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?

Dr Luke: As a clinical trialist, I may have a slightly different approach than the general community physician. Since we are required to use the CTCAE [Common Terminology Criteria for Adverse Events] grading criteria in clinical trials, it has become the default in our clinic as well. The CTCAE grading criteria is a useful tool to quantify the severity of adverse events and determine treatment and most toxicity management guidelines developed by professional societies and drug manufacturers are predicated on CTCAE.

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

Dr Luke: These adverse events can be quite costly, especially if hospitalization is required. The risk of severe adverse events can be mitigated if the patient is properly educated and counseled. For example, pyrexia from targeted therapy may be mild, and if caught early, it is easily managed; however, if the patient does not seek medical attention, it can worsen, leading to dehydration and hospitalization, which can be costly. Thus, it is important for physicians to be cognizant of this issue and counsel their patients. However, despite best practices and proper counseling, there are patients who will not contact a doctor until it is too late.

I find that the majority of patients who receive an anti—PD-1 agent generally tolerate treatment well, with little to no toxicity; however, approximately 10% of patients will experience severe toxicity that requires hospitalization and/or expensive drug therapy to treat the toxicity, such as the anti–tumor necrosis factor agent infliximab, or other immunosuppressive agent such as mycophenolate. Currently, it is not clear whether one type of therapy (immunotherapy or targeted therapy) is associated with greater costs from adverse events than the other.

AJMC^®: Do costs associated with obtaining necessary laboratory tests have a major impact on cost-effectiveness?

Dr Luke: I do not believe lab testing is a major driver of costs associated with adverse events. We tend not to do that many colonoscopies now, as diarrhea and emerging colitis can usually be easily identified. If the patient has severe diarrhea and has not recently travelled to an area where infectious diarrhea is prevalent, it is likely colitis and should be managed with steroids. If a patient was hospitalized, a colonoscopy may be considered in that setting, but it is not a common cost. 

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

Dr Luke: I have yet to see convincing data that show symptomatic treatment of adverse events related to immunotherapy drives a significant cost differential over targeted therapy, so the risk of adverse events would not be a major factor in evaluating cost-effectiveness. I believe the most important consideration in the cost-effectiveness of treatment is long-term outcomes, so we should be looking into potential markers that may predict long-term outcomes and/or cure. Generally, if a drug is drastically more effective, then it may be more cost-effective than a cheaper drug that is not as effective. The increased drug cost would have to be weighed against the added benefit of the drug. Unfortunately, we will likely see newer drugs that do not add that much more to efficacy, yet are exponentially more expensive.

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

Dr Luke: In my opinion, long-term benefit is the first and foremost outcome that reflects effectiveness. Although drug toxicity is important, the risk of severe toxicity has declined drastically over time with better drugs and better patient care. I think the toxicity piece is overblown in this arena. Drug toxicity and tolerability were major issues in the earlier days when patients with breast cancer or colon cancer were dying because they could not tolerate the cancer treatment that was available at that time. But we are not talking about that at all now. If someone gets colitis, there is only a 1% chance of death, and even then, it is likely due to lack of physician experience rather than from the drug. Also,

adverse events are often temporary while the benefits are long term. Nowadays, we are keeping more patients with cancer alive indefinitely with drug therapy. In the melanoma community for example, there is a general sense that perhaps even 50% of the patients with BRAF-mutated melanoma may be kept alive to their otherwise natural life span. That is a major development given that median survival was only about 9 months just 7 years ago. Therefore, I focus almost entirely on survival benefit when evaluating effectiveness.

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

Dr Luke: I think that the progression-free survival landmark calculations are appropriate and understandable for evaluating of the global benefit of immunotherapies. Monotherapy has a certain level of benefit, and I do not think that current combination therapy increases that level of benefit significantly enough to prefer combination therapy as frontline [therapy] in most patients. Speaking in the context of the drug therapies and data that are available now, it is difficult to justify using combination therapy relative to monotherapy in the average patient. Currently, there is no clear overall improvement in survival with combination therapy and there is substantially more toxicity compared with monotherapy. However, this is not an absolute rule because there are some patients in whom very short survival might be expected absent an immediate clinical response. In these cases, the most reasonable approach is combination therapy to maximize treatment benefit as quickly as possible despite the risk of toxicity. Therefore, if a patient presents with adverse prognostic signs, such as bone metastases, brain metastases, and/or high LDH, I would give them combination therapy immediately.

This may change in the near future with newer immunotherapies being studied. IDO inhibitors in combination with PD-1 antibodies are already in phase 3 trials for melanoma and several other cancers. Most oncologists believe that those results will be positive. If [an IDO inhibitor] is approved, it would impact the role of combination immunotherapy in melanoma. Currently, our only available combination therapy is nivolumab with ipilimumab, which significantly increases the risk of severe toxicity and marginally increases benefit compared with monotherapy. Combination therapy with a PD-1 inhibitor and an IDO inhibitor does not increase the risk of toxicity versus monotherapy; thus, if there is any added benefit with combination PD-1 and IDO inhibitor therapy, it would change the standard of care.

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

Dr Luke: There are no data to show that immunotherapy is superior to BRAF-targeted therapy. Some oncologists may prefer immunotherapy because of the concept that a patient may not require indefinite therapy if they have a complete response to immunotherapy. Conversely, stopping therapy is not as feasible with BRAF-targeted therapy and the average patient will likely require indefinite therapy if started on BRAF-targeted therapy. There is no evidence that supports choosing one over another, which is the rationale for the EA6134 clinical trial investigating the sequencing question.

AJMC^®: Have you been involved in or are you aware of any conversations that are taking place between physicians and payers to implement cost-effective melanoma therapies?

Dr Luke: I am aware of such conversations; however, many of them are misguided at this point in time, given that there are little or no data that support some of the decision steps being invoked in the various “treatment pathway” approaches, especially in melanoma. I would ask that payers start conducting randomized cost-effectiveness trials. If payers want to know what therapies are more cost-effective, they should take the initiative and design randomized trials. Payers have the greatest incentive to learn the answer to the question of cost-effectiveness. These are important questions that we need more studies to answer. The National Cancer Institute does not receive budgets for these types of randomized trials and pharma has no incentive to conduct them. The funding must come from somewhere, and it ought to come from the payers because they may benefit the most by finding the answers.

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

Dr Luke: There are no current triplet regimens; however, BRAF inhibitor plus MEK inhibitor plus PD-1 inhibitor therapy is currently in phase 3 trials. Though a reasonable clinical question, I would suggest that the trial design should include 3 arms: triplet versus targeted therapy doublet versus PD-1 inhibitor monotherapy with everyone crossing over so then we would have the data to determine the optimal therapy (eg, combination therapy versus sequential therapy).

The ongoing trials are only comparing triplet regimens against targeted therapy doublet regimens.

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

Dr Luke: I do not think guidelines would incorporate doublet and triplet regimens in patients who have relapsed without data. Unfortunately, we do not have the evidence on what the optimal therapy is for patients who have relapsed. Thus, it may become a practice in the community setting because it would be the obvious next step, independent of any evidence and assuming insurance companies will reimburse. If the phase 3 trials on triplets comes out with positive data it will be more frequently used.

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

Dr Luke: I think it has a high value, but the value should be put in context of the cost. There may be some value in giving immunotherapy prior to surgical resection, with the idea that it will reduce recurrence rates and improve overall survival. Adjuvant therapy can be exponentially expensive. In certain countries, they will not reimburse unless the treatment is effective. In the future, immunotherapy will have a prominent role in the treatment of many cancers in the adjuvant setting, but the question is, how are we going to pay for it?

AJMC^®: The eighth edition of the American Joint Committee on Cancer’s (AJCC) 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 the cost-effectiveness of therapy.

Dr Luke: I think the new staging will have a substantial impact in melanoma. There are substantial changes to stage III in AJCC 8, and stage III is where adjuvant therapy is introduced in clinical practice. AJCC 7 recommended immunotherapy in high-risk stage III patients. Those patients are classified slightly differently with AJCC 8. Importantly, the practice recommendations regarding lymph node dissection have changed based on data from the Multicenter Selective Lymphadenectomy Trial II. Lymph node dissection is not commonly done now, which complicates staging. We will not be able to accurately stage a patient if lymph node dissection is not done, and most patients with stage III disease after sentinel lymph node biopsy will therefore be staged IIIa. There are insufficient data on adjuvant therapy in patients with stage IIIa because most of the data on adjuvant therapy is on patients with stages IIIb, IIIc, and IV NED [no evidence of disease]. Consequently, there will likely be more patients who end up getting adjuvant therapy independent of stage because we will not have accurate staging information. That may impact cost-effectiveness if more people are getting therapy that is not in accordance with the guidelines. If we treat patients who did not really need the treatment in the first place, it will drive the cost-effectiveness of the drugs down

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