Melanoma: Ready for Takeoff

For several years, Bobby Harsh had strived to stay one step ahead of melanoma, as the aggressive form of skin cancer moved from a lesion on his left cheek in late 2007 to later gaining a foothold in his lungs.

The 40-year-old Maryland state trooper had extensive surgery, involving some 90 stitches that traced a horseshoe shape on the left side of his face. The melanoma, 4 millimeters in depth, was classified as stage 2C. Despite no indication that it had reached his lymph nodes, Harsh adopted an aggressive approach, enrolling in a clinical trial testing a vaccine treatment.

While he waited to qualify—all medication had to leave his system first—he decided to go ahead with a long-planned trip, visiting the national parks in a recreational vehicle with his wife and three teenage children. "I guess I would say that I'm a realist," he says, describing his mindset then. "We knew that the prognosis was very, very poor. At that point in time, you're looking for miracle kind of things."

Harsh’s “miracle” arrived in the form of a drug called Yervoy (ipilimumab), a new intravenous agent that’s designed to harness the body’s immune system to better attack the cancer. He started treatments in September 2009. Fewer than three months later, the first set of scans showed evidence of the tumors’ shrinkage.

Yervoy, which was approved by the Food and Drug Administration in March, is among the first of several long-awaited drug treatments for advanced melanoma. Melanoma, the virulent cousin of more common skin cancers like basal cell carcinoma and squamous cell carcinoma, has been traditionally difficult to eradicate once it migrates beyond the skin’s surface. Other drugs now in research development are also showing promise, building on insights into mutations of specific genes, such as BRAF and c-kit, which might influence melanoma’s growth.

Overall the five-year survival rate for melanoma—diagnosed in 68,000 people in 2010—is quite high compared with many other malignancies, 91.4 percent according to National Cancer Institute data. But it drops to 62 percent once the cancer infiltrates the lymph nodes and much further, to 16 percent, if it spreads elsewhere in the body.

Moreover, melanoma has an extraordinary capacity for dormancy, says John Kirkwood, MD, director of the melanoma and skin cancer program at the University of Pittsburgh Cancer Institute. Following surgery, scattered cells that aren’t detectable by imaging scans can lurk and perhaps won’t pose a problem for years. Kirkwood described a patient he’d seen the prior day who was treated for stage 1 melanoma two decades before. Melanoma had just emerged in a nearby lymph node that appeared to stem from the initial tumor. “Only now, like Rumpelstiltskin, it has awakened to do its havoc,” Kirkwood says.

The recent treatment advances, although exciting, don’t extend to everyone. About 30 percent of patients had some degree of response to Yervoy, according to results published last year in The New England Journal of Medicine. Vemurafenib (also called PLX4032), which targets a BRAF gene mutation, has been able to shrink tumors in a higher percentage of patients but only transiently.

Still, they show promise as another treatment tool, along with more traditional approaches like surgery and chemotherapy. In fact, there’s an alphabet soup of drug combinations, both announced and in the works, that researchers and patient advocates hope will boost survival in patients who can’t be cured by surgery alone. The challenge is how to effectively and efficiently identify the optimal treatment combinations, says Timothy Turnham, PhD, executive director of the Melanoma Research Foundation.

“We are in a strange situation where we have very few approved drugs that are effective in metastatic melanoma,” he says. “But we have a lot of drugs in the pipeline that probably will be effective if used in the right way.”

Melanoma is so named because it develops in the pigment-carrying cells called melanocytes. By far the most lethal skin cancer, with about 8,700 deaths in 2010, it’s also becoming more common. Diagnoses among whites have jumped by more than 60 percent during the past 30 years, according to the National Cancer Institute. The largest driver is excessive exposure to ultraviolet radiation, primarily from the sun and tanning beds. But other risk factors can be influential, including family history of melanoma and a past history of basal cell or squamous cell cancers. Malignancy also is far more common in whites than in other racial or ethnic groups.

For most patients, treatment begins with surgery, the extent of which depends upon various factors, including the thickness of the lesion and how far it has spread. In 2010, the American Joint Committee on Cancer updated its staging criteria for melanoma, placing less emphasis on how much the malignancy penetrates the skin’s layers. Instead, staging is assessed based on the thickness of the tumor, whether or not the outermost layer has been ulcerated, as well as the malignancy’s mitotic rate. That last measurement termed “mitotic rate” shows how rapidly the cells are dividing in the tissue, which can be influential in surgical decisions, says David Ollila, MD, associate professor of surgery in the division of surgical oncology at the University of North Carolina, Chapel Hill. “[For] anybody who gets a melanoma, that should be part of the basic pathology report now,” he says.

We are in a strange situation where we have very few approved drugs that are effective in metastatic melanoma. But we have a lot of drugs in the pipeline that probably will be effective if used in the right way.

For even relatively thin melanomas, one key question is whether cells have infiltrated the lymphatic system that forms the “railroad tracks of the body,” as Kirkwood puts it. If a swollen lymph node can’t be felt, signs of malignancy can also be detected through a sentinel node biopsy. Through this technique, a radioactive substance is injected near the tumor to trace a path through the connected lymph system, determining if cancer has reached the first—dubbed the “sentinel”—node. Once that node is identified, it’s removed and tested for cancer.

Ollila typically recommends a sentinel node biopsy for patients whose melanoma is at least 1 millimeter thick. For patients with a thinner melanoma, the mitotic rate also helps make that determination, he says. “The rate has allowed us to pick out those patients who have thin melanomas, less than 1 millimeter, but still [the melanoma] may be a bad actor, that is, it may still have spread to the lymph nodes.”

Martha Bishop’s melanoma on her lower back was far thicker, 2.2 millimeters, when the 29-year-old Tucson, Ariz., mother was diagnosed in the fall of 2009. Over the previous six months or so, the mole had darkened from light brown to blackish. “I thought, ‘It’s just a mole. How bad could it be?’ ” she says.

Bishop’s dermatologist was shocked as well when the pathology report identified a stage 3 melanoma. The sentinel node biopsy showed microscopic cancer in one lymph node. In the end, over the course of two surgeries, nearly two dozen were removed.

After the surgery was completed, Bishop completed a year’s worth of treatments with high-dose interferon, wrapping them up in December 2010. The treatment regimen, which triggers nausea, fatigue and other flu-like symptoms, was approved in the mid-1990s. A key study showed that it significantly extended relapse-free survival and, to a lesser extent, overall survival in patients considered vulnerable to recurrence, according to the National Cancer Institute. But subsequent studies haven’t identified an overall survival benefit.

“I felt like I had the flu for a year basically,” Bishop says. “We knew that the odds were really low that it would help. But because I was young and had two kids, it was worth essentially rolling the dice.”

A couple of weeks after she completed her last treatment, Bishop received disappointing results from follow-up scans. A tumor had emerged just 3 inches from the original melanoma. “It was evidence that the interferon didn’t work.” This spring she began a research trial.

This phase 3 study, involving stage 3 and 4 patients, found that the drug either shrank or stabilized the malignancy in 28.5 percent of patients. The median overall survival was about four months longer, 10.1 months compared with 6.4 months in patients taking a glycoprotein 100 peptide vaccine. Given its impact on the immune system, the treatment identified some serious and potentially fatal immune-related effects, including colitis and liver damage.

Tumor shrinkage was limited, but the malignancy wasn’t growing or spreading either, O’Day says. In some patients, the response has been extended two years and counting, he says. “It stunned the tumor, stopped it in its tracks, for years and not months or weeks as in previous treatments.”

At this point, it’s unclear why only some patients benefit, O’Day says. “That’s the million-dollar question right now.” There’s no easily discernible pattern, such as the extent of the cancer’s metastasis, he says.

Harsh, whose treatment is part of another study, received his first round of good news in early December 2009. The lesions on his lungs—the largest of which had initially measured 1.5 by 1.2 centimeters—were shrinking. By the following spring, five of the six being tracked were no longer visible. Physicians have told Harsh that the sixth is likely a granuloma or scar tissue, and not even cancer.

Harsh, now 43, has continued his Yervoy infusions and, understandably, is edgy about stopping. “It’s my security blanket,” he says.

One combination study that researchers would really like to see is the pairing of a targeted medication with Yervoy to learn if it spawns a synergistic effect, says Hwu, who also wrote The New England Journal of Medicine editorial that accompanied O’Day’s study.

Vemurafenib, for example, has been shown to cause significant but typically short-term tumor shrinkage, he says. What if the oral medication was given with Yervoy? The tumor, as it’s destroyed, releases proteins that might in turn stimulate the immune system to recognize and combat the tumor, he says. “You may be able to have a high response rate and a more durable response.”

Other types of combinations also are being investigated. Early this year, officials at Plexxikon, who are developing vemurafenib with Roche, announced encouraging interim results from a phase 3 multicenter study that’s comparing vemurafenib with dacarbazine, an already approved chemotherapy regimen for melanoma. Patients on vemurafenib had an improved overall survival compared with those on chemotherapy, they reported. Specific results were presented at this year’s American Society of Clinical Oncology meeting.

Amid all of the excitement about drug advances, it’s important that the role of surgery is not sidelined, even for stage 3 or potentially even stage 4 melanomas, UNC’s Ollila says. Too often, patients with advanced cancer are told surgery can’t help, without even referring the patient for an opinion, he says. The average survival advantage for Yervoy, he points out, is just four months, and the drug is not without toxic risks.

But Ollila is contemplating a future of expanding combination approaches. Studies are needed to determine whether the new drugs should be given prior to surgery—in an effort to shrink the malignancy—or afterwards, he says.

As research continues, Turnham has no doubt that the pernicious cancer will attempt to remain one step ahead. “This is almost, to some extent, going to be a game of Whack-A-Mole,” he says.

In that pursuit, Harsh is gaining attention for his success. Bristol-Myers Squibb, which developed Yervoy, invited him to share his experiences to inspire their sales representatives, and his story of survival was also featured in the Melanoma Research Foundation newsletter.

Bishop echoes other patients with advanced disease who are living with one eye on the research clock. As of early spring, tests couldn’t find any signs of melanoma, but doctors typically steer clear of the word “remission,” she says.

“My oncologist keeps saying that, ‘If you have to have melanoma, this is the time to have it because we are finally making advances.’” She laughs briefly, without much humor. “I still think maybe 20 years from now would be better.”

But in early 2009, shortly after the trial wrapped up, imaging scans showed evidence of metastasis: lesions on his lungs. By spring, they had doubled in size. Another research study was his only option. “The stuff in my lungs was diffuse, so they couldn’t remove it,” Harsh says.

One hallmark of melanoma is that as it spreads throughout the body, the immune system becomes increasingly impaired, allowing the malignancy to gain the upper hand, says Steven O’Day, MD, chief of research and director of the melanoma program at The Angeles Clinic and Research Institute in Los Angeles.

Yervoy works by targeting a key antigen on the surface of T-cells that acts as a brake to the T-cell, something O’Day describes as “the Pac-Man cells that normally control cancer.” By blocking that molecular T-cell checkpoint, called CTLA-4, the drug helps to energize the T-cells. “They can go out and be like super T-cells and control the cancer,” says O’Day, co-principal investigator on the Yervoy study, who first announced results at the 2010 annual meeting of the American Society of Clinical Oncology.

Meanwhile, targeted medications have piggybacked on improving insights into the genetic underpinnings of melanoma. The most frequently mutated pathway appears to be the mitogen-activated protein (MAP) kinase pathway, which drives cell growth, along which lie the proteins encoded by the BRAF, NRAS and c-kit genes. About 60 to 70 percent of melanomas contain a BRAF mutation.

One drug designed to target that BRAF mutation, vemurafenib, has proven effective in shrinking melanoma, according to data from a phase 1 study published in 2010 involving 32 patients with BRAF mutation—positive metastatic melanoma. Of that group, 26 experienced at least a partial response. The median progression-free survival for the 16 patients still in the study was more than seven months, but overall survival hadn’t yet been determined for the oral medication, according to data published in The New England Journal of Medicine.

One theory is that the drug resistance develops not due to new mutational changes in the tumor itself, but more likely because of some type of reactivation of the BRAF pathway, perhaps triggered by changes in downstream molecules, Kirkwood says.

Unraveling the source of that tumor resistance is key, say melanoma specialists, who are eager to start testing combinations of targeted medications.

Patrick Hwu, MD, uses the analogy of light switches positioned along circuits to convey different types of combinations.

“It’s possible that you can combine targeted agents along the same circuit, like a BRAF drug and an MEK inhibitor,” says Hwu, department chairman of the melanoma medical oncology department at M.D. Anderson Cancer Center in Houston. “Or you can combine two targeted agents on separate circuits.”

As one example, GlaxoSmithKline has launched a series of studies looking at an MEK inhibitor (GSK1120212) and a BRAF inhibitor (GSK2118436), both separately and in combination. This is in keeping with a strategy that is being tried in many cancers—simultaneously blocking key proteins that are involved in tumor growth and survival.