Discovering hope
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New targeted and immune therapies prolonging survival in metastatic melanoma

Even in an era of rapid medical advances, the proliferation and the promise of new drugs impacting the survival of patients with metastatic melanoma is remarkable. “Five years ago, melanoma was regarded as a malignancy where there was very little hope for patients with metastatic disease,” said Jeffrey S. Weber, MD, PhD, senior member of the H. Lee Moffitt Cancer Center and director of the Donald A. Adam Comprehensive Melanoma Research Center in Tampa, Fla. “Most oncologists would simply accept that their patients would die of their metastatic disease. There were very few real options, the trials didn’t work, and it was sort of a hopeless scenario.” Fast forward to today, and “it’s a very different story. Now that we have multiple new drugs approved, even in the community setting there’s a lot of hope for melanoma. Survival is clearly prolonged compared to five years ago.” 

Building on the success of ipilimumab, a CTLA-4 antibody approved by the U.S. Food and Drug Administration in 2011, a series of antibodies targeting different checkpoints are being tested, and researchers continue to probe for different ways to activate the immune system against melanoma. Targeted therapy, a different approach utilizing genomic analysis, made its debut with the BRAF inhibitor vemurafenib, also approved in 2011. A second BRAF inhibitor, dabrafenib, and a MEK inhibitor, trametinib, received FDA approval as single agents in 2013 and as a combination treatment in 2014.

Until a few years ago, dermatologists referred their patients with stage 3 and 4 disease to oncologists, and “really didn’t have a huge role to play with regard to helping to manage therapy,” said Lynne Anne Cornelius, MD, professor of dermatology and medicine and chief of the division of dermatology at Washington University School of Medicine in St. Louis. Now that role is changing. With the introduction of the BRAF inhibitors, “we saw that many patients were getting other types of cutaneous malignancies, namely squamous cell carcinomas and new primary melanomas. So we realized that it’s very important to have dermatologists enlisted to recognize and treat these secondary malignancies.” [pagebreak]

There are other good reasons why dermatologists should stay involved, said Delphine J. Lee, MD, PhD. “As dermatologists, we’re sort of the primary care doctor for melanoma. Patients rely on us to put them in the hands of rational, compassionate, good doctors who know their stuff, who are at the cutting edge in medical and surgical oncology. And we should also be available as a sounding board to discuss treatment options, to really have an intelligent conversation. We should know what these treatments are and stay up to date.”

Targeted therapy

Both vemurafenib and dabrafenib “can decrease the tumor bulk, magically, before your eyes,” Dr. Lee said. “Patients may come with lumpy nodules and golf ball-sized tumors under their armpits. Shortly after starting the drug the disease miraculously shrinks. The problem is that it comes back, because the tumor figures out how to bypass that blocker.” Dr. Weber agreed that vemurafenib, early on, showed a response rate “in the range of 50 percent, but unfortunately, a majority of patients relapse within a year, and many of them will die relatively quickly.”

As researchers focused on understanding the mechanisms of resistance to BRAF inhibitors, they learned that “much of the resistance is still mediated through the MAP kinase pathway, which is the pathway through which BRAF signals,” Dr. Weber noted. “MEK is one of the downstream members of the MAP kinase pathway. So if you look at the attempts to combine BRAF and MEK inhibitors, you see very impressive results.” In January the FDA approved combination treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, both manufactured by GlaxoSmithKline, after results of a clinical trial showed that 76 percent of patients treated with the combination had a response that lasted an average of 10.5 months. Overall, “it’s looking awfully good. I have a whole cohort of patients four years out from treatment,” Dr. Weber said. But, he added, “we think we might be able to do even better. For example, we’re looking at starting trials of BRAF plus MEK plus other drugs, because even with BRAF-MEK you still have resistance. Most of the patients ultimately will progress.” [pagebreak]

Immune therapy

Presentations given at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) about immune therapy for melanoma generated buzz that reached all the way to consumers via USA Today (“Melanoma drugs extend life for some patients,” June 2, 2013) and Bloomberg News (“Death sentence no longer a given for patients with cancer,” June 3, 2013). Presenting results of a phase II study combining ipilimumab with the growth factor sargramostim (GM-CSF), F. Stephen Hodi Jr., MD, of the Dana-Farber Cancer Institute, reported that one-year overall survival with the combination was 67.9 percent (among 245 patients), compared with 51.2 percent for ipilimumab alone. The combination did not significantly improve the low response rate of ipilimumab (14.7 percent vs. 11.3 percent) but it may have reduced its toxicity: seven of nine treatment-related deaths occurred in the group treated with ipilumab alone.

Two experimental agents that target a different checkpoint protein on the T-cell, programmed death-1 (PD-1), also made news at the ASCO meeting. Researchers from the Yale Cancer Center led by Mario Sznol, MD, reported data from a phase I trial of nivolumab: 31 percent of patients (33 of 107) with melanoma had tumor shrinkage of at least one-third, with a median overall survival of 16.8 months, according to Medscape (“Is nivolumab a breakthrough’ in melanoma,” June 1, 2013). In another phase I trial combining nivolumab with ipilimumab, which compared a concurrent regimen with a sequenced regimen, 53 percent of patients in the concurrent-regimen receiving the highest dose of the drugs had an objective response, all with tumor reduction of 80 percent or more (N Engl J Med 2013;369:122-33). Bristol-Myers Squibb, the manufacturer of nivolumab (and ipilimumab), is currently conducting three phase III studies of the drug in advanced melanoma, according to Reuters; meanwhile, a competitive PD-1 agent from Merck & Co., MK-3475 (formerly known as lambrolizumab) also garnered attention at the meeting (“Merck melanoma drug shrinks tumors in 38 percent of patients,” June 2, 2013). Antoni Ribas, MD, PhD, of UCLA’s Jonsson Comprehensive Cancer Center, presented results of a study of MK-3475 showing a confirmed response rate of 38 percent with the highest rate, 52 percent, observed in the group that received the highest dose. The overall median progression-free survival among the 135 patients was longer than seven months (N Engl J Med 2013;369:134-44). The FDA designated MK-3475 a “breakthrough therapy” for melanoma in April 2013. [pagebreak]

And that’s just for starters; a new class of immune agents known as PDL-1 antibodies is on the way, Dr. Weber said. “PD-1 is the receptor on the immune cell; PDL-1 is the ligand which is usually on antigen-presenting cells but, perversely, it can be present on tumor cells,” he explained. “Amazingly, tumor cells upregulate expression of PDL-1, and that gives the tumor cell this diabolical way of suppressing local immunity in the tumor microenvironment. If you interrupt that pathway of binding PD-1 and PDL-1, in early phase studies, it became clear that you’re inducing serious regression of disease, in some cases fairly quickly, and in some cases big-time bulk disease would shrink away.” In addition, Dr. Weber said, “there are new checkpoint inhibitors coming along like LAG3 and Tim3; those seem very interesting and promising, and that’s the future.”

Research drives treatment plans

Melanoma research is advancing so quickly that “if you look at the [National Comprehensive Cancer Network] guidelines, there’s no question that an experimental trial should always be your first consideration in melanoma,” Dr. Weber said. “In our institution, when we see a new patient with metastatic disease or resected high-risk disease, our first thought is can they go on a trial, because it’s highly likely that a randomized trial or a phase II trial will give you a better opportunity than a standard treatment.” For patients with the V600E BRAF mutation, experts don’t always agree as to whether they should receive targeted BRAF-inhibitor therapy or immunologic drugs first, particularly if they have indolent disease, Dr. Weber remarked. “For those with slow-growing or relatively low tumor burden, a lot of docs in my business think they should go on an immunologic drug first, not a BRAF drug.”

Continuing the effort to arm the immune system against melanoma, researchers at the Icahn School of Medicine at Mount Sinai are focusing on the role of nitric oxide (NO) and the enzyme that creates it, inducible nitric oxide synthase (iNOS). “We know that NO and iNOS are important to the growth and progression of melanoma,” said Andrew Sikora, MD, assistant professor and director of head and neck translational research in the departments of otolaryngology, immunology, oncological science, and dermatology. “We also know from prior studies that the mTOR pathway is very important for both melanoma and many, many other cancers. We found that in the presence of NO, this pathway was stimulated, and that when we blocked NO production, the pathway shut down and this was associated with decreased growth and impaired survival of the melanoma cells.” Dr. Sikora’s team studied human melanoma cells grown in the laboratory on chicken eggs (Cancer Res; 74(4):1067-78). “We spelled out the molecular mechanism by which NO targets and modifies TSC2, a critical protein regulating the mTOR pathway,” he explained. “The next step is to take this approach into clinical trials. It’s an approach that could certainly be combined with BRAF inhibition or with ipilimumab or other checkpoint blockade inhibitors.” [pagebreak]

Integral part

Dermatologists have an important role to play for patients being treated with the new melanoma therapies, even if they are not the ones administering them. In addition to SCCs and new melanomas, patients taking BRAF inhibitors can develop “hyperkeratotic squamous proliferations that aren’t squamous cells but are still very bothersome to the patient,” Dr. Cornelius said. “They look more like warts, not actinic keratosis-like lesions.” Dr. Lee added that another side effect of vemurafenib (but not dabrafenib) is “extreme photosensitivity. A patient may go out in the sun for only five minutes, or even stand in the shade for an hour, and get a crazy sunburn.”

Dr. Cornelius noted that some patients on ipilimumab get pruritic eruptions and rashes that can usually be managed with topical steroids. Similarly, patients receiving anti-PD-1 drugs “can get itching, rashes; some patients do develop vitiligo, but nothing that has caused interruption of drug treatment. That’s where the dermatologist’s role becomes very, very important, in helping to manage patients and allow them to continue through with these therapies [despite] cutaneous side effects. I think that the anti-PD-1 drugs will really revolutionize cancer treatment, not just in melanoma, but in some other cancers as well.”

Dermatologists may have an increasing role in advancing research, Dr. Cornelius remarked, because “in the era of personalized medicine, if these patients develop resistance and have cutaneous metastases, we can be very much a part of the team that harvests some of the tumors and interrogates them to see if new therapies can work. We’re not there just yet outside the research environment, but it’s not a hard thing to imagine down the road.” In the meantime, she urged dermatologists to “step up to the plate and be an integral part of the [melanoma] patient care team. If we are not at the table with our colleagues in dealing with serious disease, we stand a big chance of being marginalized as physicians. It’s so important for us to be out there.” 

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