Background: The oral Akt inhibitor IPAT is being evaluated in cancers with a high prevalence of PI3K/Akt pathway activation. In the placebo-controlled randomized phase II LOTUS trial (NCT02162719), adding IPAT to PAC as first-line therapy for metastatic TNBC improved progression-free survival (PFS) in unselected patients (hazard ratio [HR]: 0.60 [95% CI: 0.37–0.98]), with a more pronounced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (HR: 0.44 [95% CI: 0.20–0.99]) [Kim, Lancet Oncol in press]. An exploratory analysis was performed to understand better the potential associations between PIK3CA/AKT1/PTEN alterations and other biomarkers relevant to TNBC, as well as IPAT efficacy.
Methods: Pretreatment tumor samples (76 primary, 27 metastatic) were evaluated for genetic alterations using the FoundationOne® (Foundation Medicine) assay (n=103) and gene expression by RNA sequencing (n=73). Tumor-infiltrating lymphocytes (TILs) were quantified using the Salgado method [Salgado, Ann Oncol 2015] (n=118). Samples were classified into subtypes by gene expression based on the method developed by Lehmann and Pietenpol [Lehmann, J Clin Invest 2011].
Results: Of 42 patients (41%) with PIK3CA/AKT1/PTEN-altered tumors, 26 had an activating mutation in PIK3CA or AKT1 and 16 had an alteration in PTEN. Patients with PIK3CA- and AKT1-mutant tumors were enriched in the BL2 and LAR TNBC subtypes, whereas those with PTEN-altered tumors were enriched in the BL1 subtype. An internal analysis of the publicly available METABRIC dataset yielded similar results. PTEN alterations were also associated with reduced levels of stromal TILs compared with PIK3CA/AKT1-mutant and PIK3CA/AKT1/PTEN non-altered tumors. In an exploratory analysis of the 26 patients with PIK3CA/AKT1-mutant tumors, the effect of adding IPAT was particularly pronounced (PFS HR: 0.24 [95% CI: 0.06–0.83]; median PFS 12.9 months in the IPAT + PAC arm vs 5.0 months for placebo + PAC); interpretation of efficacy in patients with PTEN-altered tumors was limited by the size of the subgroup.
There was no enrichment of PIK3CA/AKT1/PTEN alterations in metastatic vs primary samples, nor in samples collected after (neo)adjuvant chemotherapy vs from chemotherapy-naïve patients. Additionally, there was no association between PIK3CA/AKT1/PTEN alterations and BRCA1/2 alterations. BRCA1/2 alterations were not associated with any differences in IPAT efficacy outcomes (PFS, objective response rate).
No association was observed between PIK3CA/AKT1/PTEN-altered status and gene signatures of immune cell infiltration/activation or tumor mutational burden. High (≥10%) vs low levels of stromal TILs showed a trend toward longer PFS in patients treated with placebo + PAC (HR: 0.74 [95% CI: 0.39–1.48]), but no difference was apparent in those treated with IPAT + PAC (HR: 1.14 [95% CI: 0.57–2.40]).
Conclusions: This retrospective exploratory biomarker analysis of the phase II LOTUS trial of IPAT in TNBC provides insight into the potential heterogeneity of disease biologies underlying PI3K/Akt pathway activation.
Citation Format: Wongchenko MJ, Dent R, Kim S-B, Saura C, Oliveira M, Baselga J, Kapp AV, Chan WY, Singel SM, Maslyar DJ, Gendreau S. Biomarker analysis of the LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) in metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-20.
