Abstract CT069: Baseline gene expression patterns of CDK4/6 inhibitor-naïve or -refractory HR+, HER2- advanced breast cancer in the phase Ib study of ribociclib plus everolimus plus exemestane

Abstract

Abstract Background: Preclinical data suggest that combination of endocrine therapy (ET) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and mammalian target of rapamycin inhibitor (mTORi) may overcome prior treatment resistance in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The Phase Ib CLEE011X2106 study (NCT01857193) is investigating ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in patients with HR+, HER2- ABC resistant to letrozole or anastrozole. The objective of this analysis is to characterize baseline gene expression patterns in the CDK4/6i-naïve and -refractory groups, and assess the potential correlation with clinical activities. Methods: Postmenopausal women with HR+, HER2- ABC resistant to letrozole or anastrozole, and who had received no prior CDK4/6i or whose disease had progressed on or within 1 month of CDK4/6i therapy, were enrolled in the CDK4/6i-naïve and -refractory dose expansion groups, respectively. More than 1 line of chemotherapy for ABC or prior treatment with EXE or an mTORi was not permitted. Patients received RIB (300 mg, 3-weeks on/1-week off) + EVE (2.5 mg, continuous) + EXE (25 mg, continuous) until disease progression or study discontinuation. Baseline tumor samples (collected after CDK4/6i therapy in the CDK4/6i-refractory group) were assessed for mRNA expression using the NanoString 230-gene nCounter® GX Human Cancer Reference panel. Results: As of May 15, 2017, the 24-week clinical benefit rate was 56% (9/16) in the CDK4/6i-naïve group and 24% (4/17) in the -refractory group. Baseline tumor mRNA expression was evaluable in 14 patients: CDK4/6i naïve, n=8 (best response: 7 stable disease [SD], 1 progressive disease [PD]); CDK4/6i refractory, n=6 (2 SD, 4 PD). Across all patients (both groups), those with SD tended to have higher ESR1 expression compared with those experiencing PD, with a trend for higher baseline ESR1 expression in the CDK4/6i-naïve group compared with the -refractory group. Also across all patients, higher overall baseline expression of cell cycle control genes and mitogen-activated protein kinase (MAPK) pathway genes appeared to trend with PD. Additionally, in the CDK4/6i-refractory group, there was a trend for higher CDK2 and/or CCNE1 expression in patients with PD compared with SD. A heat map of 24 genes indicated differences in gene expression patterns between the CDK4/6i-naïve and -refractory groups. Conclusions: Gene expression patterns differ between CDK4/6i-naïve and -refractory tumors. Higher expression of cell cycle control genes (particularly CDK2 and CCNE1) and MAPK pathway genes appears to trend with resistance to the RIB + EVE + EXE combination after progression on prior CDK4/6i. Due to the small number of samples, further investigation is needed. Citation Format: Aditya Bardia, Shanu Modi, Javier Cortes, Mario Campone, Luc Dirix, Brigette Ma, J Thaddeus Beck, Jorge Chaves, Amy Weise, Jacqueline Vuky, Gilberto Lopes, Miguel Gil-Gil, Xiaochun Liu, Wei He, Faye Su, Michelle Miller, Mariana Chavez-MacGregor. Baseline gene expression patterns of CDK4/6 inhibitor-naïve or -refractory HR+, HER2- advanced breast cancer in the phase Ib study of ribociclib plus everolimus plus exemestane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT069.