Inavolisib Receives FDA Breakthrough Therapy Designation for HR+/HER2 Breast Cancer with PIK3CA Mutation

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 after recurrence on or within 12 months of completion of adjuvant endocrine therapy.1

This regulatory decision was supported by findings from the phase 3 INAVO120 trial (NCT04191499), which showed that with a median follow-up of 21.3 months, the inavolisib-based regimen resulted in 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, resulting in a 57% reduction in the risk of progression or death (HR, 0.43; 95% CI, 0.32-0.59; 95% CI, 0.32-0.59); P < .0001).1.2 Although overall survival (OS) data were immature at the time of data cutoff, the inavolisib-based regimen demonstrated a positive OS trend, resulting in a median OS that was not evaluable (LE; 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 = 0.0338, limit 0.0098). OS monitoring will continue until the next data analysis.1

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

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

INAVO120 is a randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of inavolisib plus palbociclib and fulvestrant compared to 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 that 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 endpoint of INAVO120. Secondary endpoints 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 group versus 55.9%, 32.6%, and 21.1% in the inavolisib group. the control group. The respective 6-, 12-, and 18-month OS rates were 97.3%, 85.9%, and 73.7% in the inavolisib group versus 89.9%, 74.9%, and 67.5% in the inavolisib group. the control group.

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

In the inavolisib and placebo arms, 90.8% and 100% of patients, respectively, experienced adverse events (AEs) of any grade, and 88.3% and 82.1% of patients, respectively , had grade 3/4 AD. The most common grade 3/4 AEs were neutropenia (inavolisib group, 80.2%; control group, 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.


  1. The FDA grants breakthrough therapy designation to Genentech’s inavolisib for hormone receptor-positive, HER2-negative advanced breast cancer with a PIK3CA mutation. Press release. Genetech. May 20, 2024. Accessed May 21, 2024.
  2. Jhaveri KJ, Im S, Saura C, et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with locally advanced or metastatic breast cancer with PIK3CA mutation, hormone receptor positive, HER2 negative: primary phase III INAVO120 analysis. Presented at: San Antonio Breast Cancer Symposium 2023; San Antonio, Texas; December 5 to 9, 2023. Summary GS03-13.