UCLA Study Demonstrates Keytruda-Based Triple Combination Therapy Significantly Inhibits Progression in Advanced BRAF-Mutant Melanoma

Researchers from the University of California, Los Angeles (UCLA) have identified a combination therapy for advanced melanoma—combining checkpoint inhibitors with two targeted therapies—to extend patient survival.

Figure: Melanoma

Researchers combined Merck’s Keytruda with dabrafenib and trametinib (two BRAF inhibitors) as a first-line treatment for the disease. UCLA reported that this combination therapy is expected to provide progression-free survival in patients with melanoma harboring the potent BRAF V600E gene mutation. In addition to its efficacy, the triple-drug regimen did not cause any debilitating side effects. The research team published the results of their Phase I and II trials in Nature Medicine.

In the Phase I trial, researchers evaluated the safety of combination therapy in 15 patients with BRAF-mutant metastatic melanoma. Tumor shrinkage and disease stability were observed in 11 patients, with no further growth over a period of 12 to 27 months. Data from the Phase II trial, which enrolled 120 patients, showed that those receiving the triple-drug regimen had a median progression-free survival (PFS) of 16 months. In comparison, the control group received a different triple combination consisting of dabrafenib, trametinib, and placebo, and had a median PFS of 10.3 months. This was a 1:1 randomized study.

In the United States, approximately half of the 94,000 individuals diagnosed with melanoma each year harbor BRAF mutations. Approximately 7,000 people die from this cancer annually.

Antoni Ribas, senior author of the study and director of the Tumor Immunology Program at the UCLA Jonsson Comprehensive Cancer Center, stated that this combination therapy “sensitizes patients’ own immune systems, enhancing the efficacy of immunotherapy by inhibiting the growth driven by the BRAF and MEK genes, which cause cancer cells to proliferate uncontrollably.”

A UCLA report indicates that prior studies on this type of melanoma showed that one of the three drugs tested in these trials had a positive effect on tumor shrinkage, and dual-drug combination therapy also achieved certain positive efficacy. However, most patients receiving monotherapy experienced disease recurrence.

Previous attempts by the research team to combine one of these drugs with the checkpoint inhibitor Keytruda were unsuccessful due to the emergence of dangerous toxic side effects. In February this year, Keytruda was approved for adjuvant treatment of patients with melanoma and lymph node metastasis.

Ribas stated that combining two targeted inhibitors (rather than just one) with checkpoint inhibitors can safely and effectively treat cancer. This triple-combination therapy can halt cancer spread and stimulate the immune system. The immune response has the ability to remember foreign invaders and helps protect the body from similar future infections; mounting an immune response against cancer aims to produce a more durable therapeutic effect.

This UCLA study was conducted jointly by Merck Sharp & Dohme, the Parker Institute for Cancer Immunotherapy, and the U.S. National Institutes of Health. Currently, UCLA has not reported whether data from this trial will advance to Phase III research.

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UCLA Study Shows Keytruda Combination Therapy Limits Progress of Advanced Melanoma