It is estimated that there will be more than 95,000 new cases of melanoma diagnosed in the United States in 2019 – and more than 7,000 deaths.
Most patients will be diagnosed with early stage disease, when surgery alone is curative. However, for those who develop advanced or metastatic disease, there has been an explosion of breakthrough therapies that have proven to prolong overall survival. These offer new hope in a disease that was once considered significantly fatal.
In several types of solid tumors, chemotherapy can play an important role. But in advanced melanoma, chemotherapy has not been shown to significantly improve overall survival. Response rates are usually less than 20 percent.
Rather, doctors are changing the landscape of melanoma treatment by activating the immune system to target cancer cells via immunotherapy antibodies, as well as the use of oral molecularly targeted BRAF/MEK inhibitor combinations.
Testing for mutations
All patients with metastatic melanoma should be tested for activating mutations in BRAF, specifically BRAF V600E or BRAF V600K mutations. If present, these mutations implicate a pathway by which these cells replicate and serve as a target for drug therapy.
Studies initially showed that the BRAF inhibitors vemurafenib and dabrafenib have efficacy in treating melanoma and prolonging survival compared with chemotherapy. Now, it is known that combining BRAF inhibition with blocking a downstream target called MEK can further enhance response rates, progression free survival and overall survival.
The Food and Drug Administration has approved three combinations of BRAF/MEK inhibitors for patients with BRAF V600(E/K) mutations: dabrafenib/trametinib, vemurafenib/cobimetinib and encorafenib/binimetinib. All provide a remarkable response rate of about 70 percent.
Toxicity can be an issue though, specifically diarrhea, fevers and chills. This can require dosage adjustments or temporary interruption of therapy.
Immunotherapy or checkpoint inhibitors work by taking the brakes off the immune system and blocking inhibitory signals that prevent immune cells from attacking cancer cells. Currently, the anti-PD-1 antibodies pembrolizumab and nivolumab are approved as single agent options in patients with advanced melanoma, with or without a BRAF mutation, with objective response rates of more than 40 percent.
These immunotherapy drugs have been shown to be superior to ipilimumab, a CTLA-4 inhibitor, that was the former immunotherapy approved in this disease and was a major advance to historical high dose IL-2 treatment.
A good combination
Furthermore, the combination of nivolumab plus ipilimumab has been demonstrated to have improved responses over either nivolumab or ipilimumab alone, though at the risk of higher toxicity. As the immune system is being activated, patients can experience inflammatory immune related toxicities, which can lead to therapy interruption and sometimes the need for steroid administration.
However, a subset of patients treated with immunotherapy can have a complete response to treatment, allowing for long-term disease control and the potential to discontinue treatment after a few years.
Immunotherapy with pembrolizumab, nivolumab or the combination of nivolumab/ipilimumab are all now standard of care options in patients with new onset metastatic melanoma with or without a BRAF mutation. Patients with a BRAF V600(E/K) mutation are candidates for either molecularly targeted treatment or immunotherapy upfront. This decision is individualized, based on disease burden and symptoms, side effect profiles, patient comorbidities and, of course, patient preference.
Whether immunotherapy or targeted therapy is used upfront, either option can be reserved as a second line treatment. These therapies have not been compared head to head, though a randomized trial is underway to address the question of how best to sequence them.
Taking positive steps
All in all, we have seen a revolution in melanoma treatment in the advanced setting, with a subset of patients experiencing long-term durable responses to treatment. Numerous trials are looking at new immunotherapy as well as molecular therapy combinations.
The future is indeed bright, and there remains much optimism for continual improved therapies and advances.
Through the California Skin and Melanoma Center, Diablo Valley Oncology provides multidisciplinary care of not only melanoma, but all skin cancers. We draw upon the insight and expertise of our medical oncologists, surgeons and radiation oncologists to optimize the best treatments and care for our patients.
Join Dr. Jeffrey Zweig and other skin cancer and melanoma experts at “The Many Faces of Skin Cancer,” 6:30-8:30 p.m. April 23 at the Lafayette Library, 2491 Mt. Diablo Blvd. RSVP at 925-677-5041 ext. 272 or firstname.lastname@example.org.
Dr. Jeffrey Zweig is a board certified medical oncologist and hematologist with Diablo Valley Oncology and Hematology Medical Group. One of his sub-specialties is the treatment of melanoma. For details, call 925-677-5041 or visit dvohmg.com or calskincancer.com.