INAVO120

Background

Phase III, double-blind, placebo-controlled RCT. N=325 PIK3CA-mutated HR+ HER2- mBC relapsing during or within 12 months of completing adjuvant AI (endocrine-resistant, high-risk). Inavolisib is a PI3Kα inhibitor that selectively degrades mutant PI3Kα protein.

Interventions and follow up

Arm A: Inavolisib 9mg daily + palbociclib 125mg d1–21/28 + fulvestrant 500mg IM q28d
Arm B: Placebo + palbociclib + fulvestrant
Primary endpoint: Progression-free survival (PFS)
mFollow up: 21.3 months

Results

PFS: 15.0 vs 7.3mo, HR 0.43, 95% CI 0.32–0.59, P<.001
ORR: 58.4% vs 39.0%
OS: Immature at primary analysis

Adverse events

Hematologic: Grade ≥3 neutropenia 62.3% vs 62.5% (similar, palbociclib-driven)
Metabolic: Grade ≥3 hyperglycemia 8.6% vs 0.6%
Mucosal: Stomatitis any grade 37.3% vs 15.7% (grade ≥3: 2.5% vs 0%)
Tolerability: Inavolisib dose reduction 14.2%; discontinuation 4.9%

Conclusions

Adding inavolisib to palbociclib + fulvestrant approximately doubled PFS in PIK3CA-mutated HR+ HER2- mBC in the early-relapse adjuvant setting. The triplet represents a new standard approach for this biomarker-selected population.

Key Limitations

PIK3CA-only selection excludes AKT1-mutant/PTEN-loss patients. Highly selected population (early relapse on adjuvant AI) — generalizability to de novo metastatic or later relapse not established. OS immature; PFS surrogacy needs confirmation. Triplet toxicity may challenge older/frailer patients. Degradation mechanism may reduce toxicity vs alpelisib — longer-term comparison pending.

Clinical Context

INAVO120 establishes inavolisib + palbociclib + fulvestrant as a first-line regimen for PIK3CA-mutated HR+ HER2- mBC relapsing early on/after adjuvant AI. FDA approved 2024. The 15-month mPFS is among the longest reported first-line in HR+ mBC. Selective PI3Kα degradation may reduce off-target hyperglycemia vs alpelisib (grade ≥3 hyperglycemia 8.6% vs 36.6% in SOLAR-1).

References