First-Line Cobimetinib (C) Plus Paclitaxel (P) In Patients (Pts) With Advanced Triple-Negative Breast Cancer (Tnbc): Updated Results And Tumoral Immune Cell Infiltration Data From The Phase 2 Colet Study

Resistance to standard taxane-based chemotherapy is common in TNBC. Preclinical data suggest that MEK inhibition may overcome taxane resistance and enhance antitumor immune response. The safety and efficacy of combining C, a highly selective MEK inhibitor, with P was explored in pts with metastatic/locally advanced TNBC and no prior systemic therapy for metastatic disease. The COLET study (NCT02322814; EudraCT number, 2014-002230-32) consisted of a safety run-in (n ≈ 12) followed by a blinded 1:1 randomized stage (n ≈ 100 pts) to C + P or placebo (PBO) + P. Pts were treated with P 80 mg/m2 on days 1, 8, and 15 and C/PBO 60 mg/d on days 3-23 of each 28-d cycle. Gene expression and CD8 T-cell infiltration were measured by RNA-Seq and immunohistochemistry, respectively. Sixteen women (median age, 55.5 years) were enrolled in the safety stage. At data snapshot (April 22, 2016), all 16 pts had received ≥1 dose of study treatment. Median time on treatment was 116 d (range, 7-336) for C and 84 d (range, 0-351) for P. 94% of pts had ≥1 adverse event (AE); most were grade 1/2 (Table). Ten pts (63%) had grade 3 AEs; there were no grade 4-5 AEs. Preliminary efficacy data from safety run-in included unconfirmed partial response (n = 8, 6 confirmed), stable disease (n = 4), and progressive disease (n = 2); 2 pts had not completed a tumor assessment. To date, matched pre- and post-treatment biopsies have been tested for 2 pts and demonstrate an increase in CD8 T-cell infiltration and PD-L1 expression with treatment in the basal subtype.Tabled 1Most common (any grade ≥ 20%) AEsTreatment-emergent AEsC + P (safety run-in stage), N = 16All gradesGrade ≥3Diarrhea10 (63)1 (6)Rash8 (50)0Nausea7 (44)0Blood CPK level increase5 (31)1 (6)Alopecia5 (31)0Stomatitis4 (25)2 (13)Asthenia4 (25)1 (6)Constipation4 (25)0Dyspnea4 (25)0Peripheral edema4 (25)0Pyrexia4 (25)0Vomiting4 (25)0Abbreviations: AEs, adverse events; C, cobimetinib; CPK, creatinine phosphokinase; P, paclitaxel. Open table in a new tab Abbreviations: AEs, adverse events; C, cobimetinib; CPK, creatinine phosphokinase; P, paclitaxel. 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. Initial data are consistent with previous reports on the immunomodulatory effects of MEK inhibition. Efficacy and safety will be further evaluated in the ongoing randomized stage.