“Melanoma really had very little to offer for treatment until 2011,” stated Igor Puzanov, MD, MSCI, FACP, director of Melanoma Clinical Research for Vanderbilt University Medical Center.
Chemotherapy and surgery had been treatment mainstays. However, in 2002, researchers discovered BRAF genetic mutation in some of the melanoma tumors. It’s now known that about half of melanomas have a BRAF mutation, which causes abnormal signaling inside the cancer cell and leads to tumor growth.
“In 2011, BRAF-targeted drugs started coming through the pipeline,” Puzanov continued. During 2011 the FDA approved Zelboraf® (vemurafenib), a drug specifically targeting the BRAF mutation, and Yervoy (ipilimumab), an immunotherapy targeting CTLA4 receptor on T cells. Puzanov noted both types of treatment – immunotherapy and targeted treatments – have blossomed since then. Today, there are more than a dozen drugs and drug combinations approved for the treatment of melanoma.
Late last year, Genentech, a member of the Roche Group, announced two of their drugs – Zelboraf® (vemurafenib) and Cotellic™ (cobimetinib) – had gained FDA approval for use in combination for those with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Cotellic (cobimetinib), which is designed to inhibit the protein MEK (another cell signaling pathway), was the seventh Genentech drug approved in the last five years.
The regulatory approval came on the heels of the Phase III coBRIM study, which showed improvement in progression-free survival and overall survival with the combo drug regimen compared to vemurafenib alone. The international, randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of 60 mg once daily of cobimetinib plus 960 mg twice daily of vemurafenib compared to 960 mg twice daily of vemurafenib plus placebo.
Puzanov, who is also an associate professor of Medicine and associate director of Phase I Drug Development for Vanderbilt, served as principal investigator of coBRIM at Vanderbilt-Ingram Cancer Center.
“We were able to show the combination of Cotellic and Zelboraf was more potent,” he said, adding the combination therapy “improved the median progression-free survival from 7.2 months to 12.3 months.”
Puzanov continued, “It also improves overall survival – 22.3 months vs. 17.4 months, and two-year overall survival is 48 percent with the combination compared to 38 percent on Zelboraf alone.”
He pointed out these are median numbers so statistically half of those taking the combination treatment will do even better. “It’s a win for the patients because it is improving melanoma care,” Puzanov said, adding the side effects were shown to be relatively low.
While excited about the new option, Puzanov noted there is still a great deal of work to be done when it comes to treating melanoma. “We need to work on additional combinations after progression,” he said, “and we still don’t know how to combine the targeted therapy with the immunotherapy.”
Puzanov concluded, “Nobody has a Holy Grail, but places like Vanderbilt can do a lot of translational science. For patients, it’s better than it was … but there is still no cure.”
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