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Arguably, no drug class has more radically and rapidly altered the management of non–small-cell lung cancer (NSCLC) than inhibitors of the interaction between programmed death 1 (PD-1) and its ligand PD-L1. By impeding this negative regulatory signal for T-cell response, PD-1 and PD-L1 inhibitors result in longer survival than does chemotherapy among patients with previously treated NSCLC.1–4 In this issue of the Journal, Carbone and colleagues report on a trial that compared the PD-1 inhibitor nivolumab with chemotherapy as first-line treatment for advanced NSCLC in a population of patients selected on the basis of PD-L1 expression level.5 Progression-free survival was numerically longer with chemotherapy than with nivolumab. In contrast, in an independent study, progression-free survival with the PD-1 inhibitor pembrolizumab as first-line therapy was significantly longer than with chemotherapy among patients with advanced NSCLC who had been selected on the basis of PD-L1 expression level.6
Carbone et al. propose that imbalanced randomization could have contributed to the negative outcome in this trial. However, the most striking between-group disparities are the relative lack of women and of tumors with high PD-L1 expression in the nivolumab group, as compared with the chemotherapy group, and progression-free survival did not favor nivolumab in either of these subgroups. The discrepant trial outcomes between the PD-1 inhibitors nivolumab and pembrolizumab must reflect differences in either the evaluated therapy or the studied population. Could efficacy greatly differ between these similar drugs? In many tumor types, including previously treated NSCLC in an unselected population of patients, the two agents show remarkably similar results.7 Strong differences in efficacy that are limited to first-line therapy for NSCLC are highly improbable.
Could differences in the trial populations generate such disparate results? The most compelling potential clinical factor is the receipt of previous radiation therapy, which had been administered in nearly 40% of the patients...