NEW YORK – The genotyping era of melanoma management is poised to launch.

The era will start with genetic assessment of every patient with advanced-stage melanoma becoming the standard of care, as soon as the Food and Drug Administration approves marketing of vemurafenib, the small-molecule inhibitor of a mutated form of the BRAF gene. Reuters reports that approval is imminent, based on strikingly good results from a phase III study presented in June at the annual meeting of the American Society of Clinical Oncology, and published in the New England Journal of Medicine (2011;364:2507-16).

"If and when [vemurafenib] is approved by the FDA, we will need some sort of commercially available test to assess patients [with unresectable stage IIIC or stage IV melanoma] for BRAF [mutations]," Dr. Richard D. Carvajal said in an interview after speaking at the American Academy of Dermatology’s Summer Academy meeting. "In a large, phase III trial, vemurafenib impacted survival in patients with tumors with a BRAF mutation. You’ll need to know the BRAF status to use [vemurafenib]."

In May, Genentech, a Roche subsidiary developing vemurafenib with Daiichi Sankyo subsidiary Plexxikon, announced that it had submitted a new drug approval application to the FDA.

"At my institution and at others, it’s becoming standard of care to do genotyping on these patients. We need to know how to prioritize them to experimental or standard treatments," said Dr. Carvajal, a medical oncologist specializing in melanoma and sarcomas at Memorial Sloan-Kettering Cancer Center in New York. "In the not too distant future, it will be standard to get a panel" of genotyping results, probably also including NRAS, KIT, and several other oncogenes now emerging as important players in the genetic progression of metastatic melanoma.

"As these markers become relevant for choosing treatment, they will be available in CLIA-certified tests," Dr. Carvajal said. Genotyping "should be done on all [advanced melanoma] patients; it’s just a matter of how you pay for it. The panel of genes we’ll need to look at will grow with time."

Results from genotyping studies of metastatic melanoma tumors have shown a BRAF mutation prevalence of about 43% and a NRAS mutation prevalence of about 14%, with the remaining 43% of tumors having wild type forms of both genes, Dr. Nancy E. Thomas said in a separate talk at the meeting.

The BRAF and NRAS mutations, as well as several others found with less frequency, appear mutually exclusive, so that, for example, essentially all studied tumors with BRAF mutations are wild type for NRAS, and essentially all tumors with a NRAS mutation have wild type BRAF, said Dr. Thomas, professor of dermatology at the University of North Carolina at Chapel Hill.

When vemurafenib gets U.S. marketing approval, it will also muddy the treatment algorithm for metastatic melanoma. For the time being, ipilimumab (Yervoy), an immunotherapy approved for treating advanced-stage melanoma in March 2011, is unrivaled for survival benefits as first-line therapy.

08/10/11  

---

EXPERT ANALYSIS FROM THE AMERICAN ACADEMY OF DERMATOLOGY'S SUMMER ACADEMY MEETING

---