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Two-Drug Combination Approved for Lung Cancers with BRAF Mutations

, by NCI Staff

Credit: National Human Genome Research Institute

On June 22, the Food and Drug Administration (FDA) approved the combination of dabrafenib (Tafinlar®) and trametinib (Mekinist®) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that has an alteration in the BRAF gene called the V600E mutation.

The approval is the first specifically for patients with this type of lung cancer, known as BRAF V600E mutation-positive metastatic NSCLC. About 1-2% of lung tumors harbor the V600E mutation, which increases growth-promoting signals through the MAPK signaling pathway.

FDA also approved the Oncomine™ Dx Target Test to determine the presence of the BRAF V600E mutation in patient samples. The test screens tumor samples for multiple biomarkers associated with potential responses to targeted therapies directed against these changes. These biomarkers include alterations in the BRAF, ALK, ROS1, and EGFR genes.

“When we characterize lung tumors from patients, it’s a good idea to test the samples for all the changes that could be targeted by different drugs,” noted Bruce E. Johnson, M.D., of the Dana-Farber Cancer Institute, who co-led the clinical trials that were the basis for FDA’s approval of the combination therapy.

Dabrafenib and trametinib block different growth-promoting signals in the MAPK pathway that are activated by the V600E BRAF mutation. Dabrafenib inhibits the BRAF protein, whereas trametinib is a MEK inhibitor.

Melanoma Results Lead to Lung Cancer Trials

In 2014, FDA approved the combination of these drugs for patients with BRAF V600 mutation–positive melanomas based on studies showing that the combination improved survival compared with dabrafenib alone. The studies were sponsored by GlaxoSmithKline, which was then the manufacturer of both drugs. (These agents are now owned by Novartis.)

The results in melanoma prompted Dr. Johnson and his colleagues to develop trials to evaluate dabrafenib alone and in combination with trametinib for patients with BRAF V600E mutation-positive lung cancer.

In the dabrafenib-alone trial, which included 78 patients, the overall response rate was 33%. The median progression-free survival was 5.5 months and median overall survival was 12.7 months.     

The combination therapy trial included 59 patients. In this study, the overall response rate was 63%, and the median progression-free survival was 9.7 months. The median overall survival has not yet been reached, but 82% of the patients were alive at 6 months.

The side effects reported by patients receiving the combination therapy were similar in incidence and severity to those reported previously in patients with melanoma. The most common adverse reactions included fever, fatigue, nausea, vomiting, and diarrhea.

Serious adverse drug reactions occurring in patients receiving the combination therapy included lower-than-normal amounts of sodium in the blood, drops in white blood cell counts, anemia, and hyperglycemia. Because of such reactions, dabrafenib was stopped in 18% of the patients in the trial and trametinib was discontinued in 19% of patients.

Rare Subtypes of Lung Cancer

To recruit the 59 participants in the combination trial, the researchers screened about 6,000 patients with lung cancer. This represents a “major achievement that underlies the difficulties in completing such a trial,” noted the authors of an editorial accompanying the study.

“Diagnosis and treatment of rare lung cancer subtypes requires a coordinated approach to tissue collection and comprehensive molecular diagnosis,” wrote Gareth Rivalland, M.D., and Paul Mitchell, M.D., of the University of Melbourne, Australia.

The introduction of genetic tests that can assess multiple biomarkers simultaneously has made it more efficient and cost effective to identify patients with rare subtypes of cancer who might be candidates for certain treatments, Dr. Johnson noted.

“This work is an example of precision medicine, and we believe this story will continue to unfold in the years ahead,” he said. By characterizing the genetic changes in a patient’s tumor, doctors can select a treatment that targets these changes, if one exists.

The challenge, Dr. Johnson added, “is to identify the genetic changes that are critical for turning normal cells into cancer cells and then to develop treatments that effectively target these changes.”

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