COMMENTARY

Which Cancer Patient Is a Candidate for Immunotherapy?

Jeffrey S. Weber, MD, PhD; Michael A. Postow, MD

Disclosures

June 29, 2016

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Jeffrey S. Weber, MD, PhD: Hello. I am Dr Jeffrey Weber, medical oncologist and deputy director of the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center in New York City. Welcome to Medscape Oncology Insights, coming to you from the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO).

Immunotherapy is once again among the headlines of this ASCO meeting. Providing perspectives today on these developments is Dr Michael Postow, a medical oncologist with the Melanoma and Immunotherapeutic Service at Memorial Sloan Kettering Cancer Center in New York City. At this year's meeting, we are seeing immunotherapies becoming options across more and more tumor types. Michael, what should oncologists keep in mind in terms of patient selection and management of side effects to make these therapies more effective for our patients? How do you categorize patients with metastatic melanoma to enable you to choose what you think is the best therapy?

Immunotherapy Across Multiple Tumor Types

Michael A. Postow, MD: We are seeing this expansion of immunotherapy not only from within the melanoma treatment landscape, but also for patients with many different types of cancers. It is incumbent upon us as providers to decide whether a patient is a candidate for immunotherapy and, if so, how to most effectively deliver the treatment so that we can maximize benefits and mitigate any toxicity that might come from these types of agents.

Immunotherapy is entirely different from chemotherapy.

The most important initial concept is just recognizing that immunotherapy is entirely different from chemotherapy. It is different in terms of its mechanism of action. It is different in terms of the side effects. Unlike chemotherapy, which causes blood count suppression, hair loss, nausea, and vomiting, immunotherapy side effects are a result of immune activation in the body. Patients can have an itchy rash, they can have diarrhea, and they can have inflammation of the liver. It is important to consider this as an entirely separate category of drugs. Many patients are candidates for immunotherapy, and it is important that we think about immunotherapy for the indications that are approved by the US Food and Drug Administration (FDA), which now exist across multiple different tumor types.

Options for Patients With BRAF-Mutated Tumors

Dr Weber: Suppose you have BRAF-mutated patients and BRAF wild-type patients. The urban legend is that immunotherapy should be the preferred first-line treatment, even if you are BRAF-mutated. That seems to be a habit among academic investigators and a lot of practicing doctors. Suppose you see a BRAF-mutated patient with relatively indolent disease; how do you decide on treatment?

Dr Postow: When you have a BRAF-mutated patient who has indolent disease, it is a real question. Do you give targeted therapy like BRAF and MEK inhibitors in combination or do you give immune therapy? When you are thinking about immune therapy, the question is whether to give a single-agent PD-1 antibody or PD-1 antibody therapy in combination with the CTLA-4 blocking antibody, ipilimumab. There are many different choices for the BRAF-mutated patient with indolent disease.

Many times in this situation, we would give a patient who has indolent disease with a BRAF mutation upfront immunotherapy as opposed to upfront targeted therapy. I think the real reason for that is that many patients are treated with immunotherapy, and if they have a nice response, it can last for many, many years. In many cases, the response can even remain off treatment.[1] It is not completely true that all patients with BRAF-mutated melanoma who undergo targeted therapy will eventually have resistance in a very short time. There are subgroups of patients with BRAF-mutant melanoma who have prolonged responses to targeted therapy. I think that immunotherapy is generally the first approach in this group of patients.

Dr Weber: As you and I have discussed in the past, the interesting conundrum is that, as Georgina Long has indicated in a nice article that was just published in Journal of Clinical Oncology,[2] a patient with a low disease burden, low lactate dehydrogenase, and few sites of disease may do just as well in terms of overall survival—with modest follow-up—using BRAF and MEK inhibition versus immunotherapy. But the issue with immunotherapy is that we probably have more long-term follow-up and there is more of a sense of the plateau on the survival curve.

At the American Association for Cancer Research (AACR) Annual Meeting, Stephen Hodi presented long-term data on nivolumab in refractory melanoma.[3] There will be a presentation here on the KEYNOTE-001 trial, which will also show strong long-term survival at 3 years.[4] Maybe there is a plateau on the curve and maybe, for the first time, we can discuss "the C word." Do you talk to your patients about a cure?

Dr Postow: A cure is a very exciting idea. I do wonder if some of the patients that we have treated are cured, the patients who have been off of treatment for years with no evidence of disease. We have seen some of the long-term follow-up data from the KEYNOTE-001 study[4] presented at this ASCO meeting. After at least 3 years of follow-up of patients who were treated in the phase 1 pembrolizumab program, many of the patients who achieved complete response discontinued treatment. The vast majority of those patients (90+%) remain in a long-term response. It really does raise the possibility that these patients are cured, and it is wonderful to think about that possibility. We need many, many more years to truly know. I like the idea and I think it is giving patients a lot of hope.

Now, you have to make a survivorship plan for melanoma patients...which is a good thing.

Dr Weber: In the old days, you did not have to make a survivorship plan. Now, you have to make a survivorship plan for melanoma patients, which is required by insurance companies. That is a good thing.

Options for Patients With BRAF Wild-Type Tumors

Dr Weber: Let's go back to the BRAF wild-type population. Obviously, BRAF-MEK is off the table. When do you choose single-agent immunotherapy, usually with PD-1 blockade or PD-L1? When do you use the combination? How do you choose the patients for that? Is there an age cutoff? Is there a cutoff of tumor burden?

Dr Postow: That's a very important question: Do we give single-agent PD-1 therapy or PD-1 plus ipilimumab to patients with BRAF wild-type melanoma as the frontline treatment? How do we really make this decision? I don't think we are ready to use a biomarker quite yet. There is a lot of discussion about PD-L1 status and discussion about whether PD-L1-negative patients should be treated with the combination, and PD-L1-positive patients should be treated with the single-agent PD-1. I don't think we are at all ready to use PD-L1 in that context, to make that distinction. How do we really decide if we don't have a biomarker that is perfect?

I consider a couple of different factors. The old clinical gestalt biomarker, in my opinion, is probably more reliable than anything else. Is this a patient who may only have a shot at one line of systemic treatment before they get very sick? For that patient, I would offer the combination of both drugs together—nivolumab plus ipilimumab—because this patient may have very symptomatic disease and I want to give the combination of agents that has the highest response rate, and, hopefully, also the highest degree of median tumor burden shrinkage.

If I know that I need to palliate a patient immediately because of symptoms, and knowing that if the patient doesn't initially respond then we may have trouble with candidacy for a second-line treatment approach, those are the patients for whom I tend to favor the combination.

However, if I have a patient with very, very indolent low-volume metastatic disease, perhaps a tiny little pulmonary nodule or M1a melanoma with a little subcutaneous lesion or an involved lymph node, and particularly if the patient has comorbidities, I may think about starting with a single-agent PD-1 antibody. I would feel entirely comfortable about that because we don't yet have an overall survival advantage with the combination over PD-1 monotherapy.

I don't think we should give the combination to everyone without thinking about it.

I don't think we should give the combination to everyone without thinking about it. We really need to weigh the risks and benefits, talk to our patients, and see what their treatment goals are. Many patients don't want to have the side effects that come with combination immune therapy. Many others will say, "Give me everything you have. I want to be aggressive with this."

Dr Weber: You tailor it to the patient and the patient's emotional needs as well as the more objective assessment of disease burden. I and many of our colleagues—certainly the investigational folks in melanoma who see a lot of melanoma patients in the United States—probably feel the same way. Until proven otherwise, until we have a better biomarker or any good biomarker, I think that is the way we will conduct ourselves.

Adverse Events and Imaging to Identify Tumor Response

Dr Weber: What you said about toxicity is a nice segue into talking about the side effects. Some patients will go online and get intimidated about the toxicity rate for the concurrent ipilimumab/nivolumab regimen. How difficult has that been to manage? You have seen as many of these patients as anyone. Has it been a problem? Obviously, a significant number of patients, more than one third, will discontinue therapy because of toxicity. When they get steroids or infliximab, does that influence their ability to have a response?

Dr Postow: There are a lot of good questions in this discussion. It is absolutely true that many patients discontinue immunotherapy because of side effects, particularly with the combination. The majority of patients who discontinue therapy do so before receiving the four doses of both drugs. One thing that we have known is that their outcomes are absolutely fantastic even if they discontinue immune therapy.

The goal is not to give as much immunotherapy as you possibly can.

The goal is not to give as much immune therapy as you possibly can. The goal is to give enough immunotherapy to get the anti-tumor response. For patients who have toxicity from the treatment, I encourage investigators or clinicians to do imaging tests to see if they are having a response. In those types of situations, I feel very comfortable stopping immune therapy because we know that patients can have very, very good outcomes even without continuing immunotherapy.

In terms of managing the side effects, the bottom line is that patients who have side effects and need immunosuppression with steroids, infliximab, or other drugs have outcomes that are just as good as those of the patients who don't need immunosuppression to manage side effects. I don't think providers should be concerned about immunosuppressing these patients when they are treating a side effect. We know that the outcomes can be very good, so I would say to go ahead and give the steroids. Go ahead and give the infliximab if you need it. The outcomes can be very good long-term.

Dr Weber: An interesting urban legend that arose early on with ipilimumab[5] and continues with nivolumab and pembrolizumab is that there is some association between immune-related adverse events and outcome. Interestingly, if you look between the lines in your own article[6] or James Larkin's article[7] from the New England Journal of Medicine last year, there was a slight increase in the response rate and progression-free survival in those who had toxicity of grade 3/4 versus those who did not. I guess my argument would be that not only do the steroids and the infliximab not compromise patients, the patients probably do a little better—not because they get steroids but because they have the adverse events.

High-Risk Patients and Special Melanoma Populations

Dr Weber: There's an interesting poster[8] at this ASCO meeting by a young Australian fellow who talks about treating patients who have severe toxicity to ipilimumab, autoimmune disease, or allograft transplants with PD-1 blockades. What can you tell us about that?

Dr Postow: Now that these agents and the combinations are approved, at least in the United States, it is important to look at the patients who were not included in the clinical trials, particularly high-risk patients—patients with underlying autoimmune diseases, rheumatoid arthritis, ulcerative colitis, or other inflammatory bowel diseases—and how well they have done with the treatment. Equally importantly, how well do people respond to PD-1 therapy after having a prior toxicity from a drug such as ipilimumab?

Patients with autoimmune diseases can absolutely derive benefits from PD-1 blockade.

That poster was very, very important in telling us a couple of things. Patients with autoimmune diseases can absolutely derive benefits from PD-1 blockade. The response rates in that group of patients was approximately what we saw across patients at large. They absolutely can benefit. They may have a flare of their other autoimmune disease while they are being treated with a PD-1-type drug. However, most of those flares are easily managed with immunosuppression.

A patient with an autoimmune disease should be considered for PD-1 if they absolutely need it. It is a risk-benefit approach. Most patients with an autoimmune disease who are facing a cancer—particularly an aggressive one such as metastatic melanoma—are willing to take the chance and take the drug because of the potential for long-term benefit, even if it might mean that their side effects could be worse from their autoimmune disease.

Dr Weber: The interesting thing about the Menzies poster[8] is that the response rate in patients who had prior ipilimumab toxicity and progressed on ipilimumab was over 30%. It is actually a little better than the response rate in the refractory population, which is usually about 25%-30%. It is as if the immune system has been primed by the immune-related adverse events for the PD-1 antibody. It is almost as if it makes it easier for the tumors to regress.

Last question. In our melanoma field, are there any studies that have been or will be presented at this year's ASCO meeting that you think will change or refine your practice?

Dr Postow: We have longer-term follow-up from the CheckMate 067 study.[9] We will see more information about the duration of response in patients who were treated with the combination ipilimumab and nivolumab versus nivolumab alone versus ipilimumab alone. We are still waiting on the overall survival data from that particular study.

Other important issues that will be discussed at this year's ASCO meeting include PD-1 in special subtypes of patients with melanoma. How well does PD-1 work in uveal melanoma?[10,11] How well does PD-1 work in patients with mucosal melanoma[10] and acral melanoma?[12] It looks like acral and mucosal melanomas respond just as well to PD-1 as cutaneous melanomas. However, there may be the suggestion that uveal melanomas do not respond as well to PD-1. We need to hash that out.

Dr Weber: I get the feeling that it is more than a suggestion. In the presentation from the University of California San Francisco, the response rate was in the realm of only a few percent.[11] Hopefully, when we get a look at the ocular experience with ipilimumab plus nivolumab, it may end up being a little better.

It has been an exciting meeting so far. I am sure it will continue to be exciting. Michael, thank you very much. It has been a pleasure to talk to you.

Dr Postow: Thank you, Jeff.

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