Treatment of Malignant Melanoma - Episode 1
Jason Luke, MD, FACP:This is a 46-year-old woman who was diagnosed with a stage 3C melanoma now about a year ago, initially with a deep ulcerated primary tumor and multiple involved lymph nodes. She underwent wide local incision, completion of lymph node dissection, and appeared to be clear of disease. Her choice was not to pursue adjuvant therapy after surgery. And unfortunately, after approximately 6 months’ completion of surgery, she had the development of abdominal pain. Subsequent imaging showed multiple masses in the liver, more than 1 cm, scattered pulmonary nodules, as well as some enlarged lymph nodes, thus showing signs of stage 4 metastatic disease. She underwent a tumor biopsy, which did document melanoma, and mutational analysis showedBRAF V600Emutation being present. The question then is, what to do going forward? This patient elected to start on BRAF and MEK inhibition with dabrafenib and trametinib.
Management of patients with stage 3 melanoma is really undergoing a paradigm shift. I think all doctors agree, and the NCCN recommends, intermittent follow-up and consideration of radiologic imaging to assess for recurrence of disease. So, generally speaking, that’s on the order of every 3 to 6 months or so. The question of what to do in the adjuvant space in terms of treatment is quite fraught. Historically, interferon alfa was considered a standard of care, though the overall survival benefit of that therapy was quite modest, and a lot of doctors really advocated for observation only for patients even with stage 3 melanoma.
We now know based on the EORTC 071 data that there’s an advantage in terms of overall survival for ipilimumab at 10 mg/kg in the adjuvant space. That is controversial, however, given the high toxicity profile of ipilimumab. And then, there’s an evolving paradigm of clinical trials that we’ll be reporting out in the next 2 years looking at BRAF inhibitors, looking at PD-1 antibodies, even looking at the combination of ipilimumab and nivolumab in the adjuvant setting. So, this is a wide-open space that’s subject to a lot of physician discretion, but generally speaking, we see patients at least every 3 months, and we consider whether or not to give them ipilimumab or interferon.
Patients who appear to have symptoms consistent with the recurrence or radiologic imaging that suggest a recurrence of melanoma really should be thoroughly worked up. And I would advocate that unless the recurrence is in the exact site of where the primary lesion was or in the exact lymph node base and where lymph nodes were resected, really a biopsy should be pursued. In melanoma now, the standard of care really should be a core needle biopsy because we need that tissue then to do subsequent analyses; most importantly would be mutational analysis. So, assessing for the presence or absence of aBRAFV600mutation is really an essential part of the care of all patients with melanoma. There are even data suggesting we should also be testing forNRASmutations, with drugs being developed in that space.
And then, there’s a further debate about whether or not we should be testing patients’ tumors for PD-L1, a programmed death-ligand, to direct immunotherapy treatments. That is controversial, but it does, again, emphasize the need to get a good quality biopsy to better direct the subsequent workup. Once that’s in place and you have adequate immunohistochemical stains and histology that prove a diagnosis of melanoma, then move on to consideration of therapy, whether it be local therapy in terms of surgery or radiation, or more likely a systemic approachagain, targeted therapies towards BRAF or immunotherapies.
Transcript edited for clarity.