Anti-PD-1 Agents Now Second-Line Treatment of Choice for NSCLC

3rd AnnualMiami Lung Cancer Conference®.

In an interview withTargeted Oncology, Goldberg, assistant professor of Medicine and Medical Oncology, Yale Cancer Center, discussed the efficacy of immunotherapies, PD-L1 as a biomarker, and how these therapies will continue to alter the treatment of patients with lung cancer.

TARGETED ONCOLOGY:

How could the role of PD-L1 continue to evolve as a biomarker?

GOLDBERG:

That's one of the biggest questions that we have in the research world and in standard practice now that these drugs are available. PD-L1 is a test you can do for your patients in the clinic, but the question is should you and what does it mean when you get a positive or negative result? Patients who have PD-L1 expression in their tumor, it seems as though they have a better chance of responding to any of the agents that have been being tested — nivolumab, pembrolizumab, atezolizumab – they all seem to have more of a benefit when a tumor has PD-L1 expression.

The complicating factor is patients who do have PD-L1 expression in their tumor also show benefit from these drugs. It's lower benefit, but there still can be benefit. Then the question is why should you test if there's still benefit in the negative patients? It's a complicated answer. For some patients you don't need to test, I would say, because if you were going to use that drug anyway regardless of the results then why would you need to know the answer? That's specifically true for nivolumab regardless of PD-L1 status. So you don't need to test.

For pembrolizumab the trials were done in patients who were PD-L1—positive. That's where the benefit was seen and so that's why that drug is only approved in patients who are PD-L1 positive. To go with that drug, you should get the testing. I think there is still some benefit in patients who are PD-L1–negative, so whether or not you need to test is complicated. Overall, I don't tend to test because I feel like if you're going to use the drug anyway then I wouldn't need to know the results.

It might change when we start to use the drug in the first-line setting when you really want to know whether or not a patient is positive or negative, because you want to see that higher chance of benefit when you want to use that option, specifically a platinum-based doublet. When you have that as an option then you want to have a higher degree of confidence that you're going to get a response with that immune therapy. The drugs are only approved in the second-line setting, so for that setting I tend not to test and treat anyway.

TARGETED ONCOLOGY:

Is there a favoring of nivolumab over pembrolizumab because pembrolizumab requires testing?

GOLDBERG:

That's being seen in a lot of different practices. One of the other differences between the two drugs when they were approved is how often they're given. Nivolumab is given every 2 weeks and pembrolizumab is given every 3 weeks, so if that's a consideration then that might be a reason to test. Even if it's negative, I would still consider giving it in a lot of situations. I think oncologists need to think about testing, what it will mean for their results, and how it'll change their practice.

TARGETED ONCOLOGY:

What are some of the drugs on the horizon that are exciting?

GOLDBERG:

There are two other drugs besides nivolumab and pembrolizumab being explored for second-line treatment, those being atezolizumab and durvalumab. Those are both PD-L1 inhibitors, whereas nivolumab and pembrolizumab are PD-1 inhibitors. All of them look like they have very encouraging data, where a subset of patients responded and did well for a very long period of time. Which one is better than the other and how we'll use them is still up in the air, but now that we're getting more and more data I think we're all very encouraged about these agents.

TARGETED ONCOLOGY:

What are the difference between how PD-1 and PD-L1 inhibitors work, and what the potential pros and cons are?

GOLDBERG:

The interaction between PD-1 and PD-L1 is what we're trying to block, because that's what activates the immune cells against the cancer and we want to restore that so we can kill the cancer with the immune system. Blocking either one should in theory do the same thing, but the issue is that immune regulation is very complicated and blocking PD-1 versus blocking PD-L1 also inhibits other interactions on the cells. Theoretically there may be differences because of those other interactions that you're blocking.

It's too early to know if that will show itself clinically. There may be a benefit to one versus the other, and there may be different toxicities because blocking additional interactions may be more or less toxic based on what you're blocking. Again, I don't think clinically we know that yet and to choose one or the other isn't fair. There are no PD-L1 drugs approved yet, so that's why we tend to go with PD-1 drugs when we're just giving treatment off of a trial.

On a trial, I think we don't know if PD-1 or PD-L1 is better.

TARGETED ONCOLOGY:

Are there particular trials you're excited about and are waiting for the results from?

GOLDBERG:

There are so many trials right now and a lot of them we don't have the results. Right now the results that we have are form the second-line trials versus docetaxel. Everything else we're still waiting for.

The exciting trials are the first-line trials, where we're trying to understand information like why docetaxal has a better survival rate in the second-line but how would it do in the first-line versus chemotherapy? I'm really excited about those trials, and then there are the combination trials where investigators are looking at nivolumab plus ipilimumab and other combinations with immune therapies. I think probably most exciting is, because we know that single-agent immune therapy doesn't work for some patients, could a combination work for those patients? Those combinations are currently being used after failure of a single-agent immune therapy, and I think those are some of the most exciting trials. We get very excited about the data and for a really good reason, but the reality is that many patients won't benefit from the drugs, so then what? Looking at combinations is going to be most exciting.

There are other trials too looking at immune therapies plus targeted therapies, those are going to be really interesting. The data so far don't look as exciting as we'd hoped, but we'll wait to see the final results. Then there's moving the drugs into earlier stages, or into the adjuvant or neoadjuvant setting, where you'd have the potential to improve cure rates. Those are really exciting as well.