Abstract PD5-09: Molecular features of response to palbociclib + fulvestrant ± inavolisib in hormone receptor-positive, HER2-negative, PIK3CA -mutated advanced breast cancer as assessed from baseline circulating tumor DNA in the pivotal Phase 3 INAVO120 trial

Abstract BACKGROUND Inavolisib (INAVO) + palbociclib (PALBO) + fulvestrant (FULV) has been approved for treatment of patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2-negative, endocrine-resistant advanced breast cancer with improved efficacy over placebo (PBO) + PALBO + FULV in INAVO120 (NCT04191499; progression-free survival PFS hazard ratio 0.43; 95% CI 0.32-0.59; p 0.0001). Exploratory analyses were done to better understand the molecular features of response to this regimen using FoundationOneⓇLiquid CDx sequencing results from circulating tumor (ct)DNA collected during screening (baseline). METHODS Profiling was performed on baseline plasma-derived ctDNA from 277 pts enrolled in INAVO120. Circulating tumor fraction (TF; estimated plasma DNA fraction derived from tumor cells) was computed by Foundation Medicine, Inc. and reported as a percentage of total cell-free DNA (n = 267 pts with detectable TF). Only alterations annotated as known / likely to be oncogenic were analyzed unless noted. Q values indicate Benjamini-Hochberg false discovery-corrected p-values. Interaction analyses were used to explore the significance of the relationship between biomarkers and the differential benefit between arms. RESULTS Following PIK3CA mutation (mut), the most common alterations detected in enrolled pts were in TP53 (49.4%; 132 / 267), CDH1 (17.6%; 47 / 267), and ESR1 (14.5%; 39 / 267, 34 of which were short variants). Within each arm, pts with above median ( 3.8%) TF had shorter PFS (higher vs lower TF: INAVO arm hazard ratio 1.9; 95% CI 1.2-3.1; PBO arm hazard ratio 1.8; 95% CI 1.2-2.7). There was no interaction between TF and benefit from the INAVO regimen (p = 0.935), hazard ratio 0.5 (95% CI 0.3-0.8) and hazard ratio 0.5 (95% CI 0.3-0.8) for the above-median and at- / below-median pt subgroups, respectively. The benefit from the INAVO regimen was similar for pts with both ESR1 short variant mut (ESR1mut) detected (hazard ratio 0.2; 95% CI 0.1-0.7) and no ESR1mut detected (hazard ratio 0.5; 95% CI 0.4-0.7), interaction p = 0.705. PTEN deleterious alterations (PTENmut) were detected in 10.9% of samples (29 / 267), and benefit from the INAVO regimen in those with PTENmut was hazard ratio 0.6 (95% CI 0.2-1.4) and without PTENmut was hazard ratio 0.5 (95% CI 0.3-0.6), interaction p = 0.706. An AKT1mut was present in only one pt. The PFS benefit of the INAVO vs PBO arms was similar for pts with either multiple PIK3CAmut (20.3%; 54 / 266 hazard ratio 0.6; 95% CI 0.3-1.1) or only one PIK3CAmut (hazard ratio 0.5; 95% CI 0.3-0.7), interaction p = 0.677. An unbiased univariate association analysis of gene alteration status with PFS identified TP53mut as a negative prognostic factor in both arms (q = 6.89 × 10-4 and q = 4.59 × 10-3, INAVO and PBO arms, respectively); regardless, the INAVO arm remained superior to the PBO arm in pts with TP53mut ctDNA (PFS hazard ratio 0.5; 95% CI 0.4-0.8). In interaction analyses, no genes with an alteration prevalence ≥ 10% in the efficacy-evaluable population were associated with differential benefit between arms. CONCLUSIONS Together, these findings support the efficacy of this INAVO regimen across a variety of genomic subgroups, including those with low / high TF, a well-known prognostic feature, and regardless of ESR1mut status. TP53mut were associated with poor prognosis in both arms. Although sample sizes were small, subgroup analyses in pts with a PTENmut did not conclusively suggest lack of benefit of this INAVO regimen vs PBO. Overall, these post-hoc, exploratory findings warrant further investigation in larger datasets. Citation Format: S. Hilz, N. Turner, K. Kalinsky, S. Loibl, K. Jhaveri, S. Im, C. Saura, P. Schmid, S. Loi, T. Stout, C. Song, K. Hutchinson, D. Juric. Molecular features of response to palbociclib + fulvestrant ± inavolisib in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer as assessed from baseline circulating tumor DNA in the pivotal Phase 3 INAVO120 trial abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD5-09.