The Role of Immunotherapy in Metastatic NSCLC

Transcript:Benjamin P. Levy, MD: So, let’s save the best for last here and talk about the role of immunotherapy for our patients. I think immunotherapy has certainly reshaped the way that we are treating patients in the treatment paradigm for lung cancer. But, it’s also forced physicians to rethink how cancers behave and about this fascinating interplay between the immune system and cancer. I think what we know now is that patients who get immunotherapy, there are durable responses. Immunotherapy, importantly, has bent the survival curves, but perhaps more importantly has lifted the tail of the curve. And we’re seeing really durable responses and patients that are living longer. We currently have two drugs that are available, nivolumab and pembrolizumab, with others coming down the pike.

That said, I think that we need to remember that these drugs, as they stand now, only work in roughly 20% of patients. And we need to do better. I think part of my job when I see patients, either as a second opinion or discussing clinical trials, is to temper the enthusiasm for these drugs where they’ve seen commercials that suggest that they are going to be cured, and they’re not yet. Sarah, you have a tall order here. Can you give us a high-level overview of where we stand with nivolumab and pembrolizumab, perhaps atezolizumab, as well as perhaps their activity in subset analysis that you have performed and published?

Sarah B. Goldberg, MD, MPH: I think that these drugs have absolutely changed the paradigm for treating non-small cell lung cancer, as well as other cancers. It’s completely changed not only the way that we think about the types of drugs that work, but just how patients are doing in the long run. I think it’s an interesting point you made about tempering enthusiasm. In some ways, I agree with you, because, as you mentioned, these drugs don’t work for all patients. But, when you see patients who get these drugs and can live for years with really minimal, if any toxicity, and really good quality of life for so long, I’m very enthusiastic about them. So, in some ways I’m very enthusiastic and these drugs, again, have really changed the way that we think about treating lung cancer. But, I agree, they’re in some ways disappointing in that they’re not helping all patients.

As you mentioned, the two drugs that we have now available are nivolumab and pembrolizumab. They’ve both been FDA approved for non-small cell lung cancer in the last year or so, and both of them have been compared head-to-head with docetaxel, at the time, was our standard second-line treatment. You could argue that should be now our standard comparator arm, but that’s another discussion. Both of those drugs have shown a benefit compared to docetaxel in terms of overall survival. So, that’s our gold standard of what we look at, to see if one drug is better than another, and clearly both are.

There were interesting ways that the trials were done. Nivolumab was done in all-comers regardless of biomarker and pembrolizumab, the big comparison trial with docetaxel, was done in PD-L1-positive patients. Again, the survival benefit was there for both. And so, that’s how they were approved. Nivolumab is approved for all-comers and pembrolizumab approved for patients with PD-L1-positivity. It’s the whole discussion about biomarkers, which is very complicated and really an evolving story. But, some people think nivolumab is the one where you don’t have to check for PD-L1 and pembrolizumab is the one you do. I don’t think there’s an inherent difference in the drugs. I think it’s just the way the trials were done and the way that they got approved by the FDA. Again, there is a real benefit with these drugs. The long-term survival is incredible that we’ve seen in some patients. And, as you mentioned, it’s the tails of the curve. So, there is a benefit in terms of median survival, but, again, it’s that long-term benefit in some patients that have really changed the lives of many patients.

Atezolizumab is a PD-L1 inhibitor as opposed to the other two which are PD-1 inhibitors. That also looks to be effective in patients compared to docetaxel in the second-line setting. I think that probably will be another one where we’re seeing in the future potential approval. And then, there's others as well that we’re seeing trials of. It’s, again, a very quickly evolving story, and that’s just the single-agent discussion. There’s lots more in terms of combinations and with chemotherapy versus without chemotherapy.

Benjamin P. Levy, MD: Do you think there’s a difference between PD-1 drugs and PD-L1 drugs in terms of their efficacy? Perhaps, biologically, there may be differences in terms of their tolerability. But, in terms of their efficacy, is there any difference do you think?

Sarah B. Goldberg, MD, MPH: I don’t think so from what we’ve seen so far. They haven’t been compared head-to-head. I don’t know if they ever will be. I don’t think so. There are theoretical differences in terms of toxicity, but even that I’m not sure.

Benjamin P. Levy, MD: So, Sarah, there have been some interesting combination strategies with durvalumab and tremelimumab checkpoint inhibitors in the refractory setting. Can you briefly go over that and tell us where you think that sits with things?

Sarah B. Goldberg, MD, MPH: Durvalumab is a PD-L1 inhibitor and tremelimumab is a CTLA4 inhibitor. We mentioned that the ipilimumab/nivolumab combination is analogous to that in some ways and that it’s a combination strategy. So, this is a phase I study that, just in the last couple of months, has been published. And what’s exciting about the data is that patients can benefit regardless of PD-L1 status. Now, this is something that we’ve talked about. The PD-L1 biomarker is a challenging one anyway, but it does seem that with this combination, you can have benefit in both groups, which is, I think, important. And it doesn’t seem to be that even though there’s more benefit and positives than negatives, it seems that there’s benefit in both. Whether that will hold true in larger groups in randomized trials remains to be seen, but at least in the smaller phase I experience, that seems to have stood up. Again, I think it’s a really interesting strategy, one that may be beneficial to more patients than some of the single-agent strategies. The toxicity probably is more. It’s true for other combinations of CTLA4 and PD-1 or PD-L1. But, again, with vigilance, monitoring, and aggressively treating patients with toxicity, typically it’s manageable. There were some deaths on the trial, so it’s not something to take lightly, of course, but there’s overall manageable toxicity.

Mark G. Kris, MD: We’re taking that forward, too, in a neoadjuvant setting. Jamie Chaft at our institution has a trial just about to open looking at the combination of durvalumab and tremelimumab. In addition, this neoadjuvant setting gives you a great opportunity to actually look at the biology. We’re really hoping that that quick look over just a few months is going to really help us understand how these drugs work and why they don’t.

Benjamin P. Levy, MD: I think with further trials we’ll understand not only the optimal dosing, but the timing of each of these agents as they’re used together.

Transcript Edited for Clarity