Patrick Hwu, MD
Two new treatments for metastatic melanoma were approved in 2011—the first in more than a decade. Ipilimumab (Yervoy, Bristol-Myers Squibb), an immunotherapy, showed overall survival improvement, leading the FDA to approve the therapy for both treatment-naïve and previously treated patients in March of that year. Five months later, vemurafenib (Zelboraf, Genentech), a targeted BRAF inhibitor, was approved for use in metastatic melanoma tumors that have the BRAFV600E
mutation—about 40% of all patients with meatstatic melanoma. Even before the formal approval of the BRAF inhibitor, the two companies that manufacture ipilimumab and vemurafenib, Bristol-Myers Squibb and Genentech, respectively, entered into a collaboration to formally test the safety and efficacy of the combination therapy in patients with the BRAF
mutation. The phase I/II, 50-person, dose-escalation trial formally started in November 2011.
At the 2012 American Association of Cancer Research annual meeting held at the end of March, melanoma researchers from the MD Anderson Cancer Center in Houston, Texas, presented formal evidence supporting the combination trial.1
Patrick Hwu, MD, head of MD Anderson’s Department of Melanoma Medical Oncology, presented data showing that adding a BRAF inhibitor to immunotherapy can reverse the immunosuppressive tumor microenvironment induced by the BRAF
Additionally, the researchers found that a BRAF inhibitor increased the immune response to a tumor in a mouse tumor model. The study provided evidence that the BRAF inhibitor targeted therapy does not prohibit the immune function of patients with metastatic melanoma. This is an important result, as evidence exists that kinase-targeted treatments can have detrimental off-target effects on the cells of the immune system. Vemurafenib may not because of its specificity and minimal off-target effects, according to Gregory Lizée, PhD, of the same department, who was also a part of the study. Both human data and mouse models led to the conclusion that the combination of a BRAF inhibitor with immunotherapy may act in a synergistic way.
Another recent study addresses mechanisms of resistance to BRAF inhibitor treatment in patients with metastatic melanoma.2
Roger Lo, MD, PhD, and colleagues at the Johnsson Comprehensive Cancer Center at the University of California in Los Angeles have discovered how tumor cells are able to stop responding to treatment with vemurafenib. The team sequenced the protein-coding parts of the genome of tumors from patients treated with the drug. “Patient biopsy-oriented translational research is absolutely key to overcoming targeted drug resistance,” Lo stressed.
The research team found the tumors to have higher copy numbers of the BRAF
gene, meaning the tumor is producing extra BRAF protein, rendering inhibition by the drug ineffective. About 20% of patients (a total of 20 were sampled) who developed resistance had this amplification of the BRAF
gene. Using cell lines, the researchers also found that the combination of a BRAF and MEK inhibitor could overcome the amplification-driven resistance. This combination treatment is currently in a phase I/II clinical trial for advanced melanoma.
“[In an earlier study], we initially found no evidence of secondary mutations in the BRAF
gene,” said Lo.3
“This shifted the pharmaceutical community away from further drug development for alternative BRAF inhibitors that might circumvent mutated BRAFV600
harboring secondary mutations. The surprise is we have recently come full circle to find that alterations in BRAF
—beyond the mutation that activates this oncogene—are important.” These BRAF
mutations include truncations in the gene4
and the newly described BRAF
Researchers have discovered resistance mechanisms that account for somewhere between 60% and 70% of resistance cases; the other relapsed patients develop resistance by as yet unknown means. The next steps for Lo and his team will be to study each individual patient and find out what happens during relapse at the molecular level. This research will facilitate next-generation clinical trials and new therapies that can be combined for a more robust response. It could also result in ways to avoid needing to overcome resistance. “The goal is to understand all possible mechanisms and deduce the common denominator molecules that can be targeted, together with mutant BRAF, in combinatorial approaches,” Lo said. Already, the combination of a BRAF inhibitor with a MEK inhibitor is expected to be a “powerful two-hit,” increasing efficacy and reducing side effects, Lo said.
1. Hong DS, Vence L, Falchook G, et al. BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency. Clin Cancer Res. 2012;18:2326-2335.
2. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.
3. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;16;468(7326):973-977.
4. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387-390.