COLET study: Cobimetinib plus paclitaxel as first-line treatment in advanced triple-negative breast cancer
While targeted therapies are available for breast cancers that express the oestrogen/progesterone receptor (HR) and overexpress human epidermal growth factor receptor 2 (HER2) the mainstay of treatment for triple-negative breast cancer remains chemotherapy. Initially, tiple-negative breast cancer is highly sensitive to taxane-based chemotherapy. However, resistance to standard taxane-based chemotherapy is common in triple-negative breast cancer. Mutations and gene amplifications in the MAPK pathway that upregulate MAPK signalling are present in many triple-negative breast cancer tumors and may contribute to resistance to taxane therapy. Upregulation of the MAPK signalling 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.
Cobimetinib is a potent, highly selective inhibitor of MEK that has shown benefit when administered in combination with the BRAF inhibitor vemurafenib in BRAFV600-mutated metastatic melanoma. Clinically, the combination of MEK inhibition and taxane chemotherapy in non–small cell lung cancer patients has improved response rate and progression-free survival. The COLET study is the first study to evaluate the safety and efficacy of various combinations of cobimetinib as first-line treatment for metastatic or locally advanced triple-negative breast cancer. COLET has 3 cohorts: I, II, and III. Cohort I has 2 stages: an initial safety run-in stage followed by an expansion stage of 1:1 randomization to cobimetinib plus paclitaxel or placebo plus paclitaxel. Cohorts II and III will evaluate the safety and efficacy of adding atezolizumab to cobimetinib plus paclitaxel or nab-paclitaxel, respectively. The safety stage of cohort I is complete and the randomized stage is enrolling patients. At the San Antonio Breast Cancer Conference 2016 data from the safety run-in stage of cohort I were presented.
Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 and cobimetinib (60 mg/day) or placebo on days 3-23 of each 28-day cycle. Gene expression and apoptotic index were measured by RNA-sequencing and TUNEL staining, respectively, to assess the biologic activity of cobimetinib plus paclitaxel. Sixteen women (median age 55.5 years) were enrolled in the safety run-in stage. At the time of analysis all 16 patients had received >1 dose of study treatment. Median time on treatment was 116 days (range 7-336) for cobimetinib and 84 days (range 0-351) for paclitaxel. Fifteen (94%) patients had >1 adverse event; 5 (31%) patients had grade 1/2 adverse events and 10 (63%) patients had grade 3 adverse events. No patients experienced grade 4–5 adverse events. 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 patients with no post-baseline tumor assessment. Six patients maintained a partial response at ~20 weeks and three maintained a partial response at >40 weeks. To date, matched pre- and on-treatment biopsies were evaluable for 2 patients, 1 with a partial response and 1 with stable disease. In the patient who attained a partial response, increased expression of pro-apoptosis genes, including BIM, CASP3, FAS and MDM2, was observed; but this was not seen in the patient experiencing stable disease. The partial response patient also had an increase in apoptotic index.
In summary: COLET is the first study to evaluate cobimetinib plus paclitaxel in patients with advanced or metastatic triple-negative breast cancer. The safety profile of cobimetinib plus paclitaxel is consistent with that of known safety profiles. Efficacy and safety will be further evaluated in the ongoing randomized stage.
Brufsky A, Kim S-B, Velu T, et al. Cobimetinib combined with paclitaxel as a first-line treatment in patients with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results. Poster presentation at the San Antonia Breast Cancer Congress 2016, abstract P4-22-22.