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.

Background: The oral AKT inhibitor IPAT is being evaluated in cancers with a high prevalence of PI3K/AKT pathway activation. In the PBO-controlled randomized phase II FAIRLANE trial (NCT02301988), adding IPAT to PAC as neoadjuvant therapy for TNBC led to a numerical increase in pathologic complete response (pCR) in unselected patients (17.1% vs 13.3%), with a greater treatment effect in patients with PIK3CA/AKT1/PTEN-altered tumors (17.9% vs 11.8%). The addition of IPAT also led to an increase in complete response (CR) by MRI (27.6% vs 13.3%) that was enhanced in patients with PIK3CA/AKT1/PTEN-altered tumors (39.3% vs 8.8%) [Oliveira, AACR 2018]. We report an exploratory analysis performed to provide better understanding of potential biomarkers for response. Methods: Pretreatment tumor samples were evaluated for genomic alterations using the FoundationOne® (Foundation Medicine) assay (n=144) and gene expression by RNA-Seq (n=92). Samples were classified into TNBC subtypes based on the method developed by Lehmann and Pietenpol [Lehmann, J Clin Invest 2011]. Tumor-infiltrating lymphocytes (TILs) were quantified using the Salgado method [Salgado, Ann Oncol 2015] (n=135). Results: Of 62 patients (43%) with PIK3CA/AKT1/PTEN-altered tumors, 21 had an activating mutation in PIK3CA or AKT1 and 47 had an alteration in PTEN (6 [3 in each arm] had both PIK3CA mutation and PTEN alteration). Although only 3 patients with PIK3CA/AKT1-mutant tumors achieved a pCR, there was an increased rate of MRI CR with the addition of IPAT to PAC [Table]. In patients with PTEN alterations, both pCR rate and MRI CR rate were increased with IPAT. In patients treated with PBO + PAC, all 4 pCR patients evaluable by RNA-Seq were of the immunomodulatory (IM) subtype. However, in the IPAT + PAC arm, pCRs were also seen in patients with basal-like 1 (BL-1), mesenchymal (M), and mesenchymal stem-like (MSL) subtypes. Consistent with this observation, in the PBO + PAC arm, samples from patients achieving a pCR had significantly higher levels of stromal TILs than those from patients who did not have a pCR, while no difference was observed in the IPAT + PAC arm. Response, n (%)PIK3CA/AKT mutation (n=21)PTEN alteration (n=47) IPAT + PAC (n=11)PBO + PAC (n=10)IPAT + PAC (n=21)PBO + PAC (n=26)pCR1 (9%)2 (20%)4 (19%)3 (12%)CR by MRI5 (45%)1 (10%)8 (38%)2 (8%) Conclusions: This retrospective exploratory biomarker analysis of the phase II FAIRLANE trial of neoadjuvant IPAT for TNBC provides insight into the potential heterogeneity of response and resistance to taxane therapy. The results also hint that response to PAC alone is dependent on baseline immune infiltration and that this dependency might be relieved with the addition of AKT inhibition. Citation Format: Wongchenko MJ, Oliveira M, Saura C, Nuciforo P, Calvo I, Andersen J, Passos Coelho JI, Gil Gil M, Bermejo B, Patt DA, Ciruelos E, Singel SM, Maslyar DJ, Xu N, de la Peña L, Baselga J, Gendreau S, Isakoff SJ. Exploratory biomarker analyses of FAIRLANE, a double-blind placebo (PBO)-controlled randomized phase II trial of neoadjuvant ipatasertib (IPAT) + paclitaxel (PAC) for early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-19.

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