The medical landscape has changed dramatically for advanced melanoma since 2011, with both individual and combination therapy regimens gaining approval in even recent months. While modern genomics knowledge and knowledge of the immune system have brought about significant improvements in response and longer survival periods for some patients, there is still no cure.
Changes in advanced melanoma therapy approvals are happening fast. There have been several FDA approvals for combination, individual and adjuvant therapies in the last few months - since the National Comprehensive Cancer Network released its updated guidelines in March 2015.
“In 1975, dacarbazine was the only FDA-approved cytotoxic therapy, and interleukin 2, which has durable efficacy in 5% of patients, was approved in the late 1990s,” said Philip Friedlander, M.D., Ph.D., director of the melanoma medical oncology program at Mount Sinai School of Medicine in New York.
Since 2011, however, a steady stream of new agents for advanced disease has meant that doctors now have access to several treatment regimens that offer survival benefit. That includes FDA approvals in recent months of a combination therapy with the PD1 inhibitor nivolumab with the CTLA-4 inhibitor ipilimumab; the BRAF-MEK inhibitor combination vemurafenib and cobimetinib; T-VEC, oncolytic herpes virus injected into tumors; and new adjuvant ipilimumab therapy for patients with stage 3 melanoma.
The challenge with all the options is choosing the right therapy and sequence, according to Dr. Friedlander. It’s important, with so many options, to weed out those that aren’t making the grade.
“… you no longer see dacarbazine, which offers no survival advantage, as one of the recommended options for frontline therapy,” said Dr. Friedlander, who spoke to colleagues about advances in melanoma during the summer meeting of the American Academy of Dermatology (2015, New York). Dr. Friedlander also noted that the chemotherapy paclitaxel shows some efficacy is advanced melanoma, but no survival benefit.
A better understanding of the genetics of melanoma, and how the immune system affects melanoma, has led to new options including several new targeted and combination therapies, as well as medications for immune checkpoint modulation, Dr. Friedlander said.
Some background: A genetic variant called BRAF was reported in the early 2000s, as researchers learned about a protein chain called the MAP kinase signal transduction pathway, which communicates with cellular DNA. V 600 E is the most common location for BRAF mutations, according to Friedlander.
“Fifty percent of melanomas have BRAF mutations, while 15% to 20% have NRAS, and a subset have KIT mutations,” Dr. Friedlander said. “Therefore, techniques have been developed to block both BRAF and MEK, and that’s the standard of care now for BRAF targeted therapy.”
The new discoveries generated considerable excitement, as patients who received medicines targeting the BRAF mutation enjoyed a much better response rate- approximately 68%, compared with less than 20% for those who received the old chemotherapy. Patients who receive the new medications also enjoy an increase in survival.
“We have targeted therapies that block BRAF, one is dabrafenib, and a MEK inhibitor, called trametinib. They’re on the same pathway. They’re both approved as single agents,” Dr. Friedlander said. “But we use them, really, combined. There are higher response rates and overall survival when you combine the two.”
The FDA also gave its thumbs up to the combination of vemurafenib, a BRAF inhibitor, with cobimetinib, a MEK inhibitor.
“So, now you have two BRAF/MEK inhibitor combinations in competition with each other. We don’t have proof that one is more efficacious than the other,” Dr. Friedlander said.
Another groundbreaking approval in recent months is for the combination melanoma therapy ipilimumab and nivolumab. When combined, the drugs offer a higher response rate, according to Dr. Friedlander.
“Around 60 percent of patients get a response. The price you pay is that around 60 percent of people get a high-grade autoimmune toxicity,” Dr. Friedlander said. “When T cells come into the tumor microenvironment, they are expressing PD1 on their surface. When PD1 on the T-cell recognizes PDL1 on the tumor cell, it inactivates the T-cell.”
According to a study published last year in the New England Journal of Medicine, nivolumab, a PD1 inhibitor, was compared to dacarbazine as frontline therapy in 418 stage IV melanoma patients without a BRAF mutation. Median progression free survival was 5.1 months for those on nivolumab, compared with 2.2 months for those on chemotherapy, and most patients (72.9%) who received the PD1 inhibitor were still alive one year later, compared to only 42.1% of those who received dacarbazine (p<0.001), Friedlander points out.
According to Dr. Friedlander, response rates are higher with PD1 inhibitors than with CTLA4 targeted therapy. He cited a randomized phase 3 study of the combination of ipilimumab and nivolumab versus either one alone, in almost 1,000 stage IV melanoma patients with no prior systemic therapy for advanced disease. Both of the PD1 targeted arms had significant benefit relative to ipilimumab, but it comes at a price: 55% of patients treated with the combination in the study had high-grade toxicity.
Median progression-free survival was 11.5 months in those patients who received combination therapy, compared to 6.9 months in those who received nivolumab alone, and 2.9 months in those who received ipilimumab alone.
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“One biomarker that may be useful in predicting the effectiveness of PD1 inhibitors is the expression of PDL1 on the tumor surface,” Dr. Friedlander said. “If one looks at that in this study, one sees that in patients who had PDL1 expression in over 5% of melanoma cells, there was no difference in nivolumab alone versus the combination. But in patients who did not have PDL1 expression, progression-free survival went from 5.3 months with nivolumab alone to 11.2 months with combination therapy, suggesting that maybe in patients where we don’t detect PDL1, that the combination may at times be a better choice than the PD1 inhibitor alone….”
But what about for the 50% of patients with tumors that do not show the BRAF mutation?
“BRAF inhibitors do not show efficacy in melanomas that do not contain the BRAF mutation, and paradoxically can be harmful,” Dr. Friedlander notes. He explains that such treatment can lead to squamous cell carcinoma formation. In such cases, therefore, doctors may turn to the other group of new therapies that have emerged since 2011, immune therapies.
Most recently, the immunotherapy T-VEC has also gained FDA approval for stage 4 and unresectable stage 3 melanoma.
“That’s a novel oncolytic herpes virus that’s genetically engineered to be noninfectious and to secrete GM-CSF. It was FDA approved based on a 16 percent durable response rate at six months. It can be considered for treatment in a sub population of patients that have very limited visceral disease and largely accessible disease-either lymph nodes or soft tissue under the skin. You can inject it and get benefits in the injected lesion and also a bystander effect in nearby lesions,” Dr. Friedlander said.
Ipilimumab, which was approved in 2011 as a single agent for stage 4 and unresectable stage 3 melanoma, has now been FDA approved as an adjuvant therapy for people who have stage 3 melanoma that’s lymph node resected.
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“It is given every three weeks for four treatments and, if patients do well, it’s given once every three months for up to three years. The dose is based on weight. So, in the adjuvant setting there is a 10 mg per kg dosage. In stage 4 disease it’s 3 mg per kg-a higher dose,” Dr. Friedlander said. “The FDA approved it because of a benefit in terms of recurrence-free survival. The hazard rates are .75. We do not have overall survival data yet to know if this will translate to an overall survival. We hope it will. Toxicities are also autoimmune. There were several fatalities. Five patients had fatal toxicity, which is concerning.”
If one looks at pros and cons, targeted therapies have a high response rate. But there remain questions about durability. Immunotherapies have the benefit of durability, but limitations of response rates, according to Dr. Friedlander.
However, combining immunotherapies, while at the cost of added toxicity, has the potential to significantly increase the response rate to levels comparable with that seen with BRAF targeted therapy.
“In choosing a therapy, first you should decide if the patient has a BRAF V600 mutation, and then how long do you think the patient will stay clinically stable? How rapidly is the tumor growing? How critical is it to optimize the response at the current time?” he said.
Disclosure: Dr. Friedlander reports that he had served on advisory boards for GSK, Novartis and Genetech.
 Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-30.
 Larkin J, Chiarion-sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23-34.