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Supplements The Role of Immuno-Oncology in the Treatment of Advanced Melanoma

Expert Insights on Strategies for Managing Advanced Melanoma With Ryan J. Sullivan, MD

AJMC®: What do you feel is the optimum treatment duration for immunotherapy?

Dr Sullivan: The optimal treatment duration depends on several factors, such as single-agent therapy or combination therapy, what immunotherapy agent or agents are being used, etc. The standard therapy with ipilimumab, for example, is 4 doses over 12 weeks. For patients on combination immunotherapy of ipilimumab with nivolumab, we typically treat with combination therapy every 3 weeks for 4 doses followed by single-agent nivolumab. With that said, there are certainly some data showing that a very brief time on therapy is sufficient; however, we do not know what is the optimal amount of time on therapy. There is currently no clear answer to the question of how long do we treat patients who are responding to anti–PD-1 [programmed cell death protein 1] antibody therapy. In my practice, if a patient is receiving anti–PD-1 antibody monotherapy (either upfront or after combination therapy) and is having a complete response, a near-complete response, or a good response, I would generally treat them for 1 year. If they have stable disease, I would consider 2 years of therapy.

AJMC®: How and when do you evaluate response to treatment? At what time points do you evaluate response to treatment?

Dr Sullivan: In terms of routine surveillance for response, I usually do scans (eg, torso imaging) every 12 weeks or so, unless the patient is in a clinical trial that mandates more frequent imaging or the patient is experiencing symptoms, in which case I would monitor them sooner. If a patient does not have brain metastases, I would conduct a brain MRI every 24 weeks to monitor for any signs of a brain mass.

AJMC®: How can we quantify cure rates for melanoma in the advanced setting?

Dr Sullivan: It is hard to define which patients are cured in this anti–PD-1 antibody era because there are very little long-term data on efficacy. Long-term benefit is typically measured by a plateaued Kaplan-Meier curve that extends past 5 years. Thus, you may consider it a possible cure if that plateau occurs and it extends beyond 5 years. The “cure” rate for ipilimumab is approximately 20%. Currently, anti–PD-1 antibody monotherapy cure rates are estimated at approximately 30% to 35%, but this is difficult to determine with certainty without longer-term data. With combination immunotherapy or sequential immunotherapy, cure rates are probably 40% or more.

AJMC®: What are your thoughts on 5-year survival as a proxy measure for a cure in advanced melanoma?

Dr Sullivan: It was a decent number to use when high-dose IL-2 [interleukin-2] was the standard therapy, and I think it is still a fair metric today. We have yet to see a scenario where a 5-year proxy did not predict longer survival. For example, for high dose IL-2 and ipilimumab, a 5-year proxy predicts 10-year survival. I do not think it will be much different with the anti–PD-1 antibodies, but we have not gotten to that point yet. The largest studies currently are still in only the 3- to 5-year range. Currently, we do not have long-term data on the newest agents, which are also the most effective agents. Therefore, I believe that 5-year survival is a reasonable metric to predict where the patient will be at 10 years.

AJMC®: What are the challenges in dealing with mutations that occur in metastatic melanoma?

Dr Sullivan: The biggest challenge is determining whether we should only use immunotherapy or consider targeted therapy that blocks the mutations. In melanoma, the most common mutations seen are BRAF mutations, so we are deciding between molecular targeted therapy with a BRAF mutation inhibitor or immunotherapy. The biggest challenge with having several options is determining whether there is an optimal first-line therapy and whether there is an optimal sequence or combination. These questions are answerable with clinical trials, but there are currently insufficient data to make these determinations. There are some retrospective data available, but not substantial enough to change clinical practice.

AJMC®: What do you typically use for treatment in the second-line BRAF-mutated population?

Dr Sullivan: Generally, if immunotherapy was used [as first-line treatment], then my second-line therapy would usually be BRAF inhibitor therapy, and if I started with a BRAF inhibitor, my second-line therapy would usually be combination immunotherapy. However, it depends on the patient. Most oncologists will give frontline immunotherapy for patients who are BRAF mutant. If we happened to start with BRAF inhibitor therapy, we would likely use combination immune therapy as second-line therapy, such as nivolumab plus ipilimumab, if the patient is able to tolerate the therapy.

AJMC®: What strategies can be used to overcome mechanisms of resistance to targeted therapy?

Dr Sullivan: There are many potential mechanisms of resistance, which makes overcoming resistance challenging. There are strategies to target resistance and strategies to delay resistance. Many resistance mechanisms reactivate the pathway, so one strategy would be to treat with a drug that targets the pathway downstream. There is some data that show ERK [extracellular signal-regulated kinase] inhibitor therapy may be beneficial in some populations. Some resistance mechanisms activate the PI3 [phosphatidylinositol-4,5-bisphosphate 3]-kinase pathway, and there are strategies that target inhibiting that pathway. We are starting to research approaches that target more broadly in the resistance setting as well as the up-front setting. For example, we conducted a clinical trial targeting apoptosis to make the tumors more vulnerable to BRAF inhibition. We have also researched the use of molecular chaperones, such as heat shock protein, to target several potential

[resistance] mechanisms.

Another strategy that is being studied in a larger cooperative group is the use of intermittent therapy to delay acquired resistance, which would allow for longer [duration of] therapy. There are preclinical data that show intermittent BRAF therapy may be associated with better outcomes versus continuous therapy. Theoretically, if a patient is on therapy without interruption, it is more likely that acquired resistance pathways will develop. Therefore, the rationale behind intermittent therapy is that stopping therapy for a period will limit the growth of cells with the acquired resistance mechanism and allow [therapy-]sensitive cells to repopulate, at which time therapy would be restarted.

AJMC®: In patients with metastatic melanoma, what are the most clinically significant adverse events?

Dr Sullivan: For BRAF-targeted therapy, such as dabrafenib and trametinib, fever syndrome tends to be the most common issue, and it occurs in about half of the patients. There are strategies that minimize the risk, but it is still a major issue. For vemurafenib and cobimetinib, photosensitivity is the major issue, especially in the summertime when patients are frequently outside. However, most adverse events are transient and resolve when therapy is stopped. If they occur, we can hold therapy, reduce the dose, or adjust the schedule.

On the other hand, adverse events related to immune therapy are more complex to manage. We commonly see immune-related adverse events in almost every type of tissue—for example, colitis, hepatitis, nephritis, gastritis, myocarditis. The earlier that immune-related toxicities are diagnosed and managed, the better the outcome for the patient. But the biggest challenge is catching these adverse events early. More resistant toxicities have also been seen in some patients. These adverse events require a team to manage, especially if the patient is on combined immune checkpoint inhibitor therapy. Specialists are often needed to manage these adverse events, including gastroenterologists, rheumatologists, cardiologists, and others. These specialists are heavily invested in trying to learn more about preventing and treating these adverse events so that patients have better outcomes.

AJMC®: How do you quantify these adverse events?

Dr Sullivan: As far as incidence, we try and document each event either pathologically or radiographically. For example, if it is a rash, we would document it and maybe take a picture to monitor its resolution. If it is itchiness, we would document and quantify how much it is bothering the patient. If a patient has diarrhea, we will document and consider a colonoscopy to rule out colitis.

Methods for determining the severity of the adverse event differ between clinical trials and clinical practices (outside of clinical trials). Clinical trials commonly use the CTCAE [Common Terminology Criteria for Adverse Events] version 4 criteria to quantify the severity. Outside of clinical trials, those categories have less of an impact.

For example, in clinical practice, chronic grade 2 is functionally treated like grade 3 and you may consider treating grade 1 as if it were grade 2 if it was bothersome to the patient. The actual severity level based on CTCAE v4 is less critical in terms of driving management outside of clinical trials; thus, we tend not to give it a grade and instead document the symptoms and frequency of symptoms. We try to ask more relevant questions. For example, are they eating? Do they have pain? Is there blood? These are things that may not fall into the criteria but can be quite actionable even if the patient is not experiencing a lot of diarrhea. The same goes for other toxicities.

AJMC®: What types of costs do you see associated with treatment-related adverse events?

Dr Sullivan: The biggest cost is hospitalization. Some of these hospital stays tend to be long and can quickly result in a substantial hospital bill. We tend to intervene early with corticosteroids, which are pretty cheap, but may confirm pathology with biopsies, scopes, or imaging. The cost of laboratory tests is not something we think about often, but that can have an impact on overall cost. We would conduct more imaging in patients who are experiencing toxicities. We may have to obtain expensive blood tests in patients with abnormal side effects that we cannot quite characterize, so the cost of diagnostic blood tests can certainly add up. For the patient, I think the biggest cost is the loss of productivity, especially if the patient needs to be out of work for a few weeks.

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