Combining BRAF Inhibitor And Immunotherapy Increases Antitumor Activity In Metastatic Melanoma

BRAF Inhibitor Zelboraf Boosts Effectiveness of Immunotherapy in Mouse Model

Combining the recently approved BRAF inhibitor, Zelboraf with an engineered T cell immunotherapy to treat metastatic melanoma significantly increased tumor responses and survival in an animal model, researchers at UCLA's Jonsson Comprehensive Cancer Center have shown.

The animals in the study that received the combination therapy had better tumor responses and lived more than twice as long as those getting the BRAF inhibitor or immunotherapy alone. The findings provide strong support for testing the combination therapy in human clinical trials, which Jonsson Cancer Center researchers hope to launch within two years.

About 50 percent of patients with metastatic melanoma, or 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf. More than 50 percent of those respond well to the drug, but the responses usually last only a few months. With immunotherapy, fewer patients respond, but the responses are more durable.

By pairing the combination therapy in a one-two punch, researchers hope to maintain the high response rates associated with Zelboraf and combine them with the longer disease-free progression times seen with immunotherapy, said study first author Dr. Richard Koya, a Jonsson Cancer Center scientist and an assistant professor of surgical oncology.

"The idea was to target two different aspects of anti-cancer biology, hitting the tumor cells themselves with the BRAF inhibitor and adding in T cells educated to induce a specific anti-tumor immune response," Koya said. "The results we saw in this study were very promising."

The findings of the two-year study appear Aug. 15, 2012 in the peer-reviewed journal Cancer Research.

The researchers also found that the BRAF inhibitor helped boost the power of the immunotherapy, creating a greater combination effect, said study senior author Dr. Antoni Ribas, a Jonsson Cancer Center scientist and a professor of hematology/oncology.

"We found that both treatments were more effective when administered together, and we were surprised to see that a drug that should only be targeting the BRAF-mutant cancer cells was also having a beneficial effect on the T cells," Ribas said.

In the immunotherapy technique, called adoptive T cell transfer or ACT, lymphocytes are genetically engineered to express a receptor that recognizes melanoma cells, creating an army of immune cells that attack the cancer. The lymphocytes are modified genetically to become specific to the melanoma cells and are injected into the body.

The study was done using a model based on unique cell lines developed at UCLA. Previously, no implantable BRAF mutation-driven melanoma model able to grow progressively in a mouse with a fully competent immune system was available.

It is vital to develop new drugs to treat metastatic melanoma as few options are available for patients. Zelboraf works well, but most patients eventually relapse.

"This is a patient population that we are not able to cure," Koya said. "With what we have now we are just prolonging their lives. We need to have more options, and we hope this combination therapy proves to be an effective alternative."

About 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease.

"In conclusion, combined therapy with the BRAF-specific inhibitor Zelboraf and T cell receptor engineered adoptive cell transfer resulted in superior anti-tumor effects," the study states. "Although the absolute number of T cells infiltrating the tumor was not increased by Zelboraf, the combination increased the functionality of antigen-specific T lymphocytes. Therefore, our studies support the clinical testing of combinations of BRAF targeted therapy and immunotherapy for patients with advanced melanoma."

The study was funded by the National Cancer Institute at the National Institutes of Health (P50 CA086306 and P01 CA 132681), Seaver Institute, Louise Belley and Richard Schnarr Fund, Wesley Coyle Memorial Fund, Garcia-Corsini Family Fund, Fred L. Hartley Family Foundation, Ruby Family Foundation, Jonsson Cancer Center Foundation, Caltech-UCLA Joint Center for Translational Medicine, UCLA Tumor Biology Program, U.S. Department of Health and Human Services, Ruth L. Kirschstein Institutional National Research Service Award, Eugene V. Cota-Robles Fellowship and National Science Foundation Competitive Edge Fellowship.

View drug information on Zelboraf.

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Uncommon BRAF Mutation In Melanoma Sensitive To MEK Inhibitor Drug Therapy

An uncommon mutation of the BRAF gene in melanoma patients has been found to respond to MEK inhibitor drugs, providing a rationale for routine screening and therapy in melanoma patients who harbor the BRAF L597 mutation.

The new study by co-first-authors Kimberly Brown Dahlman, Ph.D., Junfeng Xia, Ph.D., and Katherine Hutchinson, B.S., Vanderbilt-Ingram Cancer Center (VICC), Nashville, Tenn., was published online in Cancer Discovery. The research was led by co-senior authors William Pao, M.D., Ph.D., Jeffrey Sosman, M.D., and Zhongming Zhao, Ph.D., VICC, and Antoni Ribas, M.D., Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, Calif.

Mutations in BRAF V600E or KIT are common in about 40 percent to 50 percent of melanomas, and drugs that block or inhibit BRAF V600E were recently approved for treatment of melanoma patients with these mutations. However, there has been no effective treatment for patients with wildtype (WT) melanoma that is negative for these driver mutations.

To uncover other potentially targetable mutations, the investigators studied the tumor from a 75-year-old patient with an aggressive form of melanoma which was negative for the BRAF V600E mutation. They performed whole genome sequencing on the tumor, along with DNA from matched blood, and confirmed a mutation at BRAF L597.

To determine how many similar mutations might be overlooked by assessing only the BRAF V600 position, they analyzed the mutational status of 49 additional tumor samples negative for V600, as well as recurrent mutations in NRAS and KIT. Two of the tumors (4 percent) were found to have BRAF L597 mutations and a third tumor harbored a BRAF K601E mutation.

BRAF L597 and K601 are adjacent to V600. Since V600 mutants are sensitive to both BRAF and MEK inhibitor drugs, the investigators tested whether the BRAF inhibitor drug vemurafenib and a MEK inhibitor drug could inhibit cell proliferation signals induced by these mutants in cell lines. The MEK inhibitor led to a dramatic shut down of signaling, suggesting that tumors harboring BRAF L597 and K601 mutations might benefit from treatment with MEK inhibitors.

Confirming this hypothesis, a 69-year-old patient with metastatic melanoma harboring a BRAF L597S mutation experienced significant disease shrinkage after two cycles on therapy with a MEK inhibitor drug called TAK-733, currently in Phase I clinical trials. The patient was disease progression-free after more than 24 weeks.

The authors believe these data demonstrate that BRAF L597 mutations have clinical significance in melanoma. Further study is needed to confirm these findings.

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