Keller, Daniel M. PhD
LYNN SCHUCHTER, MD
PHILADELPHIA—With a handful of new drugs against advanced melanoma on the market and in development and with available tests for molecular aberrations in the tumors, the disease is emerging from a therapy desert and coming upon a fertile oasis of treatment options. That was the overall message from Lynn M. Schuchter, MD, Professor of Hematology-Oncology and leader of the melanoma program at the University of Pennsylvania Abramson Cancer Center, speaking here at the International Meeting of the Society for Melanoma Research.
Prior to 2010, she noted, of the three drugs that were FDA-approved to treat advanced melanoma—interferon, dacarbazine, and interleukin-2—none increased overall survival, which remained at six to nine months, and there were no positive Phase III trials.
Since then, though, four additional drugs have been approved—ipilimumab, vemurafenib, dabrafenib, and trametinib—seven more are in clinical trials, and the approved drugs have shown superiority in both response rates and durable responses over what was available just a few years ago.
Schuchter noted that two approaches have proven successful so far: targeting the MAP (mitogen-activated protein) kinase pathway and using immune checkpoint inhibitors—namely, inhibitors of CTLA-4 and compounds that inhibit interaction of PD-L1 on tumor cells with PD-1 on T cells.
Both vemurafenib and dabrafenib, approved for treating unresectable Stage III or IV melanoma, target V600 mutants of BRAF—the former the V600E mutant and the latter both V600E and V600K mutants. The BRAF gene produces B-Raf serine/threonine-specific kinase, which is part of the MAP kinase signaling pathway affecting cell division and differentiation.
Vemurafenib produces a response rate of about 50 percent (compared with about 10 percent for dacarbazine), progression-free survival (PFS) of about five to seven months, and an overall survival rate at one year of 56 percent. Dabrafenib shows similar response rates and PFS but with a 70 percent one-year overall survival rate.
“Brain metastases are a huge challenge” in melanoma, Schuchter noted. Fortunately both vemurafenib and dabrafenib show activity against brain metastases.
Adverse events with both drugs include rash and uveitis as well as some additional side effects specific to each drug: Vemurafenib has been associated with skin toxicity, squamous cell carcinoma (SCC) in 20 percent of patients, and photosensitivity, but SCC is much reduced when vemurafenib is combined with a MEK inhibitor. Photosensitivity and SCC are less common with dabrafenib.
She explained that trametinib is an inhibitor of the mitogen-activated protein kinase kinase enzymes MEK1 and MEK2. Used as monotherapy, the drug has shown a response rate of 22 percent, PFS of 4.8 months, and a six-month overall survival rate of 81 percent when used to treat melanomas with V600E or V600K BRAF mutations.
When combined with the BRAF-inhibitor dabrafenib, however, the response rate is 60 to 70 percent, PFS is 9.4 months, and the overall survival rate at one year is 80 percent. Using the drugs sequentially appears to be much less efficacious than combining them, she said: A BRAF inhibitor followed by a MEK inhibitor showed a response rate of only five percent and progression-free survival of only 1.8 months.
“So to summarize where we are, single-agent BRAF inhibitor therapy is associated with a response rate of about 50 percent and a one-year overall survival rate of about 50 to 70 percent. Combination therapy with BRAF and MEK [inhibitors] appears to be better than monotherapy with BRAF inhibitor alone, but we obviously need to see the results from randomized clinical trials,” she advised.
Two other MEK inhibitors, MEK162 and selumetinib, are in development for melanoma, as well as the BRAF inhibitor LGX818, and imatinib and other compounds for melanomas containing Kit mutations (which represent about 10 percent of acral and mucosal melanomas). Selumetinib has shown a 20 percent response rate in trials against uveal melanomas, which have largely been resistant to treatment with the newly approved drugs, Schuchter noted.
Only one drug, ipilimumab, is approved to block the CTLA-4 checkpoint. When stimulated, CTLA-4 (cytotoxic T-lymphocyte antigen-4) on T cells down-regulates the immune system, allowing an immune attack against tumor cells.
In melanoma, ipilimumab produced a response rate of 15 to 20 percent, durable complete and partial responses, and a one-year overall survival rate of 46 percent, she noted. The drug is active in the setting of brain metastases.
Side effects include colitis, endocrinopathies, and immune-related problems.
Another antibody, as yet not FDA approved, is nivolumab, which inhibits PD-1 on T cells. It has produced a 28 percent response rate in melanoma and appears to have efficacy in patients who were already treated with ipilimumab, Schuchter said.
“The rapidity of the response with PD-1 is also very striking. To see rapid response in patients getting PD-1 antibodies is really interesting, as well as delayed responses. When nivolumab is combined with ipilimumab, most responses occurred by 12 weeks, with one occurring as late as 70 weeks—So these are results that we have not previously seen.”
The difference with the combination was striking, she said: Although neither drug alone achieved more than a 28 percent objective response rate (i.e., the sum of complete and partial responses and stable disease) or more than three percent of patients having tumor reduction of more than 80 percent, these percentages increased to 53 percent and 41 percent, respectively.
Other single-agent and combination therapies are in trials, Schuchter said, pointing to lambrolizumab, which may be at least as effective as ipilimumab, with a response rate of 41 percent (including a complete response rate of nine percent, and a one-year overall survival rate of 81 percent). Dual blockade of CTLA-4 with ipilimumab and PD-1 with nivolumab also appears to have potential, although grade 3 and 4 immune adverse events were 18 percent.
She summed up the results with PD-1 and PD-L1 blocking drugs with one word: “Wow!”
Resistance to BRAF inhibitors
“Resistance is the big issue,” Schuchter emphasized, occurring both upfront and at the time of disease progression. “There are multiple mechanisms of resistance even in the same patient, which is very challenging to think about.”
The BRAF V600 mutation persists at the time of progression, and there do not appear to be any new activating mutations in BRAF. She said dual MAP kinase blockade may overcome primary resistance and delay secondary resistance to BRAF inhibitors. But once BRAF-inhibitor resistance develops, clinical responses are infrequent.
Schuchter said it will be critical to understand the specific mechanisms of resistance to BRAF inhibitors to be able to develop strategies that more effectively inhibit the MAP-kinase pathway.
For all of the therapeutic approaches—BRAF and MEK inhibitors, checkpoint blockade, and those yet to be discovered—combination strategies will be important and need to be worked out, she said. In addition, biomarker development will be critical to designing better therapies and to be able to target them to appropriate patients.
Clinical Implications and Recommendations
Schuchter strongly recommended testing all patients with stage IV melanoma for all V600 BRAF mutations, not just V600E. While 50 percent of melanomas harbor BRAF mutations, NRAS gene mutations may occur in up to 25 percent of melanomas. Any melanoma tissue can be tested, so the largest specimen would be a good choice, she added.
Schuchter said that her recommendation for patients with BRAF-mutant melanoma is to use a targeted therapy first if there is a high disease burden. Otherwise, for patients with a low disease burden, few symptoms, or wild-type (non-mutant) BRAF, immunotherapy would be the first-line choice. Chemotherapy would be a second or third choice. In addition, she noted, a clinical trial is also always a good first choice.
Thinking about Cure
Vernon Sondak, MD, Chief of the Division of Cutaneous Oncology at H. Lee Moffitt Cancer Center and Research Institute, asked from the audience what proportion of patients treated with all appropriate drugs would eventually become refractory. Schuchter estimated at least 80 percent—meaning, though, that that could still as many as 20 percent of patients who do not progress.
“Until this year, I'm not sure that I would ever use the word ‘cure’ for patients with Stage IV melanoma,” she said. “We see these durable responses at three years in patients who had compete response,” and with the current drugs and ones in clinical trials, it may not be far-fetched to begin to think about curing some cases of advanced melanoma.