MEK Inhibitor/Taxane Combination Active in Triple-Negative Breast Cancer

Adam M. Brufsky, MD, PhD

A small clinical trial demonstrated encouraging clinical activity in triple-negative breast cancer (TNBC) treated with a MEK inhibitor and a taxane.

The combination of cobimetinib (Cotellic) and paclitaxel led to confirmed partial responses in 6 of 16 patients and 2 additional unconfirmed partial responses. Five of the 6 confirmed responses proved to be durable, persisting for about 20 weeks.

“This is the first study to evaluate the combination of cobimetinib and paclitaxel in triple-negative breast cancer,” Adam M. Brufsky, MD, PhD, associate chief of hematology oncology, and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh Medical Center, and colleagues concluded in a presentation at the 2016 San Antonio Breast Cancer Symposium. “The safety profile of combined cobimetinib and paclitaxel is manageable and consistent with the known safety profiles for each drug.

“Preliminary results suggest a trend for enrichment of antitumor responses in tumors of the basal subtype. The initial tumor biopsy data are consistent with a pro-apoptotic effect in tumors responsive to cobimetinib combined with paclitaxel.”

Chemotherapy continues to form the basis of treatment for TNBC. Many patients initially respond to a taxane, but most eventually develop resistance.

Preclinical models suggested that upregulation of the mitogen-activated protein kinase (MAPK) pathway induces taxane resistance, Brufsky and colleagues noted. Some TNBC tumors have genetic alterations affecting the MAPK pathway, and studies showed that adding a MEK inhibitor to a taxane increase breast cancer cells’ sensitivity to taxane therapy.

The collective data suggested that the addition of a MEK inhibitor to a taxane might offer an effective treatment option for TNBC. Toward that end, investigators evaluated the combination of cobimetinib and paclitaxel in patients with previously untreated metastatic or locally advanced TNBC. The phase I study was part of a broader evaluation of cobimetinib-containing combination therapies, including combinations with a PD-L1 inhibitor.

Brufsky and colleagues reported findings from a safety run-in evaluation of cobimetinib and paclitaxel. A 90-patient randomized comparison of the combination and paclitaxel plus placebo has been planned.

The run-in phase evaluated safety, tolerability, progression-free survival, overall survival, and potential biomarkers of response and resistance.

The 16 patients had a median age of 55.5, and all 16 had metastatic disease, 14 had a ductal histology. All but 3 of the patients had received prior treatment for nonmetastatic TNBC, and 8 had prior exposure to a taxane.

The most common adverse events (AEs; any grade) were diarrhea (n = 10), rash (n = 8), nausea (n = 7), creatinine phosphokinase (CPK) elevation (n = 5), and alopecia (n = 5). Four patients each developed stomatitis, asthenia, constipation, dyspnea, peripheral edema, pyrexia, and vomiting. Grade 3 AEs consisted of 2 cases of stomatitis and 1 each of diarrhea, elevated CPK, and asthenia.

Six patients had a total of 8 serious AEs. The serious events consisted of 2 episodes of pyrexia, and 1 each of asthenia, brain edema, presyncope, mitral valve incompetence, erysipelas, and orthostatic hypotension.

A comparison of responses with patient, tumor intrinsic molecular subtype, and genomic alterations showed that 5 of the 6 confirmed responses occurred in patients with basal tumors.PIK3CAaberrations were identified in association with 4 tumor responses and 1 patient with stable disease andTP53mutations were associated with 3 responsive tumors.

Analysis of pre- and post-treatment tumor biopsies provided evidence of pro-apoptotic gene expression, including BIM, CASP3, FAS, and MDM2. One patient with a basal subtype tumor that achieved a partial response also exhibited increased TUNEL staining, also indicative of pro-apoptotic activity.

Evaluation of the cobimetinib-paclitaxel combination’s safety, efficacy, and biomarkers will continue in an ongoing randomized trial (versus paclitaxel-placebo) in 90 patients with TNBC.

Reference:

Brufsky A, Kim S-B, Velu T, et al. Combimetinib (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. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P4-22-22.