“The melanoma community has never been more excited,” said Dr. Rhoda Alani. “The past 3 years have seen significant advances.”
Melanoma kills about 9,000 people in the U.S. each year, she reported, and Americans have a 1 in 56 lifetime risk of developing the disease. Australians, by comparison, have a 1 in 17 lifetime risk for men, and 1 in 14 for women. About 75,000 new cases are diagnosed each year in the U.S., the great majority of which can be completely removed and cured by surgery alone.
But advanced melanoma—when the disease has metastasized to other organs—remains a grave threat, limiting life expectancy for those affected to only 6-9 months. And dormant melanoma—maybe the surgeon didn’t get every last cell during excision—can reactivate suddenly.
Thanks to a better molecular understanding of how melanoma develops, due to such projects as NCI’s The Cancer Genome Atlas (TCGA), new treatments are being discovered that target the specific pathways by which melanoma gains a foothold within the body.
The recent excitement began in 2010, with a paper in the New England Journal of Medicine that “hit the ball out of the park for the melanoma community,” and made the front page of the New York Times, said Alani. It reported on an inhibitor of the BRAF pathway that had an initial 81 percent response rate that persisted, on average, for 7 months.
The problem is that melanoma wants to survive just as badly as physicians want to eliminate it; resistance to novel treatment begins almost immediately. “Virtually all patients develop resistance over time,” said Alani. “That’s the bane of our existence in 2014. There are several complex and variable pathways involved in the development of resistance.”
Investigators have used brute force in the effort to find better therapies, doing methodical reviews of every gene in the pathway leading to melanoma. “It’s important to understand the molecular characteristics of the tumor,” Alani said. “TCGA has been very helpful in understanding the genetic landscape.”
The BRAF kinase—the hero of the 2010 NEJM paper—became a molecular target in 2002, because it was linked to 60 percent of the melanoma cases under study. “It took only 8 years to get a drug (vemurafenib) and 9 years for approval—that’s fast,” Alani said.
Therapy with the new drug took only 15 days to virtually erase metastatic lesions in one patient, and garnered a 48 percent response rate in a clinical trial. Such success led not only to enthusiasm in the research community, but also heated debate over the ethics of not treating melanoma patients in the control arm of the study, Alani reported.
A newer drug, dabrafenib, approved in 2013, has even fewer side effects than vemurafenib, she added. The most recent approaches combine several inhibitors targeting multiple pathways; early trials of one show increased efficacy (a 76 percent response rate) and decreased toxicity.
Research in the field is moving so quickly that melanoma, which Alani said is many different diseases, is undergoing molecular reclassification. Future melanoma therapy, she said, will be similar to today’s HIV combination therapies.
“Ideally, we’d like to set the stage for truly personalized medicine,” she said. “We need to look more carefully at the broader landscape of other ‘driver’ mutations in melanoma, using TCGA.”
In 2012, 6 novel melanoma gene candidates were found, Alani noted. “But we want to do better than 6 new drugs,” she said. “The holy grail in melanoma, for a very long time, has been immunotherapy. But it’s very hard to harness the power of the human immune system.”
While targeted therapy acts quickly, and can yield spectacular results in the best cases within only a few weeks, immunotherapy is likely to be slower, but more durable, Alani explained.
Her prescription for moving forward? Combine agents, both serially and concurrently; blend both targeted and immunotherapeutic approaches; target paths other than the well-characterized MAP kinase pathway; and take advantage of a plethora of new T-cell targets.
“The melanoma community has never been more excited,” she said. “The past 3 years have seen significant advances.”
During a Q&A session, Alani added that, within the next 6 months, three companies are likely to market diagnostic tests based on biomarkers that will allow physicians to determine exactly what kind of tumor they are dealing with. Physicians in the lecture hall seemed gratified to have that advantage in prospect.