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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®: How do you define cost-effectiveness? Do you take into account adverse events when evaluating cost-effectiveness?

Dr Sullivan: Cost effectiveness is not a major consideration when we are determining therapy. We do not design our treatment decision making around a cost-effectiveness model in the sense that we do not think about what is the most efficient and least expensive option. We are not thinking about how to apply cost-effectiveness data for a patient population to an individual patient when we are deciding what drug is best for that individual patient.

Determining which treatment to use is more complex than evaluating which agent is more cost-effective. For example, anti–PD-1 antibodies may cause substantial toxicities that require interventions in approximately 20% of patients; however, there is a significant probability the patient will be cured. I believe there is some value in having broader discussions regarding cost-effectiveness. Cost-effectiveness research evaluating these factors may impact and help guide our clinical decisions.

In terms of preventative therapy, there is a great unmet need for methods to identify a patient’s risk of toxicity. If we could identify which patients are at high risk of toxicity, we could try to proactively prevent or lessen the toxicity with prophylactic therapy. If a patient is at low risk, we could avoid giving unnecessary and costly prophylactic therapy. We need better data and more research on potential biomarkers that can predict what therapy (eg, single agent versus combination) is optimal for an individual patient and predict which patients are at greater risk for drug toxicity.

To be truly cost-effective, we need data that can guide us in selecting the best agent for an individual patient and help predict the risk of toxicity in a specific patient. Incorporating stop dates into clinical trials can help us determine when to the stop therapy. Also, the development of blood assays and radiographic imaging that are more accurate and less costly would help increase cost-effectiveness.

AJMC®: What type of patient outcomes reflect “effectiveness”?

Dr Sullivan: The obvious one is overall survival. The patient’s quality of life, productivity, and ability to work are important outcomes as well; however, many patients are willing to sacrifice quality of life and productivity if a drug provides them with a higher chance of being cured. In my opinion, survival, productivity, and quality of life are important, but the most important factors are how well a patient tolerates and responds to therapy and their long-term benefits from therapy.

AJMC®: How do you evaluate the cost-effectiveness of first-line immuno-oncology monotherapy and combination therapies? How do you evaluate cost-effectiveness of new immunotherapies entering the market?

Dr Sullivan: Most oncologists do not think about what is the most cost-effective way of treating our patients. Rather, we would determine the most effective way of treating our patients first and then [factor in cost] later. That may or may not be the “right” approach, but it is the current approach.

It is difficult to think about cost-effectiveness on a single-patient basis. For example, one patient is given single-agent therapy for 12 months and they have a great response with little to no toxicity. Another patient receives 4 doses of ipilimumab or nivolumab, experiences substantial toxicity requiring hospitalization for 2 months, but has a great response and does not require retreatment with ipilimumab or nivolumab. Both scenarios result in a cure and are similarly cost-effective regarding the total cost of drug delivered, but one therapy is obviously better for the patient than the other. It may be preferable to give the 12-month therapy that minimally impacts the patient’s quality of life rather than have them come in every 3 weeks. Also, societal costs must be considered alongwith the direct cost of the drug. Substantial societal costs may negate the costs saved with a certain therapy. Toxicity is an important issue with combination therapy and management of toxicities can be costly. If combination therapy with newer agents is more effective and less toxic than current combination therapy options, it could be seen as more cost-effective than current therapies.

AJMC®: How does mutation status (eg, BRAF wild-type) impact your evaluation?

Dr Sullivan: It certainly is a consideration, but when treating a patient with melanoma, most oncologists will start with immunotherapy. There is no consensus on the level of impact BRAF status has in selecting first-line therapy. Some of my colleagues strongly believe that patients with a BRAF mutation should receive frontline immunotherapy, while others feel less strongly. It is another piece of information that should be taken into account, but there are not enough data to determine how it can

be utilized.

AJMC®: How does the use of doublet and triplet regimens fit into current treatment and what are the ideal settings for their use?

Dr Sullivan: Triplet regimens are only experimental at this point, so they do not exist in a standard-of-care setting. There are insufficient data to determine whether they will have a role in melanoma treatment. Currently, triplet regimens are being evaluated against the standard of care as control and only phase 1 and phase 2 data are available. The limitation with comparing a triplet regimen against standard of care is that it does not take into consideration long-term effects. The influence [triplet therapy] may have on next-line therapy is an important consideration. Right now, there are not enough data to know how to incorporate [triplet therapy] into practice, and it may be a while before we have the answers.

AJMC®: Will there be a greater place for doublets and triplets in the treatment of patients who have relapsed?

Dr Sullivan: Doublets definitely have a role in that setting. If a patient relapses after PD-1 inhibitor therapy, they may receive nivolumab plus ipilimumab therapy (if they do not have a BRAF mutation) or be enrolled in clinical study of a PD-1 agent plus another agent. The ultimate goal for oncologists is to identify the best therapy up front. A combination of immune therapy and targeted agents or different immune agents or different targeted therapy agents has a role in post-frontline therapy. However, the only combination currently available is nivolumab and ipilimumab. Other doublets and triplets are experimental.

AJMC®: What is the role of immuno-oncology in the adjuvant setting? What is the value of immuno-oncology in the adjuvant setting?

Dr Sullivan: We now have data from 2 compelling phase 3 trials using immune checkpoint inhibitors for patients with melanoma in the adjuvant setting. The older trial evaluating ipilimumab against placebo showed [an] overall survival benefit but severe toxicity in nearly half of patients. The toxicity rate was unpalatable to most of us; thus, ipilimumab was not commonly used when it was approved. The recent CheckMate 238 trial compared adjuvant ipilimumab [with] adjuvant nivolumab in patients with high risk of recurrence. It showed nivolumab was superior from a relapse-free survival point of view. These data are changing the way we think about treatment for patients with high risk of recurrence. Because the duration of treatment was only 1 year, the study’s findings are limited to short-term therapy. Patients can invariably relapse and become PD-1 resistant by the time they are diagnosed with metastatic disease. This would essentially be a different disease, newly metastatic melanoma that is PD-1 resistant, a variant that has not been studied in clinical trials. However, the data from this trial are compelling enough that [nivolumab] should be considered as an

option for patients with high-risk melanoma.

AJMC®: The eighth edition of the American Joint Committee on Cancer’s (AJCC’s) Cancer Staging Manual will be implemented on January 1, 2018. Important updates are planned for the staging criterion for T1 tumors and additional evidence-based prognostic factors are incorporated. Please comment on what changes this revision to the AJCC Cancer Staging Manual will bring to treatment and how these changes may potentially affect the cost-effectiveness of therapy.

Dr Sullivan: Truthfully, it is hard to make that determination at this time. I think from a treatment standpoint, we will be less likely to offer adjuvant therapy for the new stage IIIa because they are low-risk and we will be more likely to offer adjuvant therapy for stage IIId and maybe IIIb and IIIc.

It is important to note that staging systems are always changing. Even this new system is not accurate because it was developed before the anti–PD-1 antibody era and the data come from trials that were treating according to the old staging system. However, it is the best we have, so it is important to consider the data showing benefits in the adjuvant setting to help sort out which patients may benefit.

Another important change that complicates this new staging system is the changes in guidelines regarding which patients should receive [complete] lymph node dissection. This makes staging more challenging in some patients because the true nodal status will not be known in stage III melanoma patients who do not have a completion node dissection.

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