Pembrolizumab in First-Line Nonsquamous NSCLC

H. Jack West, MD: The KEYNOTE-189 trial was a very important trial that immediately impacted our practice. This trial was presented in the plenary session at AACR 2018 and has published in the New England Journal of Medicine. It was a randomized phase III study of just over 600 patients with advanced nonsquamous non—small cell lung cancer. Patients were randomized to receive chemotherapy with cisplatin or carboplatin and pemetrexed alone, or with placebo, or with pembrolizumab. The patients could have any degree of PD-L1 expression—from negative, or less than 1%, to a higher level of more than 50%. From a press release before the presentation, we already knew that it was positive for overall survival. But, we didn’t really know how positive it was. The answer was tremendously so—a hazard ratio of 0.49 in overall survival, which is really impressive for a trial in advanced non–small cell lung cancer.

Importantly, we also needed to clarify whether patients with lower levels of PD-L1 expression (1% to 49%, or even negative), got a benefit from concurrent first-line chemotherapy and pembrolizumab. The answer was yes. It was greatest in the patients with the highest level of PD-L1 expression, but it was still clinically and statistically significant when broken down into those other subgroups—of low level, 1% to 49%, or even negative levels of PD-L1 expression. And that was the case when we’re looking at endpoints of overall survival, progression-free survival, and response rate.

Toxicities were nothing unexpected—a bit more of the immune-mediated side effects that you’d expect, but basically a superimposition of what we’ve come to experience with the immune checkpoint inhibitors, and pembrolizumab, in particular, as well as with the chemotherapy regimens. So, this is something that is going to change practice. We already have an FDA approval for carboplatin/pemetrexed and pembrolizumab in the first-line setting based on the KEYNOTE-021g trial, which was a randomized phase II study with 123 patients. Although we have the option available to us, it has not been broadly adopted by thoracic oncology specialists or general oncologists because we’re waiting to see bigger results. We have that here, and it has been as much of a difference as we could ever expect or hope to see.

The KEYNOTE-189 trial is definitely changing practice right now. I expect that we are going to see the evolution of treatment recommendations as reflected by the NCCN guidelines and others. It will be interesting to see a breakdown, by whether patients have a higher level of PD-L1, a lower level of PD-L1, or negative PD-L1. In each of these settings, we are likely to not just have the KEYNOTE-189 trial results. We already have KEYNOTE-024, which is pembrolizumab versus doublet chemotherapy—pembrolizumab as a monotherapy. Soon we are also going to be considering the results of the KEYNOTE-042 trial, which looked at pembrolizumab as monotherapy versus a chemotherapy doublet regimen in nonsquamous and squamous patients. That’s in a broader population of patients with any degree of PD-L1 expression as well—1% in KEYNOTE-042.

In patients with nonsquamous non—small cell disease with high PD-L1 expression, we will see that pembrolizumab monotherapy remains to be an option. The efficacy is a little bit higher with chemotherapy and concurrent pembrolizumab, so I believe both will be considered as favored options. It really will be left to the judgment of the treating physician, and the individual situation, as well as the patient, about whether to go for monotherapy or a triplet with chemotherapy and immunotherapy. Soon we will see that extend to the patients with 1% as the cutoff for PD-L1, based on the combination of the KEYNOTE-189 and KEYNOTE-042 trial results. So, we’re going to see all of these options, or both of these options, of chemotherapy and immunotherapy versus monotherapy, depending on the situation and physician judgment.

And in the patients without PD-L1 expression, we will see a growing trend toward greater use of the combination, at least in nonsquamous non—small cell lung cancer, of much more carboplatin with pemetrexed and pembrolizumab, given that we already have that approval. Cisplatin will likely be included as well, based on the KEYNOTE-189 trial, but I will mention that they did have more renal toxicity in KEYNOTE-189. And so, that combination may be one that I would be less inclined to use. At the same time, in a broader setting, we’re going to have other trial results with chemoimmunotherapy, with agents like atezolizumab as a potential option in the coming months. I would envision that the NCCN guidelines are going to be revised many more times in 2018 and beyond, to reflect a growing number of options. Chemotherapy and immunotherapy with pembrolizumab is going to be high on that list.