Louis Fehrenbacher, MD

In the phase II POPLAR trial reported in The Lancet, Louis Fehrenbacher, MD, of Kaiser Permanente Medical Center, and colleagues found that the investigational anti–programmed cell death ligand 1 (PD-L1) antibody atezolizumab improved overall survival vs docetaxel in patients with non–small cell lung cancer (NSCLC) who had experienced disease progression on prior platinum-based chemotherapy.¹ Atezolizumab benefit was related to PD-L1 expression in tumor cells or tumor-infiltrating immune cells.

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 atezolizumab at 1,200 mg (n = 144) or docetaxel at 75 mg/ m² (n = 143) once every 3 weeks. Of these randomized patients, 142 received at least one dose of atezolizumab and 135 received docetaxel.

Baseline PD-L1 expression was determined by immunohistochemistry in tumor cells as 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 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.

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.

— Louis Fehrenbacher, MD

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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; and 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%; and PD-L1 TC level was 0 in 67% and 57%, 1 in 13% and 15%, 2 in 10% and 18%, and 3 in 10% and 11%. 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 epidermal growth factor receptor (EFGR) 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 recipients vs 39% of docetaxel recipients. 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% of the atezolizumab group vs docetaxel group. Treatment-related adverse events led to dose modification or 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. ■

Disclosure: The study was funded by F. Hoffmann-La Roche/Genentech Inc. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Fehrenbacher L, Spira A, Ballinger M, et al: Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): A multicentre, open-label, phase 2 randomised controlled trial. Lancet. March 9, 2016 (early release online).