Abstract P4-22-22: Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results
Authors: Brufsky A , Kim S-B , Velu T , García-Saenz JA , Tan-Chiu E , Sohn JH , Dirix L , Borms MV , Liu M-C , Moezi MM , Kozloff MF , Sparano JA , Xu N , Wongchenko M , Simmons B , McNally V , Miles D 
Published: March 2017

Abstract
Resistance to standard taxane-based chemotherapy is common in triple-negative breast cancer (TNBC). Mutations and gene amplifications in the MAPK pathway that upregulate MAPK signaling are present in many TNBC tumors. Upregulation of the MAPK signaling pathway can result in degradation of the pro-apoptotic protein BIM and upregulation of anti-apoptotic proteins, including BCL-2, BCL-XL, and MCL-1, thus promoting cell survival and desensitizing tumor cells to the pro-apoptotic effects of taxane chemotherapy. Updated data on clinical safety and efficacy are presented along with biomarker data evaluating the effects of treatment on induction of apoptosis.The COLET study (ClinicalTrials.gov ID, NCT02322814; EudraCT number, 2014-002230-32) consisted of a safety run-in (n∼12) followed by a blinded 1:1 randomized expansion stage (n∼90) to C + P or placebo (PBO) + P. The safety stage is complete and the randomized stage is enrolling pts. Two additional cohorts investigating the effect of adding atezolizumab will be recruiting and are out of scope of this submission. Pts in cohort I were treated with P 80 mg/m2 on days 1, 8, and 15 and C/PBO 60 mg/day on days 3–23 of each 28-day cycle until disease progression or unacceptable toxicity. Gene expression and apoptotic index were measured by RNA-Seq and TUNEL staining, respectively, to assess the biologic activity of C + P.Sixteen women (median age, 55.5 years) were enrolled in the safety run-in stage. At data snapshot (April 22, 2016), all 16 pts had received ≥1 dose of study treatment. Median time on treatment was 116 days (range, 7-336) for C and 84 days (range, 0-351) for P. Fifteen (94%) pts had ≥1 adverse event (AE); 5 (31%) pts had grade 1/2 AEs and 10 (63%) pts had grade 3 AEs (Table). No pts experienced grade 4–5 AEs. Among the 16 safety run-in patients, responses to date include partial response (PR; n = 8 [50.0%]), stable disease (SD, n = 4 [25.0%]), and progressive disease (n = 2 [12.5%]), as well as 2 pts with no post-baseline tumor assessment. Six pts maintained a PR at ∼20 weeks and three maintained a PR at ≥40 weeks. To date, matched pre- and on-treatment biopsies were evaluable for 2 pts, 1 with a PR and 1 with SD. In the patient who attained a PR, increased expression of pro-apoptosis genes, including BIM, was observed; but this was not seen in the patient experiencing SD. The PR patient also had an increase in apoptotic index. Updated biomarker data will be reported.This is the first study to evaluate C + P in TNBC. The safety profile of C + P is consistent with that of known safety profiles. Efficacy and safety will be further evaluated in the ongoing randomized stage.
Most common (any grade ≥20%) AEsTreatment-emergent AEs, n (%)C + P (safety run-in stage), N = 16 All gradesGrade 3Diarrhea10 (63)1 (6)Rash8 (50)0Nausea7 (44)0Alopecia5 (31)0Blood CPK level increase5 (31)1 (6)Stomatitis4 (25)2 (13)Asthenia4 (25)1 (6)Constipation4 (25)0Dyspnea4 (25)0Edema peripheral4 (25)0Pyrexia4 (25)0Vomiting4 (25)0AEs, adverse events; C, cobimetinib; CPK, creatinine phosphokinase; P, paclitaxel.
Citation Format: Brufsky A, Kim S-B, Velu T, García-Saenz JA, Tan-Chiu E, Sohn JH, Dirix L, Borms MV, Liu M-C, Moezi MM, Kozloff MF, Sparano JA, Xu N, Wongchenko M, Simmons B, McNally V, Miles D. Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-22.