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New agent approvals over the last several years and even better ones in the pipeline have displaced older therapies and improved outcomes for patients with melanoma. Some physicians say, the future may bring a cure.
Perhaps no other cancer has benefited more from treatment advances in recent years than advanced melanoma. Once a virtual death sentence, these patients now have a reason to be hopeful, thanks to agents approved in the last three years and even better ones in the pipeline, speakers said at the 3rd Annual World Cutaneous Malignancies Congress (San Francisco, October 2014).
“Nearly 20% of patients receiving the anti-CTLA4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb) are alive at five years, and even some patients who had infusions 10 years ago are still living,” says Caroline Robert, M.D., head of the dermatology unit at the Institut Gustave-Roussy in Paris, France, who has led several recent melanoma treatment trials.
“We have had many recent approvals of therapies that have displaced our old standards,” notes Antoni Ribas, M.D., Ph.D., professor of medicine, surgery and molecular and medical pharmacology, and director of the tumor immunology program at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.
Randomized trials of ipilimumab, the BRAF inhibitors vemurafenib and dabrafenib, the MEK inhibitors trametinib and cobemetinib and the anti-PD-1 inhibitors pembrolizumab and nivolumab have demonstrated that “it’s better to be on a new drug” than an old standard-of-care such as dacarbazine, Dr. Ribas says.
The anti-PD-1/PD-L1 drugs, which target the programmed cell death protein 1 (PD-1) and its ligand (PD-L1), will clearly take the treatment of advanced melanoma to the next level, according to Dr. Robert. Pembrolizumab (Keytruda, Merck) has already become FDA-approved for patients after prior ipilimumab and, if there are mutations in the BRAF gene, a BRAF inhibitor.
Thanks to these and agents to come, “I believe that one day, we will be able to cure our patients,” Dr. Robert says.
In the phase 3 CA209-037 trial, which Dr. Robert led, response rates were 32% to single-agent nivolumab and 11% to dacarbazine, median time to response was 2 months, and overall survival at 1 year was 72.9% versus 42.1%, respectively, a 58% reduction in mortality risk (P < .0001).
With pembrolizumab as a single agent, survival in phase 1 studies was reported to be 62% at 19 months, she adds.
“The drugs also have a very good risk/benefit ratio,” Dr. Robert notes. Most of the toxicity, which is limited to immune-related side effects, is manageable.
As good as these outcomes appear in advanced melanoma, the future may lie in combining anti-PD-1/PD-L1 agents with ipilimumab, the speakers agree.
The rationale is that CTLA4 and PD-1 are non-redundant immune checkpoints in T-cell differentiation and function, which is why they might have additive or synergistic effects, according to Dr. Robert.
The phase 1 CA209-004 study evaluated ipilimumab and nivolumab (Opdivo, Bristol-Myers Squibb) in combination, comparing different dosages and concurrent versus sequential use, plus maintenance nivolumab. In this combined concurrent dosing cohort of 53 patients, overall survival at 1 year was 85% and 2-year survival was 79%; in one of the individual dosing cohorts, 1-year survival topped 94%.
The concern is toxicity. In the dose-finding study, 64% of patients reported grade 3-4 events with the concurrent treatment, primarily gastrointestinal (14%), hepatic (14%) and endocrine (3%). Toxicity was much less with sequential treatment.
“These occur early and they are not trivial,” Dr. Robert notes. “We will need to see if the efficacy of this combination is worth the toxicity.”
Currently, physicians test for BRAF status and then design treatment accordingly, ie, consider whether to use a BRAF/MEK inhibitor, or ipilimumab, first line.
“This is not how we are going to treat melanoma in two years,” Dr. Ribas predicts. “We will be evaluating the interaction between the cancer cell and the immune system, and that will tell us what to do.”
In other words, clinicians will start by looking for factors predicting response to PD-1/PD-L1 blockade. This will involve the detection of CD8+ T cells and PD-1/PD-L1 at baseline, factors that limit the response of the immune system and that might be countered via a PD1/PD-L1 inhibitor.
“It sounds complicated now, but this will be a simple thing we can all detect,” he says. Only those patients with this characteristic immune profile will receive initial treatment with an anti-PD-1 or anti-PD-L1 antibody. Patients with features unlikely for a response will receive upfront combination therapy or novel approach that will bring T cells to the tumor.
The strategy taken by many clinicians-to select a treatment based on growth kinetics of a tumor-will become moot. Instead, he says, “We will be asking whether the patient is likely to respond to a PD-1/PD-L1 inhibitor or not, and whether we should give it as a single agent or in combination.”
Axel Hauschild, M.D., Ph.D., head of the Skin Cancer Working Group at the University Hospital Schleswig-Holstein in Germany and co-chair of the Global Melanoma Task Force, expressed frustration that his options in Europe are more limited than they are in the United States.
“We have a very different reimbursement situation in Europe and it’s not as easy to treat there, as in the U.S.,” he says.
While there is excitement over immunotherapy and targeted agents, no such combinations are yet approved for stage IV melanoma in Europe, and should they become approved, their cost will be an issue, he says.
He compared the approval status of the newest agents between the United States and Europe:
He added that IL-2 is virtually never used in Germany because, lacking phase 3 trial data, it has not been approved. Physicians who prescribe IL-2 off-label bear the full financial responsibility of the drug, he says.
He also indicated that clinicians in Europe largely operate without a universally accepted guideline. The general consensus is that the best guideline is the one recently developed in Germany, based on a Cochrane review, and involving 32 disciplines from the German Cancer Society. “This is now the gold standard in Europe,” he says.
Dr. Hauschild points out that while there is much excitement about immunotherapy, “targeted treatments work faster,” at least faster than ipilimumab. This is important in many cases, and should not be dismissed, as new agents emerge.
He predicts that when anti-PD-1/PD-L1 antibodies become available, the algorithm may recommend that clinicians evaluate for level of symptomatic disease. All symptomatic patients may initially receive ipilimumab, alone or in combination with an anti-PD-1/PD-L1 antibody, with BRAF status becoming important when the disease progresses. Re-treatment with combined immunotherapy or with BRAF inhibitors also may be part of the future algorithm.
This strategy is not yet evidence-based, he adds, and must prove superiority to the concept of determining BRAF status first.
“It remains unclear whether the anti-PD-1/PD-L1 antibodies or BRAF/MEK inhibitors should be given as first-line treatment in the future, until specific trial results become available,” Dr. Hauschild says. “Tumor load and symptoms might matter most for this decision.”
Trials evaluating ipilimumab plus anti-PD-1/PD-L1 combinations and trials of various sequencing approaches to BRAF/MEK inhibition, PD-1/PD-L1 blockade and ipilimumab will be critical, he said.
 Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation.New Engl J Med [early online publication]. November 16, 2014.