Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer
N Engl J Med 2018; 378:2078-2092
Abstract
<BACKGROUND>
First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.
<METHODS>
In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.
<RESULTS>
After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.
<CONCLUSIONS>
In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680. opens in new tab.)
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Hossein Borghaei, DO: KEYNOTE-189 is a phase III randomized clinical trial for patients with treatment-naïve nonsquamous non—small cell lung cancer who do not have an activated mutation. The study specifically talked about EGFR and ALK, and those were definitely excluded. Patients also had to have a good performance status, no active brain metastases, and other standard inclusion/exclusion criteria for a clinical trial. Everybody had to have adequate tissue for PD-L1 testing. PD-L1 testing results were not needed for the study randomization, but everybody had to have tissue just so that we could determine the level of the PD-L1 expression. The patients were simply randomized to a combination of carboplatin plus pemetrexed with pemetrexed maintenance, and that was the standard-of-care control arm with this study.
On the other arm, they got the exact same combination plus pembrolizumab. Now, this was built upon the results of KEYNOTE-021g, which was a randomized phase II trial with the exact same combination. Over 600 patients were randomized to these 2 arms of the study, and in the experimental arm, the arm with pembrolizumab, maintenance with pembrolizumab plus pemetrexed was allowed. I think patients were also allowed to cross over from the chemotherapy arm at the time of progression to the more active, or the experimental, arm with pembrolizumab.
Corey J. Langer, MD: KEYNOTE-021g was actually the precursor for the much larger randomized phase III KEYNOTE-189 trial. This was a randomized phase II effort that compared the control regimen of pemetrexed/carboplatin with the combination of pemetrexed/carboplatin with the checkpoint inhibitor pembrolizumab with 4 cycles of combination carboplatin given in both arms. Pemetrexed was continued as maintenance therapy in the absence of disease progression or untoward toxicity. In the investigational arm, pembrolizumab was grafted onto the pemetrexed/carboplatin and continued as maintenance along with pemetrexed for up to 2 years. The unique feature of this trial included crossover in the control arm to pembrolizumab at the time of disease progression, so that lent extra credibility to the trial in light of the results.
We observed a major improvement in response rates, initially from 28% to 57%. Both arms have inched up somewhat over the past year or so now to 30% and 60%. PFS showed a significant advantage for the pembrolizumab arm, which over time has matured to about 20.0 months versus 8.9 months. What’s remarkable there is the control arm has actually exceeded historic controls.
Initially, survival did not show much difference at 1 year: 75% for pembrolizumab in combination versus 72%. But as time has gone on, we’ve actually seen a major improvement. The median survival has still not been reached in the pembrolizumab arm, now easily exceeding 2 years; whereas it’s about 13 or 14 months in the control group. We have to remember that this was a multi-institutional, academic-oriented trial. Selection bias clearly had some play in the nature of the patients who went on it.
KEYNOTE-189 was the logical follow-up of this trial. It was a randomized phase III trial with 2:1 randomization of platinum, either carboplatin or cisplatin, combined with pemetrexed plus or minus pembrolizumab. It was placebo controlled, a distinct difference from the precursor randomized phase II trial, which did not employ a placebo. Like KEYNOTE-021g, eligibility was restricted to nonsquamous non—small cell in the absence of any activating molecular aberrations: no EGFR mutations, no ALK translocation.
Once more, there was an astounding improvement in overall response rate that was statistically significant and clinically meaningful. We essentially see a doubling in progression-free survival from 4.9 to about 8.9 months and a highly significant—in fact, unprecedently significant—improvement in overall survival. The hazard ratio here is 0.49. In my entire career of research of advanced non—small cell lung cancer, I have never seen a hazard ratio that good. The patients were evaluated based on their PD-L1 expression. The survival benefit was seen across the board but was even more pronounced in the group that had 50% or higher PD-L1 expression. The hazard ratio there was 0.42, and in that group, the response rate was about 68%, which exceeds the 45% or 46% that was seen with single-agent pembrolizumab in the KEYNOTE-024 study.
This trial was a major game changer. The phase III results validate what we had seen in the randomized phase II trial. It had a conditional approval, and now a formal approval, by the FDA for nonsquamous non—small cell lung cancer in the absence of activating mutations, regardless of PD-L1 status.
