Atezolizumab for Pretreated Metastatic Non–Small-Cell Lung Cancer

Summary and Comment |
March 17, 2016

Atezolizumab for Pretreated Metastatic Non–Small-Cell Lung Cancer

  1. Anne S. Tsao, MD

First in its class of immunotherapy agents, atezolizumab prolonged survival versus standard docetaxel.

  1. Anne S. Tsao, MD

Two recently approved PD-1 inhibitors (nivolumab and pembrolizumab) have been shown to improve outcomes in patients with pretreated metastatic non–small-cell lung cancer (NSCLC; NEJM JW Oncol Hematol Nov 2015, and N Engl J Med 2015; 373:1627; NEJM JW Oncol Hematol Feb 2016, and Lancet 2015 Dec 19; [e-pub]).

Now, investigators have conducted an industry-funded, international, randomized phase II trial (POPLAR) to evaluate the efficacy and safety of the PD-L1 monoclonal antibody atezolizumab — the first in its class of immunotherapy agents — in 287 previously treated NSCLC patients. Patients were randomized to receive atezolizumab or standard docetaxel therapy and were stratified by PD-L1 tumor-infiltrating immune cell status.

Results were as follows:

  • Overall survival (OS; the primary endpoint) was prolonged with atezolizumab versus docetaxel (12.6 vs. 9.7 months; hazard ratio, 0.73; P=0.04).

  • OS benefit increased with higher PD-L1 expression in either tumor cells or immune infiltrating cells and was associated with T-effector and interferon-γ gene signatures and high PD-L2 and B7.1 gene expressions.

  • Progression-free survival was similar with atezolizumab or docetaxel (2.7 and 3.0 months, respectively). Response rate was similar with both agents, but duration of response was longer with atezolizumab (14.3 vs. 7.2 months).

  • Rate of treatment discontinuation due to adverse events was lower with atezolizumab (8% vs. 22%), as was the rate of treatment-related grade 3 or 4 adverse events (11% vs. 39%).

Comment

This study shows that atezolizumab has efficacy in salvage metastatic NSCLC that expresses PD-L1 in either tumor cells or immune infiltrating cells. It also shows that few patients had both high tumor-cell and high immune-infiltrating–cell PD-L1 expression, indicating a mutually exclusive process that is predictive for response to atezolizumab. However, the PD-L1 immunohistochemistry biomarker remains problematic, as tumor heterogeneity could preclude a positive biopsy result. The tumor gene signature assays demonstrated that other biomarkers can be predictive of a response. Studies are currently under way to assess whether peripheral blood surrogate biomarkers can more reliably predict response to immunotherapies. The ongoing OAK phase III trial (NCT02008227) will further evaluate atezolizumab in NSCLC. However, a growing body of literature suggests that PD-L1–negative patients do not derive survival benefit from PD-1/PD-L1 inhibitors.

Editor Disclosures at Time of Publication

  • Disclosures for Anne S. Tsao, MD at time of publication Consultant / Advisory board Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Speaker’s bureau Genetech; Roche; Medimmune; Novartis; Astellas; Boehringer-Ingelheim; Eli Lilly Grant / Research support Department of Defense; SWOG Leadership positions in professional societies American Medical Association (Member); American Association of Cancer Research (Member); American Society of Clinical Oncology (Member); AACR-Women in Cancer Research (Member); International Mesothelioma Interest Group (Member); SWOG (Member); International Association for the Study of Lung Cancer (Communications Committee Chair); American Radium Society (Chair); RTOG (Member)

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