by Elizabeth C. Smyth, MD, and Richard D. Carvajal, MD
Melanoma is the deadliest form of skin cancer. When discovered early, it can usually be cured with surgery alone, but once it spreads (metastasizes) throughout the body, treatment options are limited.1 After decades of frustration for researchers, however, promising new therapies are providing hope, extending life by a year or two for many patients and in some cases virtually curing them.
Until just this year, only two drugs were approved by the US Food and Drug Administration for the treatment of advanced (stage IV) metastatic melanoma. Dacarbazine (DTIC), approved in 1975, remains the only chemotherapy licensed to treat the disease. Patients on dacarbazine have a one-in-eight chance of having tumors shrink, and no additional survival benefit has been achieved by combining it with other.2 In 1998, high-dose interleukin-2 (IL-2), an immunological (immune-boosting) therapy, was approved by the FDA for stage IV patients; it is curative in four percent of patients, but associated with very serious side effects and fatal on average for one patient in 50.3
Clearly, more effective treatments are desperately needed. Over the past 10 years, our understanding of the biology of melanoma and the body’s natural defensive responses to this disease has increased dramatically. This knowledge has been translated into many new therapies. Indeed, this past year, clinical trials testing several of these new treatments have demonstrated substantial tumor shrinkage, a prolonged remission interval, and even improved overall survival — benefits never achieved before.
Augmenting Immune Reponse
Although the immune system of a melanoma patient can recognize that melanoma needs to be eradicated, it is usually unable to do so. However, in the mid-90’s, the laboratory of James Allison, PhD, Chairman of the Immunology Program at Memorial Sloan-Kettering Cancer Center in New York City, identified the function of an immune-regulating molecule called cytotoxic T lymphocyte-associated anti- gen-4 (CTLA-4). CTLA-4 inhibits activated immune cells, preventing them from attacking the body’s own tissues. Dr. Allison theorized that if CTLA-4’s braking ability upon the immune system could be blocked, the immune system’s cancer-fighting abilities could be temporarily enhanced.
This work ultimately led to a new “anti-CTLA-4” drug called ipilimumab (Yervoy), developed jointly by Medarex and Bristol-Myers Squibb. Ipilimumab is a monoclonal antibody, an immune protein that binds to CTLA-4 and inhibits it from functioning. This gives the immune system freer rein to identify and eliminate melanoma cells. In a large phase III trial of 676 advanced, inoperable melanoma patients published in 2010 in the New England Journal of Medicine, subjects previously treated unsuccessfully with other agents who received ipilimumab or ipilimumab plus a melanoma vaccine (gp100) lived on average 32 percent longer and had a 20 percent greater chance (45 percent vs. 25 percent) of surviving one year than those who received gp100 alone.4 And 24 percent were alive after two years, compared with just 14 percent of those treated with the other therapy. The impact of this trial cannot be overemphasized, as ipilimumab was shown to be the first treatment ever to improve overall survival in advanced melanoma patients.
Now, in new study findings just announced, ipilimumab was found to increase overall survival in inoperable stage III or stage IV metastatic melanoma patients who had not received prior therapy. The study specifically showed that ipilimumab combined with the chemotherapy dacarbazine increased overall survival, while dacarbazine alone did not.
The findings will be submitted to the American Society of Clinical Oncology for potential presentation at its annual meeting in June. According to the best estimates, ipilimumab may offer many patients a 2-year survival advantage, with a smaller percentage of patients being virtually cured.
Side effects of ipilimumab are related primarily to the overactivation of the immune system, resulting in itching, skin rash and diarrhea. In fact, ipilimumab may be more effective in patients who develop these side effects. However, in rare cases more dangerous side effects can occur, so patients are urged to enter clinical trials with physicians who are well versed in treating its toxicities.
Another idiosyncrasy of the treatment is that even in patients who ultimately see benefits, the disease may initially progress before it stabilizes or the tumor shrinks. For this reason, early clinical trials were at first deemed a failure before patients started to improve. In late March, 2011, ipilimumab became the newest drug to be approved by the FDA for treatment of advanced metastatic melanoma.
Using Genetic Variability to Target Therapy
Although all melanomas arise from what was once a normal melanocyte (pigment cell), not all melanomas are genetically the same. Boris Bastian, MD, PhD, Chairman of Pathology at Memorial Sloan-Kettering Cancer Center, has identified four distinct genetic types of melanoma: (1) melanoma arising from normal, non-sun damaged skin like the trunk and thighs; (2) melanoma arising from chronically sun-exposed areas like the scalp and back of the hands; (3) melanoma arising from the palms of the hands, the soles of the feet, or under the fingernails or toenails (acral lentiginous melanoma), and (4) melanoma arising from mucosal surfaces like the sinuses, mouth, vagina or anus.5 Of the melanomas occurring on non-sun damaged skin, about 60 percent have a mutation in a gene known as BRAF. The other melanoma subtypes more often have a mutation in a gene known as KIT.6
Mutations in both of these genes are, in part, responsible for the development and progression of melanoma. The abnormal proteins created by these mutated genes essentially become stuck in the “on” position, leading to uncontrolled growth. Drug therapies have been developed to inhibit these mutations, shutting off the cancerous proliferation.
Powerful new drugs developed to target these mutations have been extremely effective in clinical trials to date. A drug called PLX4032 (also known as Rg7204 or RO5185426), developed by Plexxicon in partner- ship with Roche, targets BRAF mutations, including the v600E mutation [Figure 1]. Results from the first clinical trial of this agent demonstrated major tumor shrink- age in an unparalleled 81 percent of patients whose tumor harbored the BRAF mutation.7 Never before has a single drug been shown to induce such a significant response in so many patients. Subsequently, a published phase II study and a recently announced, but as yet unpublished, phase III study have confirmed extended progression-free survival (a longer interval without the disease worsening) as well as significantly extended overall survival compared to patients on dacarbazine, with responses lasting from two to more than 18 months. The results will likely be presented formally in June at the American Society of Clinical Oncology’s annual meeting.
A unique side effect of this drug is the development of small squamous cell carcinoma skin cancers known as keratoacanthomas, which can be cured by simple resection (surgical removal).
Unfortunately, most patients eventually have suffered melanoma recurrences, and future studies will test the drug in combination with other therapies in the quest for longer-lasting benefits.
Among the potential KIT inhibitors, imatinib mesylate has shown great promise [Figure 1] in patients with the mutated gene. Although three small initial studies of imatinib in patients with advanced melanoma showed no significant anti-tumor effect,8-10 these studies did not require the presence of a KIT mutation in patients. In newer trials that enrolled only patients whose tumors harbored genetically active KIT mutations, 20 to 30 percent of patients treated achieved a major response. A 2010 phase II study from China reported not only high response rates but prolonged progression-free survival.11,12
These results suggest that each genetic subtype of melanoma may respond differently to an identical therapy.
Optimizing treatment will require a personalized approach based upon understanding and targeting the underlying genetics of each patient and tumor. Based partly on these results, larger trials comparing the efficacy of chemotherapy versus g SK2118436, another BRAF inhibitor, in BRAF-mutant melanoma, as well as chemotherapy versus nilotinib, a newer KIT inhibitor, in KIT-mutant melanoma, are ongoing. Results from these trials are anxiously awaited.
The Next Steps
Researchers are studying ways to improve on the antitumor effects achieved with ipilimumab, PLX4032, imatinib, and other agents. Studies combining these drugs with chemotherapy, various immunologic therapies, and other novel “targeted” treatments are ongoing. A variety of other agents also warrant further investigation [Figure 1].
These therapies represent only the tip of the iceberg, as many new drugs are being developed. It is very possible that using these treatments in combination will produce even more exciting results for melanoma patients. While there is still a long path to travel in our quest to find the cure for metastatic melanoma, these drugs represent a significant step forward.
Dr. Carvajal is an Assistant Attending Physician in the Melanoma/ Sarcoma Service at Memorial Sloan-Kettering Cancer Center in New York City. His research is focused on the development of novel therapies for advanced melanoma based upon our emerging understanding of the molecular heterogeneity of this disease.
Dr. Smyth is a Special Fellow in Medical Oncology at Memorial Sloan-Kettering Cancer Center. Her research interests include melanoma, gastrointestinal oncology and developmental therapeutics.
1. Balch CM, Gershenwald JE, Soong S-j, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27:6199-206.
2. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17:2745-51.
3. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant Interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999; 17:2105.
4. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with Ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711-23.
5. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353:2135-47.
6. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24:4340-6.
7. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. New Engl J Med 2010; 363:809-19.
8. Wyman K, Atkins MB, Prieto V, et al. Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006; 106:2005-11.
9. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 2005; 92:1398-405.
10. Kim KB, Eton O,Davis DW,et al.Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer 2008; 99:734-40.
11. Carvajal RD, Chapman PB, Wolchok JD, et al. A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT. J Clin Oncol 2009; 27:15s (suppl; abstr 9001).
12. GuoJ,SiL,KongY,etal.A phase II study of imatinib for advanced melanoma patients with KIT aberrations. J Clin Oncol 2010; 28:15s (suppl; abstr 8527).