The Therapeutic Approach for Malignant Melanoma: Case 1 - Episode 3
Michael A. Davies, MD, PhD:Historically, there have been a number of factors that have been identified that really can predict outcomes in patients with stage 4 melanoma. One of the key factors includes the sites of involvement by the disease. Patients who have involvement of skin and subcutaneous tissue and lymph nodes have the best outcomes, patients who have lung involvement have intermediate outcomes, and patients with involvement of other organs have worse outcomes. Of particular note, patients with brain metastaseswhich occurs in approximately 60% of patients with stage 4 melanoma over the course of their disease—are the patients who have the worse prognosis by sites of involvement.
Another powerful prognostic factor in patients with stage 4 melanoma is serum LDH levels. And in the previous AJCC staging guidelines, the presence of an elevated serum LDH with the diagnosis of stage 4 conferred a core survival outcome regardless of the sites of involvement. As we’ve developed many new therapies for patients with metastatic melanoma that improved overall survival, we need to go back and reevaluate these factors. However, consistently across clinical trials with now FDA-approved therapies, we’ve seen that patients with high LDH generally have a lower chance of responding to therapies or tend to respond to therapies for a shorter period of time. And having large bulk of disease, having multiple large metastases, seems to also be a poor prognostic factor.
We actually, at this point, don’t have a lot of data about the continued prognostic significance of brain metastasis, as most of our registration trials did not include patients with brain metastases. However, there are significant data from multiple sources that suggest that patients with CNS involvement still have poorer outcomes compared to other patients with metastatic disease.
So, this is a patient in his 70s who presents with metastatic melanoma involving the lungs and the liver, with an elevated LDH and a wild-typeBRAFgenotype. There are multiple treatment options available for this patient. Based on existing data, probably the primary considerations for this patient will be treatment with either a single-agent PD-1 or a combined treatment with ipilimumab and nivolumab. Certainly, one of the debates we face daily is how to decide what therapy is appropriate for a patient in this situation. There’s a number of factors that generally go into that decision, based on what we know about the relative advantages and disadvantages of single-agent PD-1 and the ipilimumab/nivolumab combination therapy.
Certainly, we consider the comorbidities that the patient has. We know that, again, there’s an increased risk of toxicities with the ipilimumab/nivolumab combination. And so, often for patients who have multiple comorbidities or poor performance status, the benefits of single-agent PD-1with its lower toxicity profile—may be actually advantageous for a given patient. We do also consider the burden of disease and the serum LDH. High LDH and high tumor burden are factors that confer poor prognosis, and therefore, the more aggressive treatment with the ipilimumab/nivolumab combination may be particularly beneficial in that type of scenario. Another key factor is the presence or absence of theBRAFmutation. For patients with aBRAFmutation, we now have multiple therapeutic options, including targeted therapies in addition to the immune therapies that are approved for all patients with metastatic disease.
And finally, somewhat related to the comorbidities question is the patient’s social support network. For patients who, again, are in a community or living with other family members where they could be of assistance, if the patient were to get ill from side effects from the treatment, there’s a consideration there that they could potentially, again, be at less risk from the deleterious effects of a more toxic therapy like ipilimumab/nivolumab. In contrast, for patients who are socially isolated with little support, the increased risk that happens now with the autoimmune toxicities may push us to really use a less toxic therapy as our first therapy adoption for the patient.
Transcript edited for clarity.