Pembrolizumab with Dabrafenib and Trametinib Manageable in BRAF-Mutant Melanoma

Antoni Ribas, MD, PhD

The phase I KEYNOTE-022 study, which tested pembrolizumab (Keytruda) in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) forBRAF-mutant advanced melanoma, has shown a manageable toxicity profile in patients withBRAFV600-mutant melanoma.

According to data presented at the 2016 ASCO Annual Meeting, an ongoing phase II study will further evaluate safety and efficacy of this triplet combination as a first-line therapy forBRAF-mutant melanoma.

“The approved doses of pembrolizumab in combination with dabrafenib and trametinib administered concurrently provided a manageable toxicity profile in patients withBRAF-mutant melanoma,” said Antoni Ribas, MD, PhD, Professor of Medicine, Professor of Surgery, and Professor of Molecular and Medical Pharmacology at UCLA, and Director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center. “The recommended phase II regimen is pembrolizumab 2 mg/kg every 3 weeks plus dabrafenib 150 mg twice daily plus trametinib 2 mg daily.”

Currently, combination dabrafenib, a BRAF inhibitor, and trametinib, an MEK inhibitor, is the standard treatment forBRAF-mutant melanoma. While combination dabrafenib and trametinib may lead to rapid responses and improved survival, 50% of patients have disease progression by approximately month 12, the study authors reported.

Pembrolizumab, an anti—PD-1 antibody, has shown durable activity and a manageable toxicity profile in approximately 30% to 40% of patients with advanced melanoma.

The KEYNOTE-022 trial assessed the safety and efficacy of the triplet combination of pembrolizumab with dabrafenib and trametinib as a first-line therapy forBRAF-mutant melanoma.

Enrollment was based on characteristics ofBRAFV600E- orBRAFV600K-mutant advanced melanoma, at least 1 measurable lesion, ECOG performance score of 0 to 1, and no prior systemic treatment or treatment with BRAF/MEK inhibitors.

Fifteen patients were enrolled in the phase I arm and received pembrolizumab 2 mg/kg every 3 weeks plus dabrafenib 150 mg twice daily and 2 mg of trametinib once a day.

Dose-limiting toxicities (DLT) were experienced by 3 of 15 patients (20%), including grade 4 neutropenia, grade 4 increased alanine aminotransferase (ALT) levels, and grade 3 increased levels of ALT, aspartate aminotransferase, and gamma-glutamyltransferase. All events resolved after treatment interruption or discontinuation, the study authors noted.

Grade 3/4 treatment-related adverse events (AEs) were experienced by 6 patients (40%) and 4 patients (26.7%) discontinued treatment. There were no treatment-related deaths, Dr. Ribas reported.

Potentially immune-mediated AEs were reported in 6 patients (40%) and included: 2 cases of hyperthyroidism (1 grade 1, 1 grade 2), 2 cases of hypothyroidism (grade 1), 2 cases of uveitis (1 grade 1, 1 grade 2), and 1 case each of autoimmune hepatitis (grade 3), severe skin reactions (grade 3), and pneumonitis (grade 2).

As of the data cutoff date, there were 9 partial responses and 2 patients had stable disease. The objective response rate of 60% was still unconfirmed as of the presentation date.

Median time to response in patients with a confirmed response was 84 days. Of the 13 patients with measurable disease, 12 showed a reduction in tumor size from baseline.

Overall, the approved maximum tolerated dose of pembrolizumab in combination with standard treatment dabrafenib plus trametinib proved to be well tolerated by patients withBRAF-mutant advanced melanoma and will go on to be studied as a first-line therapy for similar patients.

Another arm of the study explored dose limitations of pembrolizumab plus trametinib for patients withBRAFmutation-negative advanced melanoma, although findings have not yet been revealed for this group.

Ribas A, Hodi FS, Lawrence DP, et al. Pembrolizumab (pembro) in combination with dabrafenib (D) and trametinib (T) for BRAF-mutant advanced melanoma: Phase 1 KEYNOTE-022 study.J Clin Oncol.2016; 34 (suppl; abstr 3014).