Review Immunotherapy for the First-Line Treatment of Patients with Metastatic Non–Small Cell Lung Cancer Pablo Martinez 1 , Solange Peters 2 , Timothy Stammers 3 , and Jean-Charles Soria 3,4 Abstract Immunotherapy has fundamentally changed the treatment landscape for many patients with cancer. mAbs targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte–associated antigen-4 immune checkpoints have received regulatory approval across a wide range of tumor types, including non–small cell lung cancer (NSCLC). Indeed, treatment approaches for a majority of patients with newly diagnosed metastatic NSCLC are evolving rapidly. Only for the small proportion of patients with metastatic NSCLC and genomic- driven tumors with EGFR or anaplastic lymphoma kinase (ALK)–sensitizing mutations (5%–15%), and possibly BRAF mutations and ROS rearrangements, have initial treatment recommendations remained unchanged, with specific tyrosine kinase inhibitors as the preferred therapy. For the remaining patients, an immunotherapy-based regimen alone or in com- bination with chemotherapy is now the preferred option based on high-level evidence obtained from randomized controlled trials and in accordance with all available guide- lines. Deciding between therapeutic options can be difficult due to the lack of direct cross-comparison studies, differences in chemotherapies and stratification factors, and differences in study populations resulting from inclusion criteria such as histology, PD-L1 expression, or tumor mutational burden (TMB). In an attempt to aid the decision-making process, we discuss and summarize the most recent data from studies using immunotherapies for the treatment of patients with previously untreated metastatic NSCLC. Introduction Because evidence emerged that blockade of the programmed cell death-1 (PD-1) signaling pathway could result in deep and durable antitumor responses in lung cancer, there has been a race to exploit the full potential of this new treatment modality across all stages of the disease. Initial evidence of this antitumor effect in non–small cell lung cancer (NSCLC) was reported in 2012 for nivolumab, a mAb that binds to the PD-1 receptor, and for BMS- 936559, which binds to the programmed cell death ligand-1 (PD- L1), expressed on tumor cells, macrophages, and dendritic cells (1, 2). PD-1/PD-L1 immune checkpoint–blocking antibodies to treat metastatic NSCLC first entered the clinic in 2015 based on results of the CheckMate 017 trial, which demonstrated superiority of nivolumab over docetaxel in patients with squamous metastatic NSCLC who had disease progression after platinum-containing chemotherapy (3). Since then, pembrolizumab and atezolizumab have also received regulatory approval in previously treated patients with metastatic NSCLC (4, 5). More recently, a surge of pivotal studies has assessed the role of immunotherapy in previously untreated metastatic NSCLC. This review discusses the impact of these new data on the choice of first- line therapy for the patients with metastatic NSCLC, defined by histology, biomarker status, and eligibility for platinum-based chemotherapy. Initial Biomarker Characterization Baseline testing for the following three independent biomar- kers may help to define the most effective first-line treatment for patients with newly diagnosed metastatic NSCLC. EGFR and anaplastic lymphoma kinase alterations Patients with a confirmed diagnosis of nonsquamous NSCLC should be tested for EGFR and anaplastic lymphoma kinase (ALK)–sensitizing alterations before initiation of any therapy. For those patients with these specific oncogene-addicted tumors, treatment with an appropriate tyrosine kinase inhibitor (TKI) remains the most effective first-line treatment option (6, 7). Tumor PD-L1 expression Several IHC assays are available for evaluating PD-L1 expres- sion levels, and specific antibodies have been used in the clinical development of different anti–PD-1/PD-L1 therapies (8). Cur- rently, PD-L1 expression levels can impact the decision as to whether patients may be treated with first-line pembrolizumab monotherapy; the preferred method is IHC testing with the 22C3 pharmDx assay (Agilent), used in the pivotal pembrolizumab studies (9). It is approved for use in biopsy specimens and categorizes PD-L1 expression on tumor cells according to the tumor proportion score (TPS). Of note, studies comparing dif- ferent IHC assays and antibodies suggest high concordance among most commercially available methods (10, 11). 1 Clinical Development Oncology, MedImmune, Gaithersburg, Maryland. 2 Department of Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland. 3 Research & Development, MedImmune, Gaithersburg, Maryland. 4 Universit e Paris-Sud, Orsay, France. Corresponding Author: Pablo Martinez, MedImmune, One MedImmune Way, Gaithersburg, MD 20878. Phone: 301-398-2527; Fax: 240-306-1443; E-mail: martinezp@medimmune.com doi: 10.1158/1078-0432.CCR-18-3904 Ó2019 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 2691 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/25/9/2691/2058743/2691.pdf by guest on 14 June 2022