Moving Programmed Death-1 Inhibitors to the Front Lines in Non–Small-Cell Lung Cancer

Immune checkpoint inhibitors have dramatically reshaped the landscape of non–small-cell lung cancer (NSCLC). In particular, monoclonal antibodies targeting the programmed death-1 (PD-1)/PD ligand 1 (PD-L1) pathway have emerged as powerful new therapeutic tools. In phase I studies, these agents demonstrated promising antitumor activity and durable clinical responses in a subset of patients with NSCLC. On the basis of these early efficacy signals, a series of randomized phase II and III studies were launched to evaluate the activity of PD-1/PD-L1 inhibitors in the second-line setting and beyond in NSCLC. In the CheckMate 017 and 057 studies, for example, the PD-1 inhibitor nivolumab produced significant improvements in overall survival (OS) compared with docetaxel in patients with previously treated, squamous and nonsquamous NSCLC, respectively. Similarly, the PD-1 inhibitor pembrolizumab improved OS compared with docetaxel among patients with previously treated NSCLC whose tumors expressed PD-L1. Together, these studies helped establish PD-1 pathway blockade as a new standard of care for patients with advanced NSCLC who experience progression on or after platinum-based chemotherapy. Recently, the activity and improved tolerability of PD-1/PD-L1 inhibitors in NSCLC have sparked a growing interest in moving these agents to the front-line setting. Currently, the standard of care for management of newly diagnosed patients without targetable oncogenic driver mutations (eg, EGFR, ALK) is platinum-based doublet chemotherapy, which is generally associated with a median progressionfree survival (PFS) of 4 to 6months andmedianOS of 8 to 10months. More recently, maintenance pemetrexed and the addition of monoclonal antibodies directed against vascular endothelial growth factor and epidermal growth factor receptor have resulted in additional, modest improvements in OS, yet long-term outcomes remain poor, underscoring the need for alternative therapeutic approaches. In the two articles accompanying this editorial, we are presented with data from two separate cohorts of the multiarm, phase IB CheckMate 012 study. Each explores a different approach to PD-1 inhibition in patients with treatment-naive NSCLC. First, Gettinger et al report findings from 52 patients with advanced NSCLC treated with first-line nivolumab monotherapy. Importantly, PD-L1 testing was not used to prospectively select patients for study entry, but mandatory pretreatment biopsies were required to evaluate PD-L1 expression retrospectively. Confirmed responses were observed in 23% of patients, including complete responses in four patients (8%). Median PFS on nivolumab was 3.6 months, but the median duration of response was not reached (range, 4.2 to 25.81months). Thus, as with other studies of PD-1/ PD-L1 inhibitors, there was a suggestion of durable clinical responses. Indeed, the median OS in this patient population was noteworthy at 19.4 months. Although the results by Gettinger et al are intriguing, it is noteworthy that the response rate to first-line nivolumab was not too dissimilar from those observed in CheckMate 017 and 057. A key issue, however, is whether this degree of activity will be sufficient to beat platinum-based chemotherapy in randomized trials. In second-line studies (CheckMate 017 and 057), the control arms received single-agent docetaxel, which set a relatively low bar to surpass (historical overall response rate, approximately 7%). By contrast, in the first-line setting, PD-1/PD-L1 inhibitors will need to overtake platinum-based doublet chemotherapy, which has been associated withmuch higher ORRs (25% to 35%). For PD-1/ PD-L1 inhibitors to succeed in this setting, a biomarker enrichment strategy may be necessary. To date, such efforts have centered on assessments of PD-L1 expression. For instance, in the KEYNOTE 001 study, pembrolizumab was associated with an ORR of 24.8% among treatment-naive patients, but the response rate increased to 50% among treatment-naive patients who were PD-L1 positive (proportion score $ 50). In part on the basis of these observations, two randomized phase III studies, CheckMate 026 and KEYNOTE 024, have been launched in PD-L1–positive patients comparing platinum-based chemotherapy versus nivolumab or pembrolizumab, respectively. Both studies have completed accrual, but results are not yet available. In the second article accompanying this editorial, Rizvi et al report a separate first-line cohort from CheckMate 012 that consisted of 56 treatment-naive patients with NSCLC who were treated with nivolumab in combination with three different platinum-based chemotherapy doublets. The authors used a dose de-escalation design, assigning participants to one of four cohorts ranging in size from 12 to 15 patients. Of note, in contrast to the currently approved nivolumab dosing regimen (3 mg/kg every 2 weeks), nivolumab was administered once every 3 weeks in this study (5 to 10mg/kg based on cohort). After completing four cycles of therapy, patients received maintenance nivolumab once every 3 weeks. Overall, no dose-limiting toxicities were observed across study arms, but 14% of patients required discontinuation as