Although targeted agents have been approved for the treatment of metastatic melanoma, such agents typically are not used in patients with earlier-stage, resectable disease who have a high risk for recurrence. But a clinical trial of targeted therapy before and after surgery aims to prolong recurrence-free survival for patients with resectable high-risk melanoma.
For patients who have high-risk stage III melanoma—disease that has spread to the lymph nodes—the standard of care is surgery followed by observation or adjuvant treatment with high-dose interferon. While interferon is the standard adjuvant therapy for this group, many physicians believe the drug’s side effects outweigh its modest benefit. “Interferon’s numerous side effects make this drug difficult to tolerate, and data suggest only a small degree of reduction in the risk of disease recurrence,” said Rodabe Amaria, M.D., an assistant professor in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center.
The need for more effective treatments for patients with high-risk stage III disease is critical, according to Jennifer Wargo, M.D., an assistant professor in the Departments of Surgical Oncology and Genomic Medicine. “Up to 70% of patients with high-risk resectable melanoma ultimately die of their disease,” she said. Drs. Wargo and Amaria think that patients with high-risk resectable disease may benefit from some of the new targeted drugs used to treat metastatic disease.
BRAF and MEK inhibitors for metastatic melanoma
Among the recent advances in melanoma treatment has been a class of drugs called BRAF inhibitors.
BRAF gene mutations occur in about half of cutaneous melanomas. The mutated BRAF protein activates MEK and other kinases along the MAP signaling pathway, stimulating cancer cell growth and proliferation. Blocking BRAF’s activity shuts down the MAP pathway, but only temporarily. “The BRAF inhibitors work well for about 6 months, but then in some patients we see reactivation of the MAP kinase pathway,” Dr. Wargo said. “So we add a MEK inhibitor to block the pathway at a different point, and that extends median progression-free survival to about 10 months in patients with metastatic melanoma.”
The oral BRAF inhibitor dabrafenib and the oral MEK inhibitor trametinib were approved separately by the U.S. Food and Drug Administration in 2013 for the treatment of patients with BRAF-mutant metastatic melanoma. The combination of the two drugs was approved in 2014 for the same indication.
Clinical trial for high-risk resectable melanoma
“Because of the success we’ve seen with dabrafenib and trametinib in patients whose melanoma has spread throughout their bodies, we’ve opened a clinical trial to extend this therapy to patients with earlier-stage disease,” said Dr. Wargo, the principal investigator of a clinical trial in which patients with high-risk melanoma receive dabrafenib and trametinib before and after cancer surgery.
The study is currently enrolling patients with stage IIIB, stage IIIC, or resectable oligometastatic (stage IV, spread to three or fewer areas) melanoma with BRAF mutations. Patients are randomly assigned to receive surgery without adjuvant therapy (the current standard of care) or surgery preceded by 8 weeks of dabrafenib and trametinib and followed by 44 weeks of the drug combination.
Thus far, the drug combination has been well tolerated by patients in the trial, although the side effects can include fever and chills, fatigue, and joint pain. Although results of the trial are not yet available, Dr. Wargo is optimistic that the drugs will decrease patients’ recurrence risk. “I’ve seen patients who were treated with this drug combination before surgery whose tumors went away entirely—a pathological complete response,” she said.
Drs. Amaria and Wargo are hopeful that neoadjuvant therapy will prove as effective against melanoma as it has against other cancers. In addition to killing micrometastases that could lead to recurrence, preoperative therapy with dabrafenib and trametinib may make local and regional disease more amenable to surgery. Neoadjuvant therapy might downstage tumors, making less extensive surgery possible in some patients or enabling negative surgical margins to be achieved.
Dr. Amaria said, “We as a community of oncologists need to think differently about how we treat patients with high-risk melanoma. If this regimen improves survival outcomes as we predict it will, I think this trial could lead to a paradigm shift in the treatment of this patient population.”
For more information, contact Dr. Rodabe Amaria at 713-792-2921 or Dr. Jennifer Wargo at 713-745-1553. To learn more about the clinical trial of BRAF and MEK inhibitors for the treatment of high-risk melanoma, visit www.clinicaltrials.org and select study No. 2014-0409 or contact Dr. Jennifer Wargo at email@example.com.
OncoLog, April 2015, Volume 60, Issue 4