Inavolisib Earns FDA Breakthrough Therapy Designation in Breast Cancer

Supporting data for the breakthrough therapy designation came from the phase 3 INAVO120 trial (NCT04191499), in which investigators evaluated treatment with inavolisib plus palbociclib and fulvestrant vs palbociclib/fulvestrant only.

The FDA has granted breakthrough therapy designation to inavolisib when administered in combination with palbociclib (Ibrance) and fulvestrant (Faslodex) for adults with hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer harboring PIK3CA mutations following prior adjuvant endocrine therapy, according to a press release from the developers, Roche.¹

Developers designed the investigational, orally available agent to potentially reduce the burden and toxicity associated with therapy for PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic disease. Based on the agent’s specificity for the PI3K alpha isoform compared with other isoforms as well as its mechanism of action for degrading the mutated PI3K alpha, developers believe it is differentiated from other available PI3K inhibitors.

“We are pleased that the FDA granted breakthrough therapy designation for inavolisib in recognition of the substantial clinical benefit observed with this regimen,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, said in the press release.¹ “This promising inavolisib-based regimen could transform the PI3K inhibitor class, potentially becoming the standard of care for this patient population in the first-line setting.”

Supporting data for the breakthrough therapy designation came from the phase 3 INAVO120 trial (NCT04191499), in which investigators evaluated treatment with inavolisib plus palbociclib and fulvestrant vs palbociclib/fulvestrant only. Updated findings from this trial were presented at the 2023 San Antonio Breast Cancer Symposium (SABCS).

The median progression-free survival (PFS) per investigator assessment was 15.0 months (95% CI, 11.3-20.5) with the inavolisib combination vs 7.3 months (95% CI, 5.6-9.3) with palbociclib/fulvestrant only (HR, 0.43; 95% CI, 0.32-0.59; P <.0001).² In each respective arm, PFS rates were 82.9% vs 55.9% at 6 months, 55.9% vs 32.6% at 12 months, and 46.2% vs 21.1% at 18 months.

In an interim analysis of overall survival (OS), the median OS was not evaluable (NE; 95% CI, 27.3-NE) in the inavolisib arm and 31.1 months (95% CI, 22.3-NE) in the comparator arm (HR, 0.64; 95% CI, 0.43-0.97; P = .0338). OS rates in each arm were 97.3% vs 89.9% at 6 months, 85.9% vs 74.9% at 12 months, and 73.7% vs 67.5% at 18 months.

Any-grade neutropenia occurred in 88.9% of patients who received the inavolisib combination and 90.7% of those who received palbociclib/fulvestrant alone. Other common adverse effects in each arm included stomatitis or mucosal inflammation (51.2% vs 26.5%), hyperglycemia (58.6% vs 8.6%), and diarrhea (48.1% vs 16.0%).

Developers plan to submit data from the INAVO120 trial to other regulatory health authorities such as the European Medicines Agency.

In the double-blind INAVO120 study, 325 patients with were randomly assigned to receive inavolisib at 9 mg orally once daily or matched placebo plus palbociclib at 125 mg orally once daily on days 1 to 21 and fulvestrant at 500 mg on days 1 and 15 of cycle 1 and every 4 weeks thereafter.

The trial’s primary end point was PFS based on investigator assessment. Secondary end points included OS, objective response rate, best overall response, clinical benefit rate, duration of response, and patient-reported outcomes.

Patients with HR-positive, HER2-negative advanced breast cancer and PIK3CA mutations as confirmed via central circulating tumor DNA or local tissue testing were eligible for enrollment on the trial. Other eligibility criteria included having measurable disease, disease progression during or within 12 months after completing adjuvant endocrine therapy, and no prior therapy for advanced breast cancer.

References

1. FDA grants breakthrough therapy designation to Roche’s inavolisib for advanced hormone receptor-positive, HER2-negative breast cancer with a PIK3CA mutation. News release. Roche. May 21, 2024. Accessed May 21, 2024. https://tinyurl.com/yc5ybf7m
2. Jhaveri KL, Im S, 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 the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS03-13.