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Assistant Attending Physician
Division of Tumor Oncology
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
Allison Betof Warner, MD, PhD, has disclosed that she has received consulting fees from BluePath Solutions, Iovance, Nanobiotix, and Novartis.
When I meet a new patient with metastatic melanoma, one of my top priorities is securing a full disease assessment and staging. Many patients arrive at my clinic with systemic imaging (eg, a CT of the chest, abdomen, or pelvis or a PET scan), but the immediate availability of brain imaging is less common. I recommend a brain MRI for every patient with metastatic melanoma because this tool guides my selection of first‑line therapy.
Another critical component of my baseline workup is BRAF mutation testing. I use this initial clinical encounter as an opportunity to order next-generation sequencing (NGS). Aside from BRAF mutation results, NGS does not directly inform my choice for first‑line therapy. However, knowing an overall mutation pattern may be essential if the patient were to need additional lines of therapy. Given that NGS results require weeks—if not months—to return, I proactively take this step at the first or second visit to ensure I have the information needed to optimize my patient’s treatment trajectory.
With BRAF mutation status and a brain MRI in hand, the conversation then centers on the choice between targeted therapy and immunotherapy. I also educate my patients about frontline clinical trials, which combine the current standard of care with either a new medication or an innovative approach that could enhance their care.
Because BRAF/MEK‑directed therapy often induces a rapid response, several key clinical scenarios warrant selection of this frontline strategy for patients with BRAF V600 mutations. The first is a patient requiring high doses of steroids for a brain metastasis or for leptomeningeal disease. Such upfront steroids, unlike steroids administered to manage an on-treatment immune-related adverse event, likely diminish the efficacy of immunotherapy. In administering BRAF/MEK-directed therapy, I am attempting to decrease the disease burden, minimize symptoms, and to get patients off steroids, with the plan to later change to immunotherapy. The second scenario involves patients who have either a lot of disease with impending visceral crisis, imminent spinal cord compression, or very symptomatic disease (eg, obstructive liver disease or painful bony disease).
Single-Agent vs Combination Immunotherapy
Beyond those scenarios, I most often consider immunotherapy in the frontline because it has the potential to produce durable disease control in the form of PRs and CRs even after discontinuation. Responses to immunotherapy typically take longer than those to targeted therapy and may result in slight progression before response, but durability is often longer than with targeted therapy.
The primary options for frontline immunotherapy are a single-agent PD-1–based treatment or combination ipilimumab plus nivolumab. Deciding between these approaches can be more of an art than a science. Certainly, comorbidities and functional status are factors along with a patient’s willingness and ability to tolerate side effects. Data from the ABC and CheckMate 204 trials on intracranial activity support the use of combination therapy with ipilimumab and nivolumab among patients with asymptomatic, untreated brain metastases. In addition, we tend to think of liver and bone metastases as more refractory to immunotherapy, and so I tend to favor combination immunotherapy in those patients as well.
One group of patients often referred to me are those who were told by another provider that they cannot receive immunotherapy because of their underlying autoimmune disease. Each of these cases calls for an individualized risk–benefit analysis. I recently met with a new patient who has brain metastases and was advised against combination immunotherapy because of a history of psoriasis. Balancing the risk of flaring psoriasis against the risk of brain metastases, my advice in this instance was to move forward with combination immunotherapy in close collaboration with the dermatologist and a plan to manage any psoriatic flares.
Potential Role of Flip Dosing for Combination Ipilimumab Plus Nivolumab
The FDA-approved dosing in melanoma for combination therapy is ipilimumab 3 mg/kg plus nivolumab 1 mg/kg (ipi3/nivo1) for first-line treatment of metastatic melanoma. Efficacy notwithstanding, substantial toxicity can accompany treatment with this combination. To determine if modified dosing could reduce adverse events while retaining a clinical benefit, the ongoing CheckMate 511 trial (NCT02714218) is evaluating “flip dosing” wherein the ipilimumab dose is reduced to 1 mg/kg and the nivolumab dose is increased to 3 mg/kg (ipi1/nivo3). Thus far, only preliminary results are available demonstrating that ipi1/nivo3 significantly decreased the treatment-related grade ≥ 3 adverse events vs ipi3/nivo1, thereby meeting the primary endpoint of the study. It is also important to note that CheckMate 511 excluded patients with central nervous system disease and was not powered to demonstrate noninferiority, so even when long-term efficacy data are available, we will not be able to say that the ipi1/nivo3 regimen is truly noninferior based on a statistical analysis. That is a really important consideration, particularly for high‑risk patients.
I foresee an eventual role for flip dosing, particularly in frail, older patients or perhaps patients with autoimmune disease where adverse events could be quite debilitating. I think those are patients for whom I would consider for flip dosing. However, my current standard for a patient with brain metastases or high‑risk disease for whom I favor combination immunotherapy continues to be ipi3/nivo1.
There is still an open question of when immunotherapy should be discontinued in patients achieving a CR, and several ongoing trials are directed at answering this question. To date, most of the clinical trials have either used 6-12 months beyond CR or a total of 2 years of treatment. In my practice, at the time of a second scan with confirmed CR, I generally open a dialogue regarding discontinuation of therapy. Based on current evidence, I recommend treatment to 1 year past CR or following a total of 2 years of therapy. These patients are monitored closely with systemic imaging every 3 months for any signs of recurrence.
Data from the KEYNOTE‑001 trial support the longevity of response to immunotherapy among patients with advanced/metastatic melanoma. At the 5-year analysis, ongoing response was reported for 90% of patients who had achieved a CR and discontinued pembrolizumab. However, in a real‑world analysis of our patients, at 3 years after discontinuation, we found a nearly 27% rate of relapse—higher than the 10% seen in KEYNOTE-001, which is why more data are needed to determine the optimal duration of treatment. To that end, we are currently enrolling patients on the PET‑Stop trial (NCT04462406), which assesses the predictive value of PET scans to inform early discontinuation of anti–PD-1 therapy.
How do you manage patients with newly diagnosed metastatic melanoma? In which patients are you recommending targeted therapy, and how do you determine whether single-agent or combination immunotherapy might be best? I invite you to join the conversation by answering the polling question or leaving a note in the comments box.