Dual BRAF, MEK Inhibition Provided Benefit in BRAF-Mutated mCRC

Blocking the MAPK pathway through dual treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib resulted in meaningful clinical activity in a subset of patients with BRAF V600-mutated metastatic colorectal cancer (mCRC), according to the results of a trial published recently in the Journal of Clinical Oncology.

“This heavily pretreated population of patients with a poor prognosis mutational subtype of mCRC achieved several partial responses and a durable complete response ongoing for 3 years,” wrote researcher Ryan B. Corcoran, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, and colleagues. “We believe this study represents an important therapeutic step forward for patients with BRAF-mutant mCRC.”

Previous research has shown that the use of vemurafenib or dabrafenib significantly delays progression and prolongs survival in patients with BRAF-mutated metastatic melanoma. Similarly, the MEK inhibitor trametinib improved survival compared with conventional chemotherapy in these patients.

In contrast, BRAF-mutated mCRC has not shown similar responses to BRAF or MEK inhibitors, possibly due to “feedback signals that reactivate MAPK signaling.”

In this study, the researchers included 43 patients with BRAF V600-mutated mCRC and treated them with dabrafenib 150 mg twice daily and trametinib 2 mg daily.

Five patients (12%) achieved a partial response or better to this combination therapy, and one patient achieved a complete response that lasted longer than 3 years. The patient who achieved the complete response was the only patient in the study that had not had prior systemic therapy. More than half of the patient cohort (56%) achieved stable disease.

The median progression-free survival was 3.5 months. Ten patients stayed on study treatment for longer than 6 months.

Seventeen patients in the study were also enrolled in a pharmacodynamic cohort undergoing mandatory biopsies before and after treatment. Nine of these patients had day-15 biopsies that were evaluable. The researchers found that all nine patients had reduced levels of phosphorylated ERK compared with levels from the pretreatment biopsies.

“Our pharmacodynamic analyses of paired pretreatment and during-treatment biopsies showed that although the combination of inhibitors suppressed MAPK signaling, the degree of inhibition was significantly less than what has been achieved in BRAF-mutant melanoma with dabrafenib alone,” the researchers wrote. “This finding is critical, because studies have suggested that robust MAPK pathway suppression is required for response in BRAF-mutant cancers.”

Mutational analysis showed that the one patient with complete response and two of three evaluable patients with partial response had PIK3CA mutations. Additionally, all but one patient with a PIK3CA mutation achieved a reduction in target lesion size.

No correlation between progression-free survival and PTEN status was found.

In their discussion of the results, the researchers suggest that since they were not able to achieve optimal MAPK pathway inhibition with this dual blockade regimen, “feedback reactivation of MAPK signaling may be limiting the effectiveness of the regimen.” Therefore, “additional studies evaluating therapeutic strategies designed to more effectively target the MAPK signaling pathway in BRAF-mutant CRC are in progress.”