In a phase three study of 676 patients with unresectable stage III or stage IV melanoma, published in the New England Journal of Medicine (2010;363(8):711-23), the patients received ipilimumab plus a glycoprotein 100 (gp100) peptide vaccine, ipilimumab alone, or gp100 alone. Median overall survival was 10 months among patients receiving ipilimumab plus gp100, 10.1 months for those receiving ipilimumab alone, and 6.4 months among those receiving gp100 alone. The ipilimumab-alone group had a two-year survival rate of 24 percent; this makes ipilimumab the first treatment ever to improve overall survival in advanced melanoma patients, Dr. Halpern noted. The most common adverse events were immune-related and most often affected the skin and gastrointestinal tract. Another phase three study, also published in NEJM (2011;364(26):2517-26), found a three-year survival rate of 20.8 percent in patients treated with ipilimumab plus dacarbazine versus 12.2 percent in a group treated with dacarbazine plus placebo. “The hope is that some of these patients who have responded completely to ipilimumab will be cured of their disease,” Dr. Halpern said.
The second new drug, vemurafenib, is the first targeted genetic therapy approved for melanoma. Approved last August, vemurafenib blocks the function of the defective V600E BRAF gene, which is present in about half of all melanomas. The FDA also approved a diagnostic test that will help determine if a patient’s melanoma cells have the BRAF V600E mutation. “There’s a MAP-kinase pathway that this gene sort of switches off,” said Darrell Rigel, MD, clinical professor of dermatology at New York University School of Medicine. “If you have this mutation of the BRAF gene, the path is constantly switched on and the cell grows uncontrollably. The idea behind the drug was to be able to turn that switch off and block the pathway, like tearing out a wire.”
A phase three trial of 675 late-stage melanoma patients with the BRAF V600E mutation compared vemurafenib with dacarbazine. Published in NEJM (2011;364(26):2507-16), the trial was designed to measure overall survival; however, overall survival could not be determined at the time of FDA approval because 77 percent of vemurafenib patients were still alive. Published results indicate a 48 percent confirmed response for the vemurafenib group (compared with 5 percent for the dacarbazine group) and an estimated median progression-free survival of 5.3 months in the vemurafenib group and 1.6 months in the dacarbazine group. The most common adverse events in the vemurafenib group were cutaneous SCC, keratoacanthoma, arthralgia, and fatigue.
“We’re just at the beginning of understanding these two drugs,” Dr. Weinstock said. “We know that neither, by itself, is a reliable cure. We don’t know a lot about using them in combination. There’s a lot of investigation into related drugs that may be better than these initial ones.” Dr. Halpern confirmed that the two drugs are now being tested in combination, and added that investigators are focusing on additional ways of targeting pathways that enable the advance of melanoma. “Because BRAF is a key component of the MAP-kinase pathway, it means that there are molecules upstream and downstream of this particular one that are also what we would call ‘drug targetable,’” he explained. “The question becomes, can we combine drugs that are hitting different parts of these pathways simultaneously? So it’s a very exciting time as these drugs are being tested both separately and in concert.”
A tool for early detection
Complementing the dramatic advances in treating late-stage melanoma was the FDA’s approval of groundbreaking technology designed to help dermatologists detect melanoma in its earliest stage. MelaFind, a hand-held imaging device approved in November, projects light of 10 different wavelengths (from blue to near infrared) on a lesion. The resulting image is analyzed using an algorithm developed from a database of 10,000 biopsied lesions. A “positive” finding is considered evidence to support biopsy, not a diagnosis of melanoma. It is intended for use only by dermatologists who have completed a training program, and only on pigmented lesions meeting specific criteria.
“Right now we’re kind of in the dark ages in terms of finding melanoma early,” said Dr. Rigel, who is on the scientific advisory committee for Mela Sciences, the makers of MelaFind. “It’s very subjective; we can’t quantify why a spot is melanoma but can only say ‘it looks like one.’ MelaFind is very easy to use, the results are available within a couple of seconds, and it’s not expensive. It’s been tested on a large data set and demonstrated a 98.4 percent sensitivity in identifying melanoma. I use dermoscopy, and this, to me, is like dermoscopy on steroids.” Dr. Halpern and Dr. Weinstock cautioned that the utility of MelaFind and its role in the dermatologist’s practice remain to be seen. “How they roll this out over the next year, what additional data they gather on how dermatologists are using it and is it proving helpful, are going to be absolutely critical to its diffusion into practice,” Dr. Halpern said. Dr. Rigel remarked that MelaFind could be particularly useful in patients who present with multiple lesions. “In a patient with 50 lesions, I could mark 20 of those that I think are potentially suspicious, and if three come out as positive I can biopsy those. What may happen over time is that you’ll start revising your own personal algorithm. But only time will tell, because there’s no other model out there like MelaFind in dermatology.” (For more discussion of MelaFind, see the article “Augmenting the naked eye” in the 2012 Buyer’s Guide.)
New drug battles BCC on two fronts
Vismodegib offers the first effective treatment for patients with inoperable, advanced BCC and a welcome alternative to multiple surgeries for those with basal cell nevus syndrome (BCNS). The drug binds to and inhibits Smoothened, an activator of the hedgehog pathway that is implicated in 90 percent of BCC tumors (see sidebar). Results from the pivotal phase two trial submitted to the FDA by Roche showed that vismodegib substantially shrank tumors or healed visible lesions in 43 percent of patients with locally advanced BCC and 30 percent of patients with metastatic BCC. (The study included 96 patients.) Based on those findings, the FDA granted the drug priority review status in October 2011 and approved the drug Jan. 30.
A second vismodegib trial, an investigator-initiated phase two study, boosted optimism even further when it was found that the drug can prevent new BCC tumors as well as shrink existing lesions. “We tested the drug on patients with basal cell nevus syndrome, also known as Gorlin syndrome,” said Jean Yuh Tang, MD, PhD, assistant professor of dermatology at Stanford University School of Medicine. “Some of these patients have really severe disease, with as many as 200 tumors. The only treatment options are Mohs surgery, standard excision, or electrodessication and curettage. These are all destructive and scarring, and a lot of our patients have significant morbidity because they’ve had so many surgeries.” Dr. Tang and principal investigator Ervin Epstein, MD, enrolled 41 adults with BCNS and randomized the subjects to receive either vismodegib or placebo. “The data safety monitoring board met and voted to end the placebo trial because vismodegib had an overwhelmingly positive effect,” Dr. Tang said. “In patients treated with the drug, we saw about two new BCCs per year, while patients in the placebo group developed 29 new BCCS.” The aggregate size of existing BCCs in the treatment group decreased by 24 cm, compared to 3 cm in the placebo group. Interim results of the study were presented at the 2011 annual meeting of the American Academy of Dermatology. The results have been accepted for publication in Elsevier’s Seminars in Cutaneous Medicine and Surgery.
“Some patients had to take a break from the medication during the study because of the side effects: taste loss, muscle cramps, hair loss, and weight loss,” Dr. Tang said. “So we’re trying to figure out whether we should give the drug a few months on, a few months off. The good news is that while you’re on the drug the tumors are almost gone; the bad news is that after a certain period of discontinuing the drug the tumors start to reappear. The time to recurrence depends on how long the patient has been on the medication.” Dr. Tang said that with the drug approved for advanced and metastatic BCC, dermatologists might begin prescribing it off-label for their patients with BCNS. “It’s wonderful for these patients; it’s changed their lives, and they’re so grateful for it.”