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

Abstract

Purpose: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative 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 was consistent with the known 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.

Figure 1.

Biomarker characterization. A, Genomic landscape. B, Stromal TILs and CD8 T cells according to PFS. The lower and upper bounds of the rectangles represent the first and third quartiles, the horizontal line represents the median, the whiskers extend to the highest and lowest values within 1.5× the interquartile range, and data beyond the end of the whiskers are outliers and are plotted as points. C, Baseline RNA-sequencing profile. Atezolizumab plus paclitaxel response represents a gene signature based on CD8-CXCL13 T cells that has previously been shown to predict better response to atezolizumab plus paclitaxel in TNBC (20). Similarly, the B-cell gene signature comprising CD19 and CXCR5 is predictive of better response to atezolizumab plus paclitaxel in TNBC. D, GSEA analysis on hallmark gene sets according to PFS. The scoring is averaged Z score of individual samples from gene set variation analysis in the subgroups with PFS <5 months and >10 months. AMP, amplification; atezo, atezolizumab; CAF, cancer-associated fibroblasts; CPS, combined positive score; DEL, deletion; EMT, epithelial–mesenchymal transition; FA BIO, fatty acid biosynthesis; IC, immune cell; ipat, ipatasertib; JAK, Janus kinase; LAR, luminal androgen receptor; MPAS, MAPK pathway activity score (30); MHC-I, major histocompatibility complex-I; Mut/Mb, mutations/megabase; NF-κB, nuclear factor kappa-B; pac, paclitaxel; RA, rearrangement; SNV, single-nucleotide variation; TEM, T effector memory.

Figure 2.

Application of pAKT model to the CO40151 dataset.