Advanced NSCLC: The Advent of Frontline IO Monotherapy


Focusing on single-agent immunotherapy in advanced NSCLC, experts review key data from the KEYNOTE-024, IMpower110, and EMPOWER-Lung 1 clinical trials.


Stephen V. Liu, MD: Like you said, Neal, we have a lot of different options here. And there’s so much nuance now. The field is so much more complex than, I think, when we had started. We want to go with targeted therapy. For most targets, for something like KRAS [mutation], where we have a targeted drug approved, we still favor immunotherapy up front. It can be increasingly hard to keep track of. But I think the point here is that, for most patients without an actionable driver, we’re really looking at immunotherapy as our frontline treatment.

I think the basis for that really is built on [the] KEYNOTE-024 [trial], [which is] probably the most important study, really, in terms of the principle of using up-front immunotherapy. When we think back to this study, it was presented at ESMO [European Society for Medical Oncology Annual Meeting] 2016 by our colleague, Dr Martin Reck, [MD, PhD]. And prior to this, immunotherapy had been introduced as initially a very salvage treatment from work done by Dr Julie Brahmer, [MD], and others. And then we saw this really quickly replace docetaxel in the second-line setting. Better response rate, better survival, better-tolerated. But docetaxel was a pretty low bar. Even now, we’re pretty eager to get rid of docetaxel.

This frontline study, where patients were [randomly assigned] to immunotherapy alone– meaning pembrolizumab monotherapy or platinum-doublet [chemotherapy]– there were people in our circles that were a little worried about this study, that were a little nervous. [I] really wondered, if people didn’t respond to immunotherapy, would they then be deprived of the benefit of chemotherapy? And we’re actually thinking the other way around. There’s no guarantee that they would get to have chemotherapy. We held chemotherapy this far because, for decades, we had espoused the value of chemotherapy improving survival [and] improving quality of life. And there were some that were a little hesitant about this study. And we know now that they couldn’t have been more wrong—that immunotherapy [is] the clear winner in this rich population. And this really changed how we view immunotherapy.

This was a first-line randomized phase 3 trial for patients with advanced non–small cell lung cancer [with] no prior treatment. And they were excluding EGFR and ALK alterations. They only included patients with PD-L1 expression of 50% or greater, meaning at least half of the cells had to express PD-L1. This was done by central confirmation...And it’s an appropriate first study in the frontline setting. We’re going out on a limb here, but we’re enriching the population for those that we really believe are going to do better [with immunotherapy].

They were [randomly assigned] to receive pembrolizumab alone every 3 weeks for 2 years or standard platinum-doublet chemotherapy for 4 to 6 cycles. And crossover was allowed in this study. In addition, when this study was done, immunotherapy was pretty available as a second-line option, even outside the trial. And thus, we are allowing crossover. Patients can cross over on the study or without the study. And what we saw here was that pembrolizumab, the clear winner. Really, not even close. We saw an improvement in progression-free survival with a hazard ratio of 0.50. And most importantly, and I think most impressively, an improvement in overall survival—a doubling of the median survival from 13.4 months to 26.3 months, hazard ratio of 0.62. Thus, a 38% reduction in the risk of death. The control arm here, chemotherapy alone, 13.4-month survival didn’t underperform. That really was what we’d expected at the time. And here we have a doubling of that survival in this select group. This really changed how we look at immunotherapy. [It] really showed us what immunotherapy was capable of.

Important lesson here is that, despite relatively high rates of crossover in the trial and outside the trial, that control arm never catches up to the experimental line. Which tells us you cannot save immunotherapy for second line or beyond. Because even factoring that in, the survival is double if you start with immunotherapy. We use our best drugs first. At diagnosis, if you say, “We’re going to do chemo alone, and I promise we’ll do immunotherapy if it doesn’t work,” that’s just a promise we can’t keep. And thus, despite crossover, there was a clear and powerful survival advantage to the use of immunotherapy.

After October 2016, it really became below standard of care to give chemotherapy alone for PD-L1–high non–small cell lung cancer. In the years that followed, we saw similar results with other drugs. [The] IMpower110 [trial] looked at a PD-L1 inhibitor, atezolizumab, [and had] a slightly different design that actually allowed patients with PD-L1 expression a much broader entry criteria but analyzed it based on different expression levels. And the randomization, again, was to PD-L1 monotherapy by itself or standard chemotherapy with maintenance chemotherapy permitted. Patients continued this until progression or loss of benefit. We saw pretty similar results. Breaking things down a little differently, if we use a 5% threshold, we didn’t see a significant benefit. Numerically, there was a benefit. Same with using a 1% threshold. It was really when you enrich the population for PD-L1 high, for using that 50% cutoff, where we saw a significant benefit.

Median survival with chemotherapy in that PD-L1–high group was 14.7 months compared [with] 20.2 months with the use of atezolizumab. That’s a hazard ratio of 0.76, clearly significant. And if we do some adjusting based on nonprotocol therapy, some statistical corrections, we see that hazard ratio even better at 0.69. Atezolizumab, [a] PD-L1 inhibitor, also [is] approved as monotherapy for PD-L1–high non–small cell lung cancer.

And the most recent approval was [the] EMPOWER-Lung 1 [trial]. And this looked at a different PD-1 inhibitor, cemiplimab[-rwlc]. That may be familiar to some of us who treat skin cancers and dermatologic cancers. Cemiplimab was also studied in a randomized phase 3 trial using that 50% threshold. [The trial included patients who were] PD-L1 high, excluding EGFR, ALK and ROS1, and [they were randomly assigned] to cemiplimab monotherapy...or standard chemotherapy. And, as you might expect, fairly similar results. The use of cemiplimab associated with better progression-free survival, with a hazard ratio of 0.54, very statistically significant. And what’s most important, an improvement in overall survival—median of 14.2 with chemo [and] not yet reached for cemiplimab. This is more of a recent study, but the hazard ratio here is 0.57. And this does have FDA approval.

And thus, we now have 3 monotherapy options—pembrolizumab, atezolizumab, [and] cemiplimab—for PD-L1–high non–small cell lung cancer, which numerically represents about a third of non–small cell lung cancer out there. In my mind, I think all 3 of these are pretty reasonable options.

Neal, I don’t know what your practice has been [choosing] between these 3. Does one stand out as different than the other?

Neal Ready, MD, PhD: No. I don’t think so. And I think, just based on data, I think they’re all appropriate options. Where I am in the mid-Atlantic, we have patients who come from great distances. Hence, the opportunity to give pembrolizumab every 6 weeks is helpful for our patients who live 2, 3, and 4 hours’ drive away.

Stephen V. Liu, MD: It’s a great point. Pembrolizumab [has] now [been] approved to be given every 6 weeks. Atezolizumab we can give every 4 weeks. Some differences there, and they are different drugs. They have different epitopes. I just don’t believe that, today, we’re able to leverage any of those differences in a meaningful way. And the way I would look at it, all these drugs are better than chemotherapy. And what they have in common—I think the key with immunotherapy and why we keep coming back to immunotherapy—is that they all have the potential for long-term benefit, for durable, meaningful benefit. And that’s just not something we see with chemotherapy. Before the use of immunotherapy—I know that we’re so used to it now—but before the use of immunotherapy, responses were transient. Survival was limited. Not everyone gets that long-term benefit from immunotherapy, but a lot of patients do. That’s been your experience as well?

Neal Ready, MD, PhD: Yes. And I was really surprised how much of an improvement in overall survival it is for so many patients. When the American Cancer Society has looked at survival in cancer overall, there have been marked changes over the last 5 years, with improvement in survival. And a lot of that improvement is due to improvement in survival in stage IV lung cancer, which is just amazing. And I think it’s due to both the molecular therapies that we have and, clearly, the 5-year survivals that we’re seeing with immune therapy now.

Transcript edited for clarity.

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