FDA Approves Dabrafenib/Trametinib Combo for BRAF+ Thyroid Cancer

Richard Pazdur, MD

The FDA has approved combination therapy with the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) for the treatment of patients with unresectable or metastatic BRAF V600E—positive anaplastic thyroid cancer.

The approval is based on an open-label trial that accrued patients with rare cancers harboring a BRAF V600E mutation. Among 23 patients evaluable for efficacy, 57% achieved a partial response and 4% reached a complete response. Among the 14 responders, 64% (n = 9) had no significant tumor growth for at least 6 months.

“This is the first FDA-approved treatment for patients with this aggressive form of thyroid cancer, and the third cancer with this specific gene mutation that this drug combination has been approved to treat,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients,” added Pazdur.

In the approval notice, the FDA reported that adverse events (AEs) with the combination were similar to those observed in patients with other tumor types who received dabrafenib plus trametinib. The most frequently reported AEs included pyrexia, rash, chills, headache, arthralgia, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, hypertension, and dyspnea.

In results previously published in the Journal of Clinical Oncology, nearly 7 in 10 patients with locally advanced or metastatic BRAF V600E—mutated anaplastic thyroid cancer (ATC) responded to treatment with the combination of dabrafenib and trametinib.

This phase II, open-label trial was designed to allow the simultaneous evaluation of efficacy and safety in responses to dabrafenib and trametinib combination therapy in patients with BRAF V600E—mutated cancer in prespecified histologies. A total of 100 patients with BRAF V600E—mutated rare malignancies enrolled between March 2014 and August 2016 and were treated with dabrafenib at 150 mg twice daily plus trametinib at 2 mg once-daily.

These results represent an analysis of 16 patients with ATC. The median patient age was 72 years, 63% were female, and 63% were of Asian heritage. Prior treatments included surgery (88%), external beam radiotherapy (81%), and chemotherapy (38%).

The primary endpoint was investigator-assessed ORR. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety.

As of August 26, 2016, median duration of follow-up for the ATC cohort was 47 weeks. Half of patients remained on study treatment and 2 patients died of disease progression within 30 days of the last study treatment.

Investigators collected representative CT scans of primary and metastatic lesions at baseline and after 8 weeks of treatment. In the population of patients with centrally confirmed BRAF V600E (n = 15), the investigator-assessed ORR was 73%. Independent radiologic review showed an ORR of 63% in the intent-to- treat population and 67% in the BRAF V600E centrally confirmed population.

Median duration of response, PFS, and OS were not reached as a result of ongoing responses that resulted in insufficient progression and death events at the time of the data cutoff. The 12-month Kaplan-Meier estimate for duration of response was 90%, 79% for PFS, and 80% for OS.

Median duration of exposure was 10 months for dabrafenib and 9 months for trametinib.

Across all 100 patients in the study, 93% experienced any adverse event (AE) and 42% experienced a grade 3/4 event. Thirty patients experienced AEs leading to dose reduction, 38 had dose interruption/delay, and 8 discontinued treatment.

Investigators said the overall safety profile of dabrafenib and trametinib across all histologic cohorts was similar to previous reports in advanced or metastatic melanoma and non—small cell lung cancer. The safety profile in the ATC cohort was similar to that of all treated patients, although the small size of this cohort limited conclusions.

The most common AEs of any grade in the ATC cohort were fatigue (44%), pyrexia (31%), and nausea (31%). The most common grade 3/4 AE was anemia (13%). Three patients with ATC experienced treatment-related serious AEs.

ATCs make up 1% to 2% of all thyroid cancers in the United States and up to 10% of thyroid cancers worldwide. This disease is highly aggressive—patients diagnosed with ATCs have a median survival of 5 to 12 months and a 1-year OS rate of 20% to 40%.

The dabrafenib/trametinib combination also has approved indications in melanoma and lung cancer.

Subbiah V, Kreitman RJ, Wainberg AZ, et al. Dabrafenib and Trametinib treatment in patients with locally advanced or metastatic BRAF V600—mutant anaplastic thyroid cancer. J Clin Oncol [published online ahead of print October 26, 2017] doi: 10.1200/JCO.2017.73.6785.

The confirmed overall response rate (ORR) was 69% (11 of 16; 95% CI, 41-89). One patient had a complete response and 10 had partial responses. Seven patients had ongoing responses at the time of the analysis.