Abstract PS2-07-25: Genomic biomarkers of response to ipatasertib in hormone receptor-positive, HER2-negative metastatic breast cancer

Abstract Background: AKT inhibitor therapy is approved in combination with fulvestrant for patients with AKT1/PIK3CA/PTEN-mutant, HR+/HER2- metastatic breast cancer (MBC). Molecular factors which impact sensitivity to AKT inhibition are poorly defined. The TAKTIC trial tested the combination of ipatasertib with endocrine therapy, with or without palbociclib, for endocrine-resistant MBC (Wander et al., SABCS 2023). This study aimed to identify genomic biomarkers in circulating tumor DNA (ctDNA) that are associated with differences in response to ipatasertib combination therapy. Methods: TAKTIC was a phase Ib trial evaluating ipatasertib with fulvestrant or an aromatase inhibitor (Arms A/B), or fulvestrant plus palbociclib (Arm C) in patients with HR+/HER2– MBC with disease progression after ≥1 prior line of metastatic therapy. An exploratory end point was to identify genomic predictors of response/resistance to AKT inhibitor therapy via ctDNA sequencing. Progression free survival (PFS) on ipatasertib was compared in patients with versus without alterations detected in baseline liquid biopsy samples. Matched baseline and post-progression ctDNA sequencing was also examined for acquired mutations. Eligibility required baseline sequencing within 61 days prior to treatment initiation and post-progression sampling within 30 days pre- or any time post-progression. ctDNA was profiled via Guardant360; only oncogenic/likely oncogenic alterations were analyzed. PFS was estimated via the Kaplan–Meier method, and hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Firth’s Cox models, adjusting for relevant covariates as permitted by sample size. McNemar’s test assessed mutation changes in paired baseline and post-progression ctDNA. Results: Of 77 TAKTIC patients, 39 were included for baseline biomarker analysis. This subgroup included 19 patients treated with doublet therapy (Arms A/B) and 20 with triplet therapy (Arm C). Patients were heavily pretreated (median of 3 prior therapies and 85% with prior CDK4/6i) consistent with the overall population. Median PFS was 5.8 months, comparable to 5.5 months in the overall population. Baseline amplifications in FGFR1 were detected in 13% of ctDNA (n=5/39) and associated with shorter PFS on ipatasertib (HR 5.21, 95% CI 1.68–14.37). Mutations in ERBB2 (n=4/39, 10%) and amplifications in EGFR (n=3/39, 8%) also correlated with worse PFS (HR 3.44, 95% CI 1.05–9.10; and HR 4.75, 95% CI 1.17–15.20, respectively). Based upon multivariate gene analysis combining PI3K pathway alterations, patients with PIK3CA, PTEN, and/or AKT1 mutations had significantly improved PFS on triplet therapy compared to those without (n=9/20; HR 0.21; 95% CI 0.05–0.68); however, no association was seen with doublet therapy or in the overall cohort. ESR1 mutations were detected in 31% of patients and associated with shorter PFS approaching statistical significance (n=12/39, HR 2.09, 95% CI 1.00–4.21). Paired baseline and post-progression ctDNA analysis (n=27) was constrained by limited sample size. FGFR1 amplifications emerged in 4 cases (15%) at progression but were absent at baseline. Further analyses are ongoing and will be presented at the meeting. Conclusions: Genomic biomarkers detected in ctDNA correlated with PFS on ipatasertib therapy in this heavily pretreated population with HR+/HER2- MBC. Activating alterations in FGFR1, ERBB2, EGFR, and ESR1 were linked with inferior PFS, and triplet therapy prolonged treatment benefit in patients with PI3K pathway mutant disease. These exploratory findings are hypothesis generating and require clinical and preclinical validation to inform personalized AKT inhibitor treatment. Citation Format: Z. Bagheri, M. Lloyd, G. Fell, E. Scott, J. Keenan, L. Spring, J. Shin, S. Isakoff, L. Ryan, S. Padden, E. Fisher, A. Newton, B. Moy, A. Varkaris, L. Ellisen, D. Micalizzi, D. Haber, D. Juric, A. Bardia, S. Wander. Genomic biomarkers of response to ipatasertib in hormone receptor-positive, HER2-negative metastatic breast cancer 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 PS2-07-25.