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February 16, 2015

Outsmarting Melanoma

Enormous medical gains have been made against melanoma over the past four years, and more are waiting in the wings.
BY Erik Ness
PUBLISHED February 17, 2015
Peter Daly knew he was running out of options.

In 2002—on his 49th birthday—he’d been diagnosed with metastatic melanoma. After evaluating the dismal track record of the few available treatments, he decided he’d rather take his chances with a clinical trial. He enrolled in an anti-cancer vaccine study, but just six months later his cancer returned.

His doctors in Madison, Wisc., treated him with interferon alfa-2b as the cancer spread, literally from head to foot. Finally another trial opened, this time for the immunestimulating drug Yervoy (ipilimumab), at the National Cancer Institute in Bethesda, Maryland. A phase 1/2 trial, its primary goal was figuring out if the human body could tolerate the drug, and how much of it. So little was known that the consent documents Daly signed contained information on how it had worked in monkeys.

He knew the trial could kill him, but he also knew if he did nothing the melanoma would kill him. Daly’s body did not handle Yervoy well. After just two doses he developed colitis—a common side effect. He was willing to risk a third dose, but the doctors declined.

But two doses had been enough. Within weeks, Daly felt the tumors shrinking. A couple of large growths had to be removed or irradiated, but, spurred by the Yervoy, his own immune system gradually beat back the myriad tumors. Within a few years he was declared cancer-free—an early success story to buoy researchers.


Peter Daly took the immune-stimulating drug Yervoy (ipilimumab) in a clinical trial before the drug’s FDA approval, and remains cancer-free. Photo by Noah Willman.

It would take another seven years of clinical trials, but in 2011 Yervoy—often called ipi—was finally approved by the Food and Drug Administration (FDA). It was the first new drug for the treatment of metastatic melanoma in 13 years. And it was the first melanoma drug ever to show overall survival benefit in a randomized phase 3 clinical trial.

Yervoy was just the beginning. Six additional drugs have been approved since, and more are imminent. Among them are some promising immunotherapies, including a vaccine called T-Vec, which could be approved by the FDA by July 28.

“For years we really didn’t have any effective therapy,” says Lynn Schuchter, chief of hematology/oncology at the Abramson Cancer Center at the University of Pennsylvania, who has been a melanoma specialist for more than 25 years. “It’s been quite remarkable to suddenly have tears of joy in clinic and not just tears."

EXCITEMENT OVER IMMUNOTHERAPY 

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.

For all the excitement and fanfare, Yervoy may soon be eclipsed by a different kind of immunotherapy—PD-1 (and related PD-LI) checkpoint inhibitors. Like Yervoy, they also focus on T cells, but turn off a different molecular switch to release their power to seek and destroy cancer cells. Early studies suggest that PD-1 inhibitors may be twice as effective as Yervoy. In September 2014, the FDA used its new expedited approval process to quickly approve Keytruda (pembrolizumab). And soon afterward, it awarded breakthrough designation for the anti-PD-1 drug Opdivo (nivolumab), moving in December 2014 to approve the drug for use in patients with melanoma who have previously been treated with Yervoy.

No one can foresee the outcome of FDA decisions, but the feeling among experts is that PD-1-focused immunotherapy, which causes fewer side effects than previously approved treatments and is more active against the disease, could soon become the first line of attack for metastatic melanoma.

TARGETED THERAPY REMAINS IMPORTANT

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.

Quieting BRAF Mutations IllustrationAnother 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.”

VACCINES HOLD PROMISE

It’s long been hoped that a vaccine might be the ultimate immunotherapy and provide a cure for melanoma, but numerous efforts have tried and failed. Currently, two more vaccinebased treatments for melanoma are in trial phase: T-Vec, engineered from a herpes virus, and Cavatak, derived from a cold strain, have both shown some promise and are being tested alone and in combination with other approaches. T-Vec is under review by the FDA, which plans to make a decision by July 28. In a phase 3 trial whose results were reported last year, patients taking T-Vec experienced a significant improvement in durable response rates, but no boost in survival.

Perhaps the most technologically alluring immunotherapy is adoptive cell therapy: the idea that we can grow, train and transplant parts of the human immune system.

In 2009, Jamie Goldfarb had a small melanoma removed from her leg, and the surgeon declared her cancer-free. Over the next year, several infections developed around the scar, another small tumor was found and treated, and again she was declared cancer-free. Goldfarb got pregnant, had a baby, and then, just as she was preparing to return to work in January 2011, her oncologist suggested a precautionary scan. Everyone was surprised to discover metastatic disease in her pancreas and liver. She had no symptoms.

Goldfarb lives in the D.C. area, and even before the biopsy, her doctor realized he was out of his depth and got Goldfarb an appointment at the National Cancer Institute. Just three days after the biopsy confirmed cancer, she was learning about an adoptive cell therapy called TIL—for tumor infiltrating lymphocytes.

Lymphocytes are white blood cells, and, in TIL therapy, a tumor is harvested from a cancer patient, and then the white blood cells inhabiting the tumor, which hold the power to fight the disease, are harvested and multiplied in the lab over several weeks. Goldfarb met the scientists who grew her cells, and viewed them under the microscope. “They basically built me a new immune system in the lab,” says Goldfarb. “I thought that was awesome.”

While she was waiting for the TIL cells to multiply, Goldfarb took a round of IL-2, which knocked the tumors in her pancreas and liver back for a few months. But by August, a new scan had found 35 new tumors and it was time for the TIL. With a dose of strategic chemotherapy, Goldfarb’s immune system was wiped out, and the billions of new immune cells were introduced with a simple I.V. “Very anticlimactic,” she says—she felt like there should have been a parade.

Monthly scans showed continued tumor growth, and by December her doctors suggested it was time to think about next steps. Goldfarb said she needed a little more time, and then she caught an ordinary winter cold. She only remembers it because while she was sick she sensed her immune system jump to life. And she felt the tumors shrinking. By the time of the January scan they were significantly decreased, and kept on shrinking. As of about a year ago, there was no evidence of disease.

TIL is still only available via clinical trial, and it’s controversial. If you look at those who get to treatment, the response rates are very strong. But it’s expensive and tricky,and a lot of patients can’t qualify, or get rejected partway through the process.

And yet the hope provided is extraordinary. “This is why we invest so much time and money on these trials. We’re trying to provide a long-lasting impact because we know the majority of these drugs are not going to save people. They will treat people for a period of time,” says Amaria, of MD Anderson, who is working with TIL. “These immune therapies have the chance to give someone a second life, from a diagnosis that’s going to cause death in nine months to maybe not dying of melanoma at all.”

FINDING THE BEST AVAILABLE THERAPY 

“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]

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