Abstract P5-21-01: Cobimetinib combined with paclitaxel as first-line treatment for patients with advanced triple-negative breast cancer (COLET study): Primary analysis of cohort I
Authors: Brufsky A , Miles D , Zvirbule Z , Eniu A , Lopez-Miranda E , Seo JH , Orditura M , Le Du F , Wongchenko M , Poulin-Costello M , Simmons B , McNally V , Loi S , Kim S-B 
Published: February 2018

Abstract
Chemotherapy is the mainstay of treatment for triple-negative breast cancer (TNBC), but taxane resistance remains problematic. TNBC tumors often demonstrate upregulation of the MAPK pathway and increased sensitivity to MEK inhibition. We hypothesized that adding a potent and selective MEK inhibitor such as cobimetinib (C) to paclitaxel (P) would modulate intrinsic taxane resistance and improve progression-free survival (PFS). COLET (NCT02322814) is a phase 2 study with multiple cohorts, including an open-label safety run-in stage and a randomized, placebo (pbo)-controlled stage. Cohort I evaluated C + P vs pbo + P. Cohorts II and III are evaluating triplet combinations of C plus the anti–PD-L1 agent atezolizumab with either P or nab-P.For Cohort I, 90 patients (pts) with previously untreated locally advanced or metastatic TNBC were randomly assigned 1:1 between August 27, 2015, and October 31, 2016, to receive P 80 mg/m2 intravenously on days 1, 8, and 15 and either C 60 mg or pbo orally once daily on days 3 through 23 of each 28-day cycle until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included safety, confirmed and unconfirmed overall response rate (ORR), duration of response, and overall survival.In the primary analysis for the Cohort I randomized stage only, median follow-up was 8 months. All pts were women; 61% had prior adjuvant or neoadjuvant taxane for TNBC. The safety profile of C + P was consistent with that known for the individual drugs, though gastrointestinal and dermatologic adverse events were more frequent than previously reported for C or P alone. Efficacy outcomes in the overall study population are summarized in the table. Median PFS was 5.5 months for C + P vs 3.8 months for pbo + P (HR, 0.73; 95% CI, 0.43–1.24; P = 0.2). Efficacy will also be evaluated in patient subgroups defined by gene expression subtypes, genetic alterations, and PD-L1 expression. COLET is the first randomized, pbo-controlled study to evaluate C + P as first-line treatment for locally advanced or metastatic TNBC. Consistent with the hypothesis that C modulates intrinsic taxane resistance, both median PFS and ORR were increased with the addition of C to standard treatment with P.
Efficacy Outcomes C + P (n = 47)Pbo + P (n = 43)Duration of follow-up (months) Mean (SD)8.4 (3.7)7.8 (3.4)Min, max1.6, 16.80.7, 15.7PFSPFS events, n (%)31 (66.0)31 (72.1)Median, months (95% CI)5.5 (4.2–7.4)3.8 (1.9–7.2)HR (95% CI)0.73 (0.43–1.24)Best responseConfirmed ORR, n (%)18 (38.3)9 (20.9)Complete response, n (%)00Partial response, n (%)18 (38.3)9 (20.9)Stable disease, n (%)18 (38.3)16 (37.2)Progressive disease, n (%)8 (17.0)17 (39.5)Unknown, n (%)3 (6.4)1 (2.3)CI, confidence interval; HR, hazard ratio; ORR, overall response rate; PFS, progression-free survival; SD, standard deviation.
Citation Format: Brufsky A, Miles D, Zvirbule Z, Eniu A, Lopez-Miranda E, Seo JH, Orditura M, Le Du F, Wongchenko M, Poulin-Costello M, Simmons B, McNally V, Loi S, Kim S-B. Cobimetinib combined with paclitaxel as first-line treatment for patients with advanced triple-negative breast cancer (COLET study): Primary analysis of cohort I [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 P5-21-01.