A Bright Update on Melanoma Treatment

Posted on: March 28, 2019

By Dr. Jeffrey Zweig

Melanoma skin cancer is unfortunately on the rise worldwide, and is now considered the 5th most common cancer diagnosis in the United States. It is estimated that in 2019, there will be over 95,000 new cases of melanoma diagnosed in the US and over 7,000 deaths. Luckily, most patients will be diagnosed with early stage disease whereby surgery alone is curative. However, for those that develop advanced or metastatic disease, there has been an explosion of breakthrough therapies over the years that have been proven to prolong overall survival, offering new hope in a disease that was once considered significantly fatal.

In contrast to several other types of solid tumors whereby chemotherapy can play an important role, in advanced melanoma, chemotherapy has not been shown to significantly improve overall survival, with response rates usually less than 20%. Rather, activating the immune system to target cancer cells via immunotherapy antibodies as well as the use of oral molecularly targeted BRAF/MEK inhibitor combinations have changed the landscape of melanoma treatment.

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. It was initially shown 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. As of 2019, there are now 3 combinations of BRAF/MEK inhibitors approved by the FDA for patients with BRAF V600(E/K) mutations – dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib. All provide a remarkable response rate of around 70%. Toxicity can be an issue though, specifically diarrhea, fevers, and chills, and can require dosage adjustments or temporary interruption of therapy.

Immunotherapy or checkpoint inhibitors work by taking the breaks 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 over 40%. 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. 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. Excitedly though, 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. In those patients with a BRAF V600 (E/K) mutation, they are candidates for either molecularly targeted treatment or immunotherapy upfront, and 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.

All in all, melanoma treatment in the advanced setting has undergone a revolution in the last years, with a subset of patients that experience long term durable responses to treatment. Numerous trials are underway, 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 as time progresses. We at Diablo Valley Oncology, through the California Skin and Melanoma Center, provide multidisciplinary care of not only melanoma, but all skin cancers, drawing 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. Zweig and other skin cancer and melanoma experts at the Many Faces of Skin Cancer on April 23, 2019 at the Lafayette Library from 6:30 – 8:30pm. Reservations recommended, call 925-677-5041,extn 272 or email sjung@dvohmg.com

Dr. Zweig is a board certified Medical Oncologist and Hematologist with Diablo Valley Oncology and Hematology Medical Group. One of his sub-specialty interests is in the treatment of melanoma. To reach Dr. Zweig, please call 925-677-5041 or visit these websites: www.dvohmg.com or www.calskincancer.com