Immunotherapy Agents Preferred Second Choice in NSCLC, But Questions Remain

Sarah Goldberg, MD, MPH

Though the immunotherapy agents nivolumab (Opdivo) and pembrolizumab (Keytruda) have gained traction in the treatment paradigm of non—small cell lung cancer (NSCLC) and are also preferred as a second-line treatment of choice, several questions still remain—including the efficacy of PD-L1 as a biomarker, explains Sarah Goldberg, MD, MPH.

In October 2015, pembrolizumab was granted an accelerated approval by the FDA as a treatment for patients with pretreated advanced NSCLC across all histologies whose tumors express PD-L1. The agent was approved along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, and is indicated for patients who progressed on or after platinum-containing chemotherapy or EGFR- or ALK-targeted agents in patients harboring those mutations.

Most recently, the FDA accepted a supplemental new drug application for pembrolizumab as a treatment for patients with advanced NSCLC with PD-L1 expression on >1% of tumor cells.

Also in October 2015, the FDA expanded the approval of nivolumab (Opdivo) to include patients with nonsquamous NSCLC who progress on or following platinum-based chemotherapy, or EGFR- or ALK-targeted agents in patients who have those mutations.

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

In an interview with at the Miami Lung Cancer Conference® Goldberg, an assistant professor of Medicine and Medical Oncology at Yale Cancer Center, discusses the efficacy of immunotherapies, PD-L1 as a biomarker, and how these therapies will continue to alter the treatment of patients with NSCLC.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 not have PD-L1 expression in their tumor also show benefit from these drugs. It is a 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. Therefore, 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 undergo 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; therefore, I wouldn't need to know the results.

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

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.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 are given. Nivolumab is administered 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 is 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.

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

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.

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

Which one is better than the other and how we'll use them is still up in the air. However, now that we're getting more data, I think we're all very encouraged about these agents.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. However, 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.

Are there particular trials you're excited about and are anticipating the results of?

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

The exciting trials are the first-line trials, where we're trying to understand information on 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.

Then, there are the combination trials where investigators are looking at nivolumab plus ipilimumab and other combinations with immune therapies. Because we know that single-agent immunotherapy doesn't work for some patients, could a combination work for them? Those combinations are currently being used after failure of a single-agent immunotherapy, and I think those are some of the most exciting trials.

We get very excited about the data and for a really good reason. 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 immunotherapies 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 is moving the drugs into earlier stages—or into the adjuvant or neoadjuvant setting—where you would have the potential to improve cure rates. Those are really exciting, as well.