INAVO120: Phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with <i>PIK3CA</i> -mutated, hormone receptor-positive (HR+), HER2-negative (HE

1003 Background: INAVO, a highly potent and selective PI3Kα inhibitor that also promotes mutated p110α degradation, is FDA-approved in combination with PALBO + FULV for PIK3CA -mutated, HR+, HER2–, endocrine-resistant aBC, based on the primary analysis of INAVO120 (NCT04191499), which showed a statistically significant and clinically meaningful investigator-assessed progression-free survival (INV-PFS) benefit in the INAVO arm vs. the PBO arm (hazard ratio 0.43; 95% confidence interval [CI] = 0.32–0.59; p &lt; 0.0001). At that analysis, interim OS results were immature. Here we report the final OS analysis, including updated efficacy and safety. Methods: Pts received INAVO (9 mg orally once daily [PO QD]; Days 1–28 of each 28-day cycle)/PBO + PALBO (125 mg PO QD; Days 1–21 of each cycle) + FULV (500 mg intramuscularly; Cycle 1 Days 1 and 15 then every ~4 weeks). OS and objective response rate (ORR) were formally tested; updated INV-PFS and safety analyses are descriptive. Results: Data cut-off was Nov 15, 2024, at 34.2 months (mo) of median follow-up. Median OS was 34.0 mo (95% CI = 28.4–44.8) in the INAVO arm and 27.0 mo (95% CI = 22.8–38.7) in the PBO arm (stratified hazard ratio 0.67; 95% CI = 0.48–0.94; p = 0.0190 [boundary = 0.0469]). The OS benefit was consistent across key subgroups. The survival probability at 6, 12, 18, 24, and 30 mo was 96.8%, 87.0%, 74.3%, 65.8%, and 56.5% in the INAVO arm and 90.1%, 76.7%, 67.2%, 56.3%, and 46.3% in the PBO arm. ORR was 62.7% (95% CI = 54.8–70.2) and 28.0% (95% CI = 21.3–35.6), respectively (p &lt; 0.0001). Median time to chemotherapy (TTC) was 35.6 mo (95% CI = 25.4–not reached) in the INAVO arm and 12.6 mo (95% CI = 10.4–16.1) in the PBO arm (stratified hazard ratio 0.43; 95% CI = 0.30–0.60). Updated median INV-PFS was 17.2 mo (95% CI = 11.6–22.2) in the INAVO arm and 7.3 mo (95% CI = 5.9–9.2) in the PBO arm (stratified hazard ratio 0.42; 95% CI = 0.32–0.55), with landmark analyses supporting durable benefit. 90.7% of pts in the INAVO arm and 84.7% in the PBO arm had grade 3/4 adverse events (AEs); there were no new grade 5 AEs; 63.4% and 13.5% experienced any-grade hyperglycemia (grouped term); and AEs led to INAVO and PBO discontinuation in 6.8% and 0.6% of pts, respectively. Conclusions: INAVO + PALBO + FULV demonstrated a statistically significant and clinically meaningful OS benefit compared with PBO + PALBO + FULV. Improvement in INV-PFS was maintained during longer follow-up, along with a substantial and statistically significant improvement in ORR. TTC was also substantially delayed (by ~2 years) by the addition of INAVO to PALBO + FULV. With longer exposure to INAVO, no new safety signals, nor changes in the safety profile, were noted, supporting good tolerability (reflected in low discontinuation due to AEs). Clinical trial information: NCT04191499 .