Inavolisib Receives FDA Breakthrough Therapy Designation for PIK3CA-Mutated, HR+/HER2– Breast Cancer

The FDA has granted breakthrough therapy designation to inavolisib (GDC-0077) plus palbociclib (Ibrance) and fulvestrant (Faslodex) 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.¹

This regulatory decision was supported by findings from the phase 3 INAVO120 trial (NCT04191499), which showed that at a median follow-up of 21.3 months, the inavolisib-based regimen elicited a median progression-free survival (PFS) of 15.0 months (95% CI, 11.3-20.5) vs 7.3 months (95% CI, 5.6-9.3) for palbociclib plus fulvestrant, translating to a 57% reduction in the risk of progression or death (HR, 0.43; 95% CI, 0.32-0.59; P < .0001).^1,2 Although overall survival (OS) data were immature at data cutoff, the inavolisib-based regimen demonstrated a positive OS trend, eliciting a median OS that was not evaluable (NE; 95% CI, 27.3 months–NE) vs 31.1 months (95% CI, 22.3-NE) with control (stratified HR, 0.64; 95% CI, 0.43-0.97; P = .0338, boundary of 0.0098). OS follow-up will continue to the next data analysis.¹

“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 Genentech, said in a news release. “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.”

Inavolisib is an investigational, oral agent that is distinct from other PI3K pathway inhibitors due to its high potency and specificity for the PI3K alpha isoform. Its mechanism of action degrades mutated PI3K alpha.

INAVO120 is a randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of inavolisib plus palbociclib and fulvestrant compared with palbociclib plus fulvestrant in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer with disease progression during or within 12 months of completing adjuvant endocrine therapy who had no prior exposure to systemic therapy for metastatic disease. A total of 325 patients were randomly assigned to the investigational (n = 161) or control (n = 164) arms.^1,2

Investigator-assessed PFS serves as the primary end point of INAVO120. Secondary end points include OS, overall response rate (ORR), best overall response, clinical benefit rate (CBR), duration of response (DOR), and patient-reported outcomes.

The respective 6-, 12-, and 18-month PFS rates were 82.9%, 55.9%, and 46.2% in the inavolisib arm vs 55.9%, 32.6%, and 21.1% in the control arm. The respective 6-, 12-, and 18-month OS rates were 97.3%, 85.9%, and 73.7% in the inavolisib arm vs 89.9%, 74.9%, and 67.5% in the control arm.

The ORR was 58.4% with inavolisib vs 25.0% with control.² The CBRs in these respective arms were 75.2% vs 47.0%. The median DOR was 18.4 months (95% CI, 10.4-22.2) for the inavolisib arm vs 9.6 months (95% CI, 7.4-16.6) for the control arm (stratified HR, 0.57; 95% CI, 0.33-0.99).

In the inavolisib and placebo arms, 90.8% and 100% of patients, respectively, experienced any-grade adverse effects (AEs), and 88.3% and 82.1% of patients, respectively, had grade 3/4 AEs. The most common grade 3/4 AEs were neutropenia (inavolisib arm, 80.2%; control arm, 78.4%), thrombocytopenia (14.2%; 4.3%), stomatitis/mucosal inflammation (5.6%; 0%), anemia (6.2%; 1.9%), hyperglycemia (5.6%; 0%), diarrhea (3.7%; 0%), nausea (0.6%; 0%), decreased appetite (<2%; <2%), COVID-19 (<2%; <2%), headache (<2%; <2%), and leukopenia (6.8%; 10.5%). Grade 5 AEs occurred in 3.7% and 1.2% of patients in the inavolisib and control arms, respectively.

References

1. 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 21, 2024. https://www.gene.com/media/press-releases/15025/2024-05-20/fda-grants-breakthrough-therapy-designat
2. Jhaveri KJ, 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: 2023 San Antonio Breast Cancer Symposium; San Antonio, Texas; December 5-9, 2023. Abstract GS03-13.