First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results

Schmid P.; Turner N.C.; Barrios C.H.; Isakoff S.J.; Kim S.-B.; Sablin M.-P.; Saji S.; Savas P.; Vidal G.A.; Oliveira M.; O'Shaughnessy J.; Italiano A.; Espinosa E.; Boni V.; White S.; Rojas B.; Freitas-Junior R.; Chae Y.; Bondarenko I.; Lee J.; Mattos C.T.; Rodriguez J.L.M.; Lam L.H.; Jones S.; Reilly S.-J.; Huang X.; Shah K.; Dent R. · Clinical Cancer Research (2024) · DOI: 10.1158/1078-0432.ccr-23-2084

Resumen

Purpose: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triplenegative breast cancer (mTNBC). Patients and Methods: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. Results: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months.The safety profile wasconsistent with theknown toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. Conclusions: In patients with mTNBC receiving an ipatasertib/ atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.