Early Experience; Immunotherapy + Chemotherapy for NSCLC
Insights From: Roy S. Herbst, MD, PhD, Yale School of Medicine; Corey J. Langer, MD, University of Pennsylvania; Vassiliki A. Papadimitrakopoulou, MD, University of Texas MD Anderson Cancer Center
Vassiliki A. Papadimitrakopoulou, MD: The updated analysis of KEYNOTE-021, with 5 additional months of follow-up, confirmed the data that we saw at the 2016 ESMO Congress, published in The Lancet Oncology in 2016. With the additional follow-up, we have seen confirmation of the superior response rate, which was the primary endpoint of the study, as well as superior progression-free survival for patients treated with the combination of chemotherapy and pembrolizumab. We have also seen evidence of early separation of the curves for overall survival with a hazard ratio of 0.69; however, this is not the primary endpoint of this study and the data are still maturing.
Corey J. Langer, MD: My personal experience with the combination has been largely limited to the clinical trial. Since the recent approval in May of 2017, I have had the opportunity to start 2 patients on the regimen. But it’s way too soon to actually gauge therapeutic benefit. To date, both on trial and off trial, it’s been an extremely well-tolerated regimen. Most of the toxicity, to be frank, has been driven by the PD-1 inhibitor. We see arthralgia; sometimes, rash; occasionally, parotitis without rash; and, rarely, diarrhea. And, in my own personal experience, I’ve observed a fair amount of hypothyroidism, which can sometimes come on abruptly. A THS level is normal 1 week and then, 3 weeks later, it has jumped up to 80 or 100 points, and the patients feel it. They’re quite fatigued. But fortunately, we can fix it very readily with levothyroxine, with essentially, replacement therapy.
Roy S. Herbst, MD, PhD: For anyone who is PD-L1–high, greater than 50%, they will get immunotherapy—pembrolizumab—alone. Anyone who is low would be a candidate for this combination of carboplatin, pemetrexed, and pembrolizumab. Certainly, if there was a trial of 2 immunotherapy agents, or something else going on—a vaccine—I might consider that first. But I think that this is a combination that can be used in the front-line setting or, by the way, in second-line therapy. It particularly might have some activity in those patients who are PD-L1–negative or low. It’s probably doing something to kill tumor cells—activating neoantigen to simulate the immune response—and is probably having an effect on the immune microenvironment to rev things up. But, definitely, this is something that is worth exploring, considering, and discussing with patients.
Vassiliki A. Papadimitrakopoulou, MD: The clinical trial data suggest that patients can benefit from this therapy, irrespective of their PD-L1 status. For patients with high PD-L1 expression, this point is 50% or more. I think there’s going to be a glamming consideration in practice on whether I’m going to be using single-agent pembrolizumab for these patients versus the combination therapy. Certainly, excluded from this consideration will be patients that would be poor candidates for chemotherapy, either due to comorbid disease or declining performance status. I will present the options and the data to my patients, and we will be making decisions together.
Roy S. Herbst, MD, PhD: Immunotherapy used as maintenance therapy is going to be very promising. We already know from a press release not too long ago, that for durvalumab, a PD-L1 antibody in stage 3 lung cancer—meaning lung cancer that’s locally advanced with either ipsilateral or contralateral lymph node involvement—there was an improvement in progression-free survival with it, the PD-L1 inhibitor, versus placebo. Data are not released yet, although we know a trial was stopped early, which suggests that there were compelling results.
I think with these drugs, if they’re active, the best thing to do now would be to move them up and use them a little earlier. Why wait for a disease to progress? Use them earlier. Give them time to have their effect. I think we’re going to see them moved up to the maintenance setting. I think we’ll see them moved to adjuvant therapy. Neoadjuvant therapy trials are already ongoing. And, maybe someday, they will even be considered from chemotherapy prevention settings.
Vassiliki A. Papadimitrakopoulou, MD: Based on the clinical trial results, the patients received 4 cycles of chemotherapy in combination with pembrolizumab, before switching to maintenance therapy. The dose of pembrolizumab used was a flat dose of 200 mg every 3 weeks. The clinical trial was based on the use of pembrolizumab for 2 years, after completion of chemotherapy in combination with pembrolizumab. We do not know yet what the optimal duration of maintenance therapy is in this setting. That clinical question should be answered in a clinical trial.