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

Clinical Perspectives in the Evolving Role of Immuno-Oncology Treatment With Jason J. Luke, MD, FACP

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

Dr Luke: Unfortunately, that is a difficult question to answer, on multiple levels, and there is no straightforward answer. It primarily depends on the type of immunotherapy. A common question currently is, what is the optimal duration of therapy for PD-1 [programmed cell death protein 1] checkpoint inhibitor agents (eg, nivolumab or pembrolizumab). It’s a question to which we don’t know the answer. The only evidence available is from a trial in patients with lung cancer who received PD-1 inhibitor therapy for 1 year and then were randomized to either continue therapy or stop. The trial results showed a significant difference favoring continuation of therapy beyond 1 year. However, there are no further data to address how long a patient should receive therapy.

There is very little evidence that supports any decision making at this point, so it is really an art of medicine–a decision making process and a conversation with the patient. In clinical practice, if a patient has a complete response, we will stop treatment after about 6 months. If a patient has a major response, but not a complete response, I will discuss with them the pros and cons of discontinuing treatment. If they had limited response or they have stable disease, we would usually continue therapy because they are at risk of recurrence.

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

Dr Luke: Most clinical trials will monitor the patient every 2 to 3 months. In practice, I usually evaluate the patient every 3 months.

AJMC®: Are there circumstances that would warrant more frequent monitoring or less frequent monitoring?

Dr Luke: It may be a consideration in the future; however, this is not currently done in practice. There are no data to support monitoring more frequently than every 2 to 3 months, so it does not make sense from a healthcare utilization point of view. We do not know the long-term kinetics of these drugs so the default is monitoring every 2 to 3 months.

If a patient has been receiving treatment for a year and is responding well, you could consider stretching out the frequency of monitoring. However, if they are doing so well, the more relevant question is, can therapy be discontinued?

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

Dr Luke: Cure is a loaded term, and there is no clear clinically meaningful definition. If we are looking at the number of patients with a complete response, that rate is usually 5% to 10% for anti–PD-1 monotherapy and 15% to 20% for combination anti–PD-1 plus anti–CTLA-4 [cytotoxic T-lymphocyte-associated protein 4] therapy in melanoma. There are patients who have a good response, are doing well, have stable disease, and are fine for years after therapy is stopped. They still have some tumor on the scans, but they are doing well and we are not treating them, so would they be considered cured? Tumors could start to grow again at some point or never be problematic. Thus, how to define what cure means becomes kind of a loaded question.

Some pharma companies have advanced an idea of “time off treatment” as a useful healthcare evaluation metric. Ipilimumab/nivolumab combination therapy has a high rate of severe toxicity, around 50% to 75%, but many patients have a great response [and] can stop therapy and still be relatively well for years after. There are high expenses with treatment up front and the patient may experience severe toxicity for those few months; however, patients may have long-term benefits even after stopping therapy and thus not require costly intervention. It is a slightly backward approach from how we historically evaluated drug utilization. This is an evolving area where further time will be needed to better evaluate these questions.

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

Dr Luke: Generally, I think landmark analyses of survival are appropriate, though a 5-year timepoint currently has little data. In contrast, evaluating median overall survival is becoming more difficult, at least in melanoma. For example, if a patient received BRAF inhibitor therapy, did not have a complete response, then was given ipilimumab/nivolumab combination therapy and went into a complete response, which drug would you credit? In general, the idea of 3 years, 5 years, or, maybe one day, 10 years as a landmark marker for overall survival is useful to assess the global benefit of immunotherapy. The issue is that we have these more effective, newer agents that we are using, but we do not know the best way to utilize them because there are not enough data. We therefore have a bit of a cart-before-the-horse problem in trying to define the best long-term indicator measures of optimal drug utilization.

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

Dr Luke: We do not have a definitive answer on whether to use BRAF-targeted therapy or immunotherapy as frontline therapy. There is an ongoing, randomized trial evaluating patients who initially receive BRAF-targeted therapy or combination immunotherapy and then cross over to receive the other therapy. Unfortunately, that trial is progressing slowly and I do not know if the trial will answer the question.

We do have some markers that identify which patients would benefit the most from BRAF-targeted therapy. Those patients have good performance status, low number of metastatic sites, and low levels of LDH [lactate

dehydrogenase]. But, these are also the patients who would likely respond the best to immunotherapy.

In many practices, there seems to be a tendency to use immunotherapy as a default first-line therapy. The rationale behind this may be the idea of time off treatment. In other words, there is the potential that the therapy might be permanently discontinued at some point due to benefit. BRAF-targeted therapy, however, requires indefinite therapy, so the patients would have to be dosed ad infinitum. There are ongoing trials evaluating BRAF inhibitors with MEK [mitogen-activated protein kinase] inhibitors and PD-1 inhibitors given simultaneously.

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

Dr Luke: This is a tough area because there is no evidence from randomized trials to support decision making in the second-line setting and a lot of the decision making is dependent on how the patient is responding in clinic. For example, if a patient was started on pembrolizumab or nivolumab and was responding but then the disease started to progress and worsen, drug therapy would then depend how they are progressing. If the patient was progressing quickly, I would give BRAF inhibitor therapy immediately. However, if they have low-volume progression, I may consider second-line immunotherapy with ipilimumab and reserve BRAF-targeted therapy for further line therapy. This it is not a hard-and-fast rule though. If they were started on BRAF-targeted therapy and they had low-volume progression, anti–PD-1 therapy could be used. If they were progressing rapidly, then combination ipilimumab/nivolumab would be given. It is really the clinical factors that dictate treatment options. We need more data from randomized trials that can guide us in decision making, but, unfortunately, there is no market-based impetus for large pharma [companies] to conduct such trials.

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

Dr Luke: There are multiple ways of approaching resistance, either by reducing the risk of resistance or overcoming resistance. In other words, we could: (1) use the drugs we have more effectively and/or (2) develop better drugs. Importantly, there are data suggesting that resistance to targeted therapy can lead to resistance to immunotherapy, perhaps indicating that mechanisms of resistance may be overlapping. Considering this, there are ongoing trials evaluating a treatment strategy to limit resistance using what has been called a “sandwich” approach. The idea is to give the patient BRAF-targeted therapy for several months until the patient achieves an optimal response, and then, prior to resistance, switch to immunotherapy. I think those are very interesting trial concepts to consider.

There are many new interesting drugs and concepts to overcoming resistance that are currently being studied.

Many new and novel drugs are expected to reach the market in the near future, such as IDO [indoleamine 2,3-dioxygenase] inhibitors. Another major area of immunotherapy drug development surrounds innate immunity as an approach to overcome resistance by driving T-cell inflammation into treatment-resistant or “cold” tumors. The overall approach to resistance is to use the drugs we already have more effectively and continue to focus on this explosion of new immunotherapeutic concepts. There are many new drugs and novel agents coming.

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

Dr Luke: In immunotherapy, we commonly see immune-related adverse events that are fairly low grade and manageable, such as fatigue, rash, dermatitis, and arthritis. Colitis and thyroiditis are also commonly seen but can generally be easily managed if caught early (eg, steroids, thyroid supplement).

BRAF-targeted therapy adverse effects varies by the combination regimen. For dabrafenib and trametinib combination therapy, a common adverse event is pyrexia, or fever syndrome. Approximately 50% of patients will experience grade 3 pyrexia, which can require hospitalization without early intervention. Grade 1 and 2 pyrexia can also be very bothersome for patients, however. For vemurafenib and cobimetinib combination therapy, there is less occurrence of pyrexia, but there is a greater issue with skin reactions, such as photosensitivity, dermatitis, and skin eruptions. There are also higher incidences of gastrointestinal [GI] disturbances, such as nausea and abdominal pain. MEK inhibitors have been associated with visual disturbances, cardiac toxicity, and GI upset. There are several strategies to help in managing these adverse effects, such as treatment interruption or dose reduction.

AJMC®: How do you quantify these adverse events?

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