Keith Flaherty, MD, Associate Professor of Medicine, Harvard Medical School; Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital
Q: A lot has happened in the field of Metastatic Melanoma since March, 2016. In April of 2017, would your reply be any different? If so, in what way, and why?
A: The only change from 2016 to 2017 in terms of treatment options for a young patient with metastatic disease is that the 2016 leaning toward combination CTLA-4/PD1 immunotherapy has come back to PD1 monotherapy versus BRAF/MEK combination therapy. With two-year follow-up data from the BMS 067 trial, there was very little difference in survival (5%) versus the very large difference in risk of severe toxicity. But, PD1 antibody therapy with CTLA-4 antibody therapy as a backup remains a very compelling option for BRAF wild-type patients and BRAF/MEK combination therapy as a first-line or second line therapy for those with a BRAF mutation remains on the menu.
Response from March 2016
Q: What is your basic approach to handling a new young adult patient in good general health who is referred to you with a diagnosis of Malignant Melanoma, metastatic to liver or lung? The primary cutaneous melanoma, 1.5 mm in thickness, was diagnosed in Maine 5 years ago and was of skin on the forearm; treated there by wide resection with clear margins and no lymph node dissection. There was no molecular/genomic testing of the primary.
A: In a case like this, there are a few additional elements of data that I always try to obtain:
- Brain MRI
- Serum LDH
- V600 BRAF mutation status (younger patients are significantly more likely than older patients to have a V600 BRAF mutation), so it’s likely that this patient has one
- Presence or absence of disease-related symptoms
- Prior scans that might allow the pace of disease progression to be ascertained (not always possible in a very recently diagnosed patient; but even if 4-6 weeks have passed since the first assessment prior to me seeing the patient, I’ll consider repeating imaging of the lungs and liver to glean the pace of progression.
The factors above go into determining disease burden and pace of disease progression. Presence of brain metastases does not necessarily impact choice of first-line systemic therapy, but certainly informs the need for resection (for single large metastases) or stereotactic radiation for one or several small metastases in parallel with pursuing systemic therapy. The presence of numerous brain metastases would push me to select BRAF/MEK combination therapy if a V600 BRAF mutation were found. Elevated serum LDH, the presence of disease-related symptoms, or evidence of rapid disease progression each push me toward considering of BRAF/MEK combination therapy (presuming BRAF mutant), and certainly two or three of these three factors would force that decision. In the absence of any of these factors, first-line immunotherapy is generally my approach. For most patients that means single-agent PD-1 antibody therapy. But, for young patients who are not deterred by a high rate of severe toxicity and for patients with any of the three “aggressive’ disease warning signs indicated above, I would favor combined CTLA-4/PD-1 antibody therapy. This is based on the higher initial response-rate and short-term ability to control the disease with the combination compared to PD-1 antibody monotherapy. We do not yet know that this combination improves overall survival compared to sequential therapy with PD-1, CTLA-4 and/or BRAF/MEK inhibition. In the absence of that data, I favor PD-1 monotherapy first-line for most patients. If a patient progresses on first-line PD-1 antibody therapy, then I reassess the same warning sign factors as above, now informed by the rate of progression evident on follow-up scans. Modest evidence of progression pushes me to consider CTLA-4 antibody therapy as the second-line approach versus BRAF/MEK combination therapy for more aggressive evidence of disease progression. Recent evidence that the same strategy will soon be an option with MEK inhibitor monotherapy in NRAS mutant melanoma patients. These decision points for selecting first, second and even third line therapy are currently informed by clinical factors. However, we know that each treatment approach can produce years-long remissions as first-line treatment. Thus, it is imperative that we continue to conduct clinical research to develop additional diagnostic methods for identifying those patients predicted to achieve long-term benefit from each of therapies and relay on these for navigating among these multiple treatment options.