Antoni Ribas, MD, PhD
The past decade of drug discovery has brought a dramatic expansion in the number of new therapies to treat patients with advanced or metastatic melanoma in 2 modalities: checkpoint blockade immunotherapies and molecularly targeted drugs. In both areas, these therapeutic categories have grown from single-agent regimens into combination strategies.
Now, investigators are seeking to determine whether triplet regimens that combine an immunotherapy that targets the PD-1/PD-L1 pathway with small molecules that inhibit BRAF and MEK signaling would be more effective than single- or dual-agent approaches.
The rationale for the multipronged strategy has been building for several years, according to Antoni Ribas, MD, PhD, a leading melanoma investigator who discussed clinical trial findings at recent conferences. Ribas, a 2015 Giants of Cancer Care®
award winner, is a professor of medicine, surgery, and molecular and medical pharmacology at the University of California, Los Angeles.
Overall, approximately 65% of melanomas harbor mutations that activate signaling in the RAS/RAF/ MEK/ERK pathway, Ribas has observed.1 These mutations cause aberrations within the melanoma cell that in turn spark interactions with T lymphocytes whose activity is controlled by immune checkpoints such as PD-1 (FIGURE).1
Figure. Merging Strategies in Melanoma Therapy1
The triplet strategies combine a monoclonal antibody targeting either PD-1 or PD-L1 with drugs that inhibit BRAF and MEK kinases, which are key components of the protein signaling pathway within the melanoma cell.
The safety and efficacy of such combinations have been explored in phase I studies, Ribas noted during a presentation at the Ninth World Congress of Melanoma, held in Brisbane, Australia, in October 2017. The regimens proved to be safe, and most patients had either stable disease or a response, a level of efficacy that Ribas called “surprising.” In these studies, very few patients did not demonstrate some level of clinical benefit, he said. These early results led to several ongoing later-stage studies, which are now enrolling participants, representing a potential new standard of care on the horizon (TABLE).
Table. Selected Melanoma Trials Exploring 3-Drug Combinations
“Three phase I trials attest to the overall safety of combined full-dose therapy with a BRAF and a MEK inhibitor with anti–PD-1/PD-L1 and provide early encouraging evidence of combined efficacy,” Ribas said. “There are toxicities, but they are usually responsive to stopping the targeted therapies for a little bit of time and then restarting.”
In preclinical models, the triplet combination of dabrafenib (Tafinlar), trametinib (Mekinist), and pembrolizumab (Keytruda) demonstrated superior antitumor activity in mouse models of BRAF
Dabrafenib is a BRAF inhibitor, trametinib is a MEK inhibitor, and pembrolizumab targets PD-1.
Mechanistically, treatment with BRAF plus MEK inhibition was found to increase T-cell accumulation at the site of the tumor. “The triple therapy, but also the doublet of the BRAF and MEK inhibitor, had the highest accumulation and expansion of the T-cell intratumor,” Ribas noted.
In RNA sequencing data, the BRAF/MEK combination was found to increase CD8, interferon gamma, granzyme B, and the PD-1:PD-L1 ratio, resulting in a more immunogenic microenvironment. Additionally, BRAF inhibition was found to increase PD-L1 expression.
“Those who received the doublet of dabrafenib and trametinib had increased immune signaling in the tumor,” Ribas said. “Another thing that was important was an upregulation of PD-L1 with dabrafenib inside of the tumor and not in the spleen. It was localized to where the targeted therapy has activity.”