For Melanoma, A New Day

August 6, 2010

Late-stage melanoma has almost always been a death sentence. Now, a defined genetic mutation, a drug that disables it and a corps of doctors with a fervent belief in personalized medicine have turned that around in a shining example of the promise of genetically targeted drugs for cancer.

Emily Black had just returned home to Milwaukee from a semester abroad in Mexico and was enjoying the summer before her junior year at the University of Wisconsin-Whitewater. That’s when her mother noticed it. Emily was wearing a tank top shirt, exposing her upper back. She remembers her mom’s words as a terrifying blur: Hold on there, her mom had said, Emily — this mole on your back is blackish, bigger and, well — different.

Emily was 20 years old on that day in 2006. A trip to the dermatologist was scheduled, then a biopsy. The results were shocking: stage-four melanoma, advanced-stage cancer that began on the surface of the skin and that has spread within the body. Individuals with that diagnosis typically don’t live longer than a year.

She pulled out of school and began a series of treatments, mostly clinical trials of — by definition — experimental drugs, the only real hope for her since melanoma is known to respond minimally, if at all, to traditional chemotherapy. While her college friends were thinking about their careers and out socializing into the wee hours of the night, Emily opened her eyes every morning to the overwhelming task of staying alive.

Four years later, she has beaten the odds despite the tumor’s growth. It expanded into the lymph nodes under her arms and into her liver and lungs. Treatments in Milwaukee and Madison, Wisconsin, Bethesda, Maryland, and Chicago helped hold the tumor at bay with varying success, and the most recent one eradicated it from her liver and lungs, then ceased to be effective. She soon found herself searching her closet for baggy pants and long skirts when a growth the size of a melon took shape in her left thigh.

But none have quite attacked her cancer with the vigor of her fifth and current clinical trial at the Massachusetts General Hospital Cancer Center.

The trial is one of two multi-center national trials totaling 130 patients, both based at MGH, that are testing the efficacy of a new drug that targets a genetic mutation in melanoma, called BRAF. About half of all patients with late-stage melanoma possess this mutation. The drug, tentatively called PLX4032 until it wins expected approval from the Federal Drug Administration (FDA), is evidencing unprecedented results in the deadly disease and is both more effective, by far, than traditional chemotherapies and less toxic. It is a pill taken orally daily.

In the trial Emily is in, all patients receive PLX4032. In a recently initiated trial, PLX4032 will be compared directly to the only FDA-approved chemotherapy drug for melanoma, dacarbazine. Patients will be randomly assigned to one drug or the other.

“Until this drug, stage-four melanoma was a rather imminent death sentence,” says Keith Flaherty, MD, director of Developmental Therapeutics at the Mass General Cancer Center, who is heading the trials. “Now there is a ray of light, even a pretty big ray of light, for those patients with this mutation in the BRAF gene.”

Since the phenomenal results of a phase I trial of the drug were publicized a year ago — with response rates hovering at about 80 percent in a small group of 32 patients — Dr. Flaherty says he’s been fielding hundreds of requests for participation. Meanwhile, oncologists worldwide are following its success, since it likely has broad implications for cancer treatment. That’s because this is one of the more dramatic cases in which a drug targeting a specific genetic abnormality — commonly known as “personalized” or “targeted” medicine — is not just preventing tumor growth but causing dramatic regression and, in some cases, eradication, and doing so in one of the deadliest cancers.

About 70,000 Americans per year receive a diagnosis of melanoma, and about 9,000 die. Melanoma has a high cure rate if diagnosed early, but traditional chemotherapy is virtually powerless for advanced-stage disease, usually evidenced by large, black tumors on the skin and often protruding from it. Once it spreads to the lymph nodes, the threat of further metastatic spread is increased; once the cancer enters the internal organs the average survival time is less than a year.

BRAF’s role in cancer was discovered by a group of scientists at the Sanger Institute in the United Kingdom in 2002. They published results of a study that showed how the BRAF mutation alters the structure of a protein so that it fuels the growth of cancerous tumors. It was a watershed event for melanoma. Other genetic abnormalities had been found in the disease before, but none were of any therapeutic value. BRAF had previously been known to exist, but what these scientists discovered was its central role in seven percent of all cancers — and a whopping half of melanomas.

Everyone has the BRAF gene, and it produces a protein that spurs cells to multiply in normal cell growth. But a mutation in the gene produces a defective protein (referred to as braf, in lower case), one that is perpetually switched on, leading to rapid cell growth — and in some cases, cancer. PLX4032 binds to the defective protein, disabling it. Ultra-violet radiation from sun exposure likely comes into play as well, perhaps by mutating other genes that cooperate to jump-start the cancer, but to what degree isn’t yet known. Cancer is also known to begin due to random genetic damage, so UV radiation isn’t necessarily required to instigate the disease. (In skin cancers like squamous cell and basal cell cancer, sun exposure is known to play a large role, however).

The British discovery caused many oncologists to take notice, but for Dr. Flaherty, it was a career-changing moment. Then an oncologist at the University of Pennsylvania Medical Center, he fixated on what it could mean for the treatment of patients. And, frustrated by years of witnessing patients die when traditional chemotherapies failed to help, he set out on an impassioned mission to identify the drug that would target the toxic braf protein.

Dr. Flaherty had led several trials testing a drug that proved to be unable to adequately block the protein. Then, he and Paul Chapman, MD, at Memorial Sloan-Kettering Cancer Center in New York, partnered as co-investigators, and, when a promising new anti-braf drug came forward, they spent two years finding the right formulation of the drug and developing and running early clinical trials that tested its safety, effectiveness and dosage.

Those years were marked by numerous ups-and-downs: moments of disappointment, frustration, hope and elation. Initially the medication didn’t seem to work, so he and Dr. Chapman upped the dosage. Patients without the mutation who were taking the drug weren’t getting better — which had been expected, but the efficacy in that group still needed to be tested — so they were taken off the early trials. Some patients with the mutation got better fast, then relapsed and died. For a long time, it seemed the drug could only temporarily halt tumor growth for a few months. But that was still considered a long time for a melanoma drug, so the pharmaceutical company Roche, which had licensed PLX4032, kept producing and perfecting it.

Finally, in 2009, with a new formulation of the drug, things changed. In June of that year, Dr. Flaherty and his colleagues presented the results of phase I of a trial in which a relatively small group of patients were enrolled. It took the oncology world by storm when it reported responses in more than half of the patients with the BRAF mutation and metastatic melanoma, whose tumors shank and in some cases disappeared altogether.

When the news emerged, patients and their family members from all over the world frantically dialed and e-mailed him to see if they could qualify for the next phase of the trial — the current phase, in which Emily Black entered last winter. Dr. Flaherty was staying up late to respond personally to each appeal, while his wife packed boxes for their move from Philadelphia to Boston, to his new job at Mass General.

David Fisher, MD, PhD, director of the Melanoma Program at the MGH Cancer Center and chief of the MGH Department of Dermatology, some of whose past research has also focused on targeted therapies, had been following the PLX4032 story for several years and recruited Dr. Flaherty to MGH. “His work embodied the direction in which cancer therapy is going and thus fit with the Cancer Center’s goals and vision,” says Dr. Fisher. Dr. Fisher is also leading groundbreaking studies on treatment resistance in melanoma, which is informing a better understanding of melanoma broadly and paving the way for improved treatment.

The job offer was one Dr. Flaherty couldn’t refuse, partly because he knew that few hospitals have the capacity to undertake large-scale genetic testing of tumors. “It’s a piece of cake to run a trial in all BRAF mutant cancers at MGH,” he says. “There’s no other institution in the country that can do that using a validated method such as the one used in its pathology lab. Some institutions may get to that point, but only MGH can handle the testing for every single one of the cancer patients who walks in the door. That’s rocket science in terms of logistics.” In addition, he says, the Cancer Center is taking the “right approach” to cancer diagnosis and treatment in moving away from defining many cancers by their tissue of origin and towards the genetic abnormality that underlies them.

Publicity of the trial’s success abounded. In its three-part front-page series last winter, the New York Times declared, “To chronicle the trial of the drug known as PLX4032 is to ride a roller coaster of breakthroughs and setbacks at what many oncologists see as a watershed moment in understanding the genetic changes that cause cancer.”

While a 70 percent-rate in an additional group of patients enrolled at the end of the phase I trial made headlines, however, Dr. Flaherty was furrowing his brows over those who didn’t respond or who did respond but only temporarily. “In melanoma, this was phenomenal,” says Dr. Flaherty. “We didn’t think we’d be here by 2015. But to cure 100 percent of these patients we realize we need to find multiple pathways — new combinations of drugs, perhaps, that target the mutation in different ways.”

In the meantime, a new glitch had arisen. Another mutation surfaced in some patients, and Dr. Flaherty engaged additional companies including GlaxoSmithKline, Novartis, Pfizer and Bristol-Myers Squibb, which were producing similar drugs that he thought might improve results if given in combination with PLX4032. There was still work to be done.

More advanced phases of the trial began last fall and winter nationwide, with Dr. Flaherty and his Mass General Cancer Center colleague, Donald P. Lawrence, MD, who is clinical director of the Melanoma Program at the Cancer Center, at the helm.

Amidst the tsunami of requests to enroll in the trial, Emily Black lucked out. After testing positive for the BRAF mutation and undergoing a series of other exams for eligibility, she enrolled in the phase II trial and received PLX4032. Last spring, shortly after one of her first doses, Emily held her breath as she met with Dr. Lawrence, who gave her news of a recent body scan. He told her, “There is no evidence of disease in your lungs, liver and lymph nodes. Your whole torso looks clean.” And the tumor in her leg had receded by more than half of its original size. She didn’t need anyone to tell her that part, though; she was already back in her old jeans.

Like other patients on the trial, she is experiencing some side effects, including rashes and joint pain. She finds them irritating but, she says, “tolerable”.

Stephen Beisheim, a food manager at Costco Wholesale Corp. from Whitman, Mass., and another MGH patient in the trial, initially had an intolerable rash, but now with a reduced dosage, he experiences only minor side effects. Previous medications had done little to beat back the cancer in his right leg and beside his rib cage. Mere weeks into the trial, Dr. Lawrence told Stephen the good news that his scans were “clean”. His right leg, where the melanoma began, was still pockmarked with dozens of black circles the size of nickels, but, Dr. Lawrence reassured him, “Just think of them as tattoos. They might not be pretty, but there’s no disease there.”

But because no one has taken this drug for more than 22 months, there’s no way to predict the future of patients on it today, says Dr. Flaherty. “All we can do is say, ‘So far, so good,’ and hope the drug doesn’t stop working. Maybe it will stop working, or maybe these patients will be on it for years and years, being kept alive by it.”

Though he expects FDA approval within a year, Dr. Flaherty is already planning for improving outcomes for patients with the genetic mutation and figuring out how to treat the other 50 percent of advanced melanoma patients who don’t possess the mutation. “We know the drug works, but we don’t really understand precisely how. We have to study the molecular mechanisms that allow some tumor cells to survive, which will guide how we might tweak it in the future or combine it with other drugs to improve outcomes even more, and perhaps make this translate for other cancers,” says Dr. Flaherty.

Already, Dr. Lawrence is leading a multi-center clinical trial that tests treatment for patients with BRAF mutations but have cancers other than melanoma. “BRAF mutations are found in a wide array of cancers, albeit at much lower frequency than in melanoma,” he says.  “If our paradigm is correct, new agents that target this pathway may be beneficial in the subsets of  lung, colon, thyroid, ovarian and other cancers that harbor these mutations. We are on the verge of treating cancer selectively based on its genetic fingerprints rather than empirically based on its anatomic site of origin.