was a randomized, double-blind, placebo-controlled study that enrolled patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer harboring PIK3CA mutations whose disease progressed during treatment or within 12 months of completing adjuvant endocrine therapy. Prior systemic therapy for metastatic disease was not allowed.¹

Patients who were pre- or perimenopausal needed to undergo luteinizing hormone-releasing hormone agonist therapy for at least 2 weeks prior to day 1 of cycle 1 of treatment. 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.³

Patients were excluded if they had metaplastic breast cancer; had any history of leptomeningeal disease or carcinomatous meningitis; received prior treatment with fulvestrant or any selective estrogen-receptor degrader, except for in the neoadjuvant setting if treatment lasted no longer than 6 months; had any prior treatment with a PI3K, AKT, or mTOR inhibitor; had known and untreated, or active central nervous system (CNS) metastases; or had symptomatic active lung disease. Notably, patients with a history of treated CNS metastases were allowed to enroll.

The study enrolled 325 patients who were randomly assigned to receive oral inavolisib on days 1 to 28 of each 28-day cycle plus oral palbociclib on days 1 to 21 of each 28-day cycle and intramuscular fulvestrant once every 4 weeks; or oral placebo on days 1 to 28 of each 28-day cycle plus oral palbociclib on days 1 to 21 of each 28-day cycle and intramuscular fulvestrant once every 4 weeks.^1,3

Investigator-assessed PFS served as the trial’s primary end point. Secondary end points included OS, objective response rate, and clinical benefit rate.¹

Data from INAVO120 will also support filing submissions to other global regulatory agencies, including the European Medicines Agency.

References

1. FDA grants priority review to Genentech’s inavolisib for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. News release. Genentech. May 28, 2024. Accessed May 29, 2024. https://www.gene.com/media/press-releases/15026/2024-05-28/fda-grants-priority-review-to-genentechs
2. FDA grants breakthrough therapy designation to Genentech’s inavolisib for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. News release. Genentech. May 20, 2024. Accessed May 29, 2024. https://www.gene.com/media/press-releases/15025/2024-05-20/fda-grants-breakthrough-therapy-designat
3. 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 May 23, 2024. Accessed May 29, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04191499