COMMENTARY

New Immunotherapies Bring New Questions in Lung Cancer

Mark G. Kris, MD

Disclosures

April 28, 2016

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Hello. I'm Mark Kris from Memorial Sloan Kettering, and I'd like to do a series of three pieces here in our Medscape video. The pieces are called "Our Job Just Got Better but Harder," and the first example of that is the emergence of nivolumab, and now pembrolizumab, for the treatment of patients with lung cancers.

It is a great opportunity for all of us and even more so for our patients. We suddenly have an additional treatment and we also have a totally different class of treatments—the immune checkpoint inhibitors. Though there's more work to be done, it appears today that the benefits here are additive to the other treatments that we have—be it surgery, radiation, chemotherapy, or targeted therapies. This is a great advance.

Even though we have these drugs at our disposal now, we really have many, many difficult questions to answer. The more choices that we have, the more need for us to be very, very careful about how to use these medications. The first question is, who should we give them to? It appears that right now there is good evidence that they could be given to any patient with a thoracic malignancy. Obviously, most studies so far have been in patients with adenocarcinomas and squamous cell carcinomas of the lung.

When should we give them? This is a very, very difficult situation. To get the drugs approved, they needed to be tested in a defined space. The defined space for all of the agents available targeting PD-L1 has been the failure of initial therapy, and the comparator in those trials—that have had comparator trials—has been docetaxel. I caution you that even though the drugs have been tested and approved in this space, it was done to allow a very clean and quick drug approval. But it by no means says that this is the best way to use these drugs. For now, you are safe to use it in this setting. However, please be aware that this may not be the right setting to do it. It may be that giving it first, maybe giving it after a definitive therapy or after chemotherapy, is the best way to go. Additional trials will answer that.

Is there a biomarker today that can be used to select these agents? The truth is, no. PD-L1 testing has been used and it's been clearly shown that there are higher rates of response. The approval for pembrolizumab includes a companion diagnostic, which, if you test for PD-L1 expression, you have a higher rate of response. However, even with positive PD-L1 testing, a minority of patients still have a response; patients with negative PD-L1 testing can still have a response with nivolumab and pembrolizumab.

Probably the best way to go today is not to make your decision based on testing. However, a positive result could help you decide whether to recommend pembrolizumab or nivolumab sooner. Many of you may have seen the US Food and Drug Administration label for nivolumab for adenocarcinomas of the lung. That label includes a so-called complimentary diagnostic, another monoclonal antibody–based test to look for a PD-L1 expression to help doctors decide when to use it. Clearly, also, is mutational burden. My colleagues Matt Hellmann and Naiyer Rizvi were leaders in showing that the higher numbers of mutations—greater mutational load—means a greater likelihood of benefit.[1] When you couple that with PD-L1 testing, it's an even more potent predictor of benefit. But it's still not perfect. More to come on that. Last, please remember that even with PD-L1 testing, the majority of patients do not have a major response from these agents.

The toxicity is much less than with comparators, particularly the docetaxel comparator in the trials that have been done. It is very, very important to monitor these patients carefully and get them off the anti-PD-L1 drugs quickly, but not too quickly so as to make sure that the patient would not derive benefit at some point. We're going to hear a lot more about this; it requires very, very careful monitoring. For now, a symptomatic patient whose symptoms are worsening on these treatments should be taken on to another therapy.

We have great news: new drugs, a new class of drugs. The responses we see are deep and they are durable, but they only occur in a minority of patients. So it's incumbent on us to use the drugs wisely and to stop them as soon as we are sure that a patient is not benefiting from them.

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