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In a prior study, survival was significantly longer with first-line pembrolizumab monotherapy than with platinum-based chemotherapy in patients with metastatic, non-EGFR or non-ALK mutated non–small-cell lung cancer (NSCLC) and PD-L1 tumor proportion score (TPS) ≥50% (KEYNOTE-024; NEJM JW Oncol Hematol Jan 2017 and N Engl J Med 2016; 375:1823). Now, investigators have conducted an industry-funded, international, randomized, open-label, phase III study (KEYNOTE-042) to determine if comparable results can be achieved in similar patients with PD-L1 TPS ≥1%.
A total of 1274 chemotherapy-naive NSCLC patients received pembrolizumab for up to 35 cycles or chemotherapy (carboplatin-paclitaxel or carboplatin-pemetrexed) for up to 6 cycles. The primary endpoint was overall survival (OS) in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%.
Median OS was significantly improved with pembrolizumab versus chemotherapy in patients with PD-L1 TPS ≥50% (20.2 vs. 12.2 months; P=0.0003), PD-L1 TPS ≥20% (17.7 vs. 13.0 months; P=0.002), and PD-L1 TPS ≥1% (16.7 vs. 12.1 months; P=0.0018). However, an exploratory analysis showed no OS benefit with pembrolizumab versus chemotherapy for patients with PD-L1 TPS 1%–49% (13.4 and 12.1 months, respectively).
Mok TSK et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non–small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet 2019 Apr 4; [e-pub]. (https://doi.org/10.1016/S0140-6736(18)32409-7)
Smit EF and de Langen AJ.Pembrolizumab for all PD-L1-positive NSCLC. Lancet 2019 Apr 4; [e-pub]. (https://doi.org/10.1016/S0140-6736(18)32559-5)
Comment
The results of KEYNOTE-042 should not significantly change current practice, given that the OS benefit was driven by patients with PD-L1 TPS ≥50%. Based on these findings, it is not advisable to give first-line pembrolizumab monotherapy to patients with PD-L1 TPS 1%–49%. These patients should be considered for regimens from KEYNOTE-189 (carboplatin-pemetrexed-pembrolizumab for non–squamous cell NSCLC), IMPower150 (carboplatin-paclitaxel-bevacizumab-atezolizumab for non–SCC NSCLC), or KEYNOTE-407 (carboplatin-taxane-pembrolizumab for SCC NSCLC). However, in wild-type patients who are not able to tolerate chemo-immunotherapy, frontline pembrolizumab can now be administered with the new expanded indication. It is likely that this indication will evolve as future studies with alternative biomarkers — possibly tumor mutation burden, which does not correlate to PD-L1 expression — may improve our ability to identify patients likely to benefit from single-agent immunotherapies.