Melanoma is skin cancer that forms from melanocytes, the cells in the skin that contain pigment. Basal cell and squamous cell carcinoma are easily treated and far more common forms of skin cancer—they are not even reported to cancer registries. Far rarer, melanoma still accounts for the majority of deaths from skin cancer. Caught early enough, surgery can cure it. But once the disease escapes and becomes metastatic, it ranks among the most aggressive and difficult of cancers.
Dacarbazine has been the approved chemotherapy for metastatic melanoma since 1975, but with minimal success. Chemotherapy focuses on directly killing cancer cells, but the new generation of melanoma drugs are more clever: Immunotherapy harnesses the body’s own immune system to fight cancer. Targeted therapy interferes in other cellular processes within the cancer that can slow or shut it down.
Melanoma has been a primary focus in immunotherapy research because of intriguing evidence that some people’s immune systems are better able to keep the cancer in check. In one remarkable case, a patient contracted melanoma from a kidney transplant; the donor had been presumed surgically cured 16 years before the organ donation. Melanoma is also the most mutated of cancers, so is more likely to look like a foreign body to the immune system, according to Roda Amaria, a melanoma specialist at MD Anderson Cancer Center in Houston.
Interleukin 2 (IL-2), approved in 1998, was an early effort in immunotherapy. A naturally occurring molecule in the body, it helps activate the immune system to recognize and destroy cancer cells, shrinking tumors in about 15 percent of patients. A lucky 5 percent enjoy a remission that can last beyond seven years. The side effects are extreme, ranging from nausea and vomiting to dangerously low blood pressure caused by leaking blood vessels.
Yervoy is a more precise drug. It works by energizing just the T cells, specialized white blood cells which have the ability to recognize and destroy cancer cells. Yervoy turns off a switch (CTLA-4) in the T cell that would otherwise inhibit this power. Clinical trials so far suggest that Yervoy works in 10 to 20 percent of patients.
Cancer cells are complicated but flawed biochemical engines, and identifying their weak points provides targets for drug development. Targeted therapy takes advantage of years of intensive research into how different cancers operate.
In melanoma, the most common target is the BRAF gene, first identified as an oncogene in 2002. In healthy cells, BRAF helps direct cell growth. But in about half of melanomas, a mutation sets BRAF on high, amplifying and ultimately distorting growth signals. Since then, researchers have been developing drugs to hit that target. In August of 2011, just five months after Yervoy cleared the FDA, Zelboraf (vemurafenib) was approved, along with a genetic test to identify the most common BRAF mutation. A less common mutation in melanoma is the c-KIT gene. Gleevec (imatinib) and Tasigna (nilotinib) block c-KIT’s activity and have been approved for use in other cancers; trials are now underway in melanoma.
Another BRAF inhibitor, Tafinlar (dabrafenib), debuted in 2013, along with Mekinist (trametinib), which takes aim at a related target called MEK. Even more promising was the discovery that the two drugs work better together than either does alone. The FDA approved their use together for advanced melanoma in early 2014. Using them in combination also decreases the debilitating rash that can be the most difficult side effect.
In cancer treatment, drugs often are more effective in combination, and over the next few years researchers will be mixing and matching more therapies to unlock the ideal combinations.
Part of the puzzle is resistance. Targeted therapy typically works only for 6 to 12 months, after which the cancer often adapts. Will different combinations of drugs slow down resistance?
Ravi Amaravadi, co-leader of the cancer therapeutics program at the Abramson Cancer Center at the University of Pennsylvania, is developing drugs that fight resistance by dampening a cellular recycling process called autophagy. “Autophagy is the way cells get rid of damaged parts,” explains Amaravadi. So if a treatment is damaging the cancer, it may be able to mend itself through autophagy. “We’re trying to block that healing capacity.” An already approved malaria medication, hydroxychloroquine, has shown promise in early trials, and new trials with a BRAF and MEK inhibitors are already underway.
Another important arm of research is focused on predicting which drugs will work on which patients. As of now, researchers have no idea why people like Peter Daly have experienced such dramatic results using immunotherapy, while others see no benefit. Finding biomarkers, either in the genetic code or the immune system, will help make sure patients get the right treatment. “These are expensive drugs with fairly substantial toxicities,” explains Schuchter. “We want to be able to identify the proper patients.”
For all of these improvements, Schuchter is still not satisfied, and worries that the field needs to restock its cupboard of big ideas. The blockbuster ideas have been realized, she says, and developments over the next few years “will be more nuanced.”
“These new therapies are effective, but they are not helping most patients,” she says. “We still need new approaches.”
“We can definitely see a time, possibly within the next five years, where a majority of melanoma patients will have their disease changed...to something that is either cured or turned into a chronic condition,” says Tim Turnham, executive director of the Melanoma Research Foundation. But we’re not there yet.
In 2013—two years after the introduction of Yervoy and Zelboraf —more than a quarter of patients in the U.S. with metastatic melanoma were still being treated with dacarbazine. “If you’re not offered one of the other drugs first, then the likelihood of you surviving this cancer is radically reduced,” Turnham says. “Where you are treated, by whom you’re treated, makes a big difference, and it’s getting broader as we get new drugs on the market.”
Turnham suggests three simple rules to guide your melanoma treatment. First, if you’re offered dacarbazine, you probably should think about finding a new doctor. Second, your doctor should talk to you about clinical trials. There may be a good reason not to do a clinical trial, but there is no good reason not to discuss what they have to offer. And ask your doctor about the long-range treatment plan he suggests. “We now know several things that might work, but nobody knows what one thing will work,” he says. “I guarantee you the good doctors always have a plan B.”
“I think there is still a lot of art in treating melanoma,” Turnham says, and the key is experience. Doctors who treat a lot of melanoma know the drugs, have a better sense of how to manage the possible side effects, and are more likely to have access to clinical trials.
For the past 10 years, it was a given among melanoma specialists that the best options were only available in trials. That may change very soon as new treatments permeate through the system and evidence accumulates from ongoing clinical trials.
But for now, Schuchter still thinks it’s “the best choice to enroll someone in a clinical study.” Some of the best reported treatment outcomes, he says, are for drug combinations that are still available only in clinical trial.
That makes sorting through treatment options all the more challenging for patients thrown into the whirlwind of a cancer diagnosis.
It would be hard to find someone more prepared for this than Jamie Goldfarb—her husband’s job is managing clinical oncology trials. Still, they were totally overwhelmed.
“It is essential for oncology patients to be their own advocates,” she says, “but there are so many things to think about.”
[Read "Can the Tan" about melanoma prevention]