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In a prior phase II study (POPLAR), the programmed death-ligand 1 (PD-L1) monoclonal antibody atezolizumab prolonged survival versus standard docetaxel in previously treated non–small-cell lung cancer (NSCLC) patients (NEJM JW Oncol Hematol May 2016, and Lancet 2016; 387:1837).
To further compare the two agents, the investigators have conducted an industry-funded, multicenter, randomized, open-label, phase III trial (OAK), involving 850 patients previously treated with platinum-based chemotherapy for stage IIIB or IV NSCLC.
Median overall survival (OS; the primary endpoint) was prolonged with atezolizumab versus docetaxel (13.8 vs. 9.6 months; hazard ratio, 0.73; P=0.0003), as was the median duration of response (16.3 vs. 6.2 months; HR, 0.34; P<0.0001). Progression-free survival (PFS) and objective response rate (ORR) were similar between the two treatment arms. In the subgroup analysis, all patients had improved OS with atezolizumab versus docetaxel, but those with the highest PD-L1 immunohistochemical (IHC) expression in tumor cells (TC3) or tumor-infiltrating cells (IC3) had the greatest OS benefit (20.5 vs. 8.9 months; HR, 0.41). Atezolizumab recipients had fewer grade 3 or 4 adverse events than docetaxel recipients (15% vs. 43%) and fewer toxicities leading to treatment discontinuation (8% vs. 19%).
Rittmeyer A et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial. Lancet 2016 Dec 12; [e-pub]. (http://dx.doi.org/10.1016/S0140-6736(16)32517-X)
Comment
Atezolizumab now joins the programmed death-1 (PD-1) inhibitors nivolumab and pembrolizumab as FDA-approved salvage therapies for NSCLC. Although atezolizumab is a PD-L1 inhibitor, it appears to be similar to PD-1 inhibitors in its efficacy and toxicity profile, as well as in demonstrating a lack of a survival benefit in EGFR-mutated patients, which supports the premise that oncogene-driven tumors are less immunogenic and derive less benefit from immunotherapies. But unlike PD-1 inhibitors, it provided an OS benefit, despite the lack of PFS and ORR improvement, in patients with central nervous system disease and those with low or undetectable PL-L1 IHC levels. Whether the PD-L1 inhibitors will have any benefit if given after a PD-1 inhibitor, or vice versa, remains to be determined.