Atezolizumab Improves Survival vs Docetaxel in Advanced NSCLC in Relation to Increased PD-L1 Expression
In the phase II POPLAR trial reported in The Lancet, Fehrenbacher et al found that the anti–PD-L1 (programmed cell death ligand 1) antibody atezolizumab improved overall survival vs docetaxel in patients with non–small cell lung cancer (NSCLC) who had progressed on prior platinum-based chemotherapy. The benefit was related to PD-L1 expression in tumor cells (TC) or tumor-infiltrating immune cell (IC).
Study Details
In the open-label study, 287 patients from 61 academic medical centers and community oncology practices in 13 countries in Europe and North America were randomly assigned between August 2013 and March 2014 to receive intravenous (IV) atezolizumab at 1,200 mg (n= 144) or docetaxel at 75 mg/m2 (n = 143) once every 3 weeks. Of them, 142 and 137 received the study drug, respectively.
Baseline PD-L1 expression was determined by immunohistochemistry in tumor cells as the percentage of PD-L1–expressing tumor cells (ie, TC3 ≥ 50%, TC2 ≥ 5% and <50%, TC1 ≥ 1% and < 5%, and TC0 < 1%) and PD-L1–expressing tumor-infiltrating immune cells as the percentage of tumor area (ie, IC3 ≥ 10%, IC2 ≥ 5% and < 10%, IC1 ≥ 1% and < 5%, and IC0 < 1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups.
For the atezolizumab and docetaxel groups: median age was 62 years in both; 65% and 53% were male; tobacco use history was never for 19% and 20% and current for 17% and 15%; Eastern Cooperative Oncology Group performance status was 0 for 32% and 1 for 68% in both; histology/pathology was nonsquamous in 66% in both; PD-L1 IC expression level was 0 in 43% and 44%, 1 in 37% and 38%, 2 in 13% in both, and 3 in 7% and 6%; PD-L1 tumor cell level was 0 in 67% and 57%, 1 in 13% and 15%, 2 in 10% and 18%, and 3 in 10% and 11%; and the number of previous lines of therapy in the advanced or metastatic setting was 1 in 65% and 67% and 2 in 35% and 33%. Among those with data, 12% and 10% had EGFR mutation, 0% and 5% had EMLA-ALK translocation, and 33% and 43% had KRAS mutation.
Improved Overall Survival
Median follow-up was 14.8 months in the atezolizumab group and 15.7 months in the docetaxel group. Median overall survival was 12.6 months (95% confidence interval [CI] = 9.7–16.4 months in the atezolizumab group vs 9.7 months (95% CI = 8.6–12.0 months) in the docetaxel group (hazard ratio [HR] = 0.73, P = .04). Improvement in overall survival for atezolizumab vs docetaxel was associated with PD-L1 expression; hazard ratios were 0.49 (P = .068; 15.5 vs 11.1 months) for TC3 or IC3, 0.54 (P = .014; 15.1 vs 7.4 months) for TC2/3 or IC2/3, 0.59 (P = .005; 15.5 vs 9.2 months) for TC1/2/3 or IC1/2/3, and 1.04 (P = .871) for TC0 and IC0 (9.7 vs 9.7 months). In an exploratory analysis, patients with preexisting immunity defined by high T-effector–interferon-γ–associated gene expression had improved overall survival with atezolizumab (HR = 0.43, 95% CI = 0.24–0.77).
Adverse Events
Treatment-related grade 3 or 4 adverse events occurred in 11% of atezolizumab patients vs 39% of docetaxel patients. The most common atezolizumab-related grade 3 adverse events were pneumonia (2%) and increased aspartate transaminase (2%). The most common adverse events of any grade that differed in incidence by ≥ 5% between groups were (in decreasing order of frequency) decreased appetite, dyspnea, pyrexia, arthralgia, insomnia, musculoskeletal pain, pneumonia, and hypothyroidism in the atezolizumab group, compared with alopecia, nausea, diarrhea, asthenia, myalgia, neutropenia, peripheral neuropathy, and febrile neutropenia in the docetaxel group. Serious adverse events occurred in 35% vs 34%. Treatment-related adverse events led to dose modification/interruption in 11% vs 24% and to treatment discontinuation in 1% vs 18%. Treatment-related adverse events led to death in one atezolizumab patient and three docetaxel patients.
The investigators concluded: “POPLAR is the first study of a PD-L1 checkpoint inhibitor in a randomised clinical trial of patients with previously treated NSCLC…. Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.”
The study was funded by F. Hoffmann-La Roche/Genentech Inc.
Louis Fehrenbacher, MD, of Kaiser Permanente Medical Center, is the corresponding author of The Lancet article.
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