The study by Leapman and colleagues1 presents the results of an analysis of the Flatiron Health Database concentrating on the use of programmed cell death ligand 1 (PD-L1) testing and immune checkpoint inhibitors (ICIs) in patients with previously untreated, metastatic non–small cell lung cancer (NSCLC). The good news is that there has been rapid uptake of testing and use of ICIs in the appropriate population. Furthermore, as studies have been reported that expanded the indication for treatment with ICIs, practitioners quickly adopted these new approaches, frequently ahead of regulatory authorities. The bad news is that enthusiasm for these agents also led to overuse, in that a substantial proportion of patients whose PD-L1 status was less than 1 or who were untested received single-agent pembrolizumab, despite evidence that the drug was less effective than standard chemotherapy in this population.
Management of patients with a diagnosis of metastatic NSCLC has changed dramatically in recent years.2 Molecular testing using a comprehensive next-generation sequencing platform is now a standard part of our treatment algorithm, with at least 7 actionable variants known (ie, with an available US Food and Drug Administration–approved agent) and others likely to emerge in the near future.3,4 As noted, PD-L1 testing has also become standard, based on the results of a number of studies showing an association between level of PD-L1 expression and clinical efficacy of ICIs.5-7 Given this wealth of developments and increasing complexity of treatment algorithms, it is imperative that biomarker testing be correctly interpreted and used. Data from the current report1 indicate that PD-L1 testing has had rapid uptake; however, other studies have found less use of molecular markers, such as epidermal growth factor receptor and anaplastic lymphoma kinase, among others.4 This could be because of the ease of obtaining an immunohistochemistry-based assay, such as those for PD-L1 expression, vs the more tissue- and time-consuming process of DNA sequencing. Nonetheless, as the work by Leapman and colleagues1 shows, even when biomarker results are at hand, the decision-making process does not always follow recommended guidelines or existing data. Practitioners will frequently use drugs in settings where data are scant or even negative, perhaps based on the perception of fewer toxic effects or through misplaced enthusiasm. The influence of direct-to-consumer advertising of these agents should also not be underestimated.
Furthermore, we now have data whose interpretation is not as clear as it was based on subset analysis of trials. Trials with immunotherapy were designed to compare chemotherapy with either the ICI alone or in combination with chemotherapy.8-10 Now that ICIs have demonstrated clear efficacy and superiority in several settings alone or in combination with chemotherapy, it is time to ask the converse question; specifically, what is the role and timing of chemotherapy with immunotherapy? This question will be answered in the currently accruing INSIGNA trial. Successful completion of trials such as INSIGNA either could lead to a confirmation of current guidelines or could establish a new treatment strategy among patients with NSCLC. It is imperative that we base clinical decision-making on evidence. We can limit the potential toxic effects (including financial) of these drugs in patients who will not benefit from treatment and ultimately serve our patients better.
Published: June 8, 2020. doi:10.1001/jamanetworkopen.2020.7171
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Borghaei H et al. JAMA Network Open.
Corresponding Author: Hossein Borghaei, DO, Department of Hematology and Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111 (email@example.com).
Conflict of Interest Disclosures: Drs Borghaei and Edelman reported receiving grant funding from the National Cancer Institute and being supported by the Cancer Center Core Grant P30 CA006927. Dr Borghaei reported receiving grants from Millennium, Merck/Celgene, and Bristol-Myers Squibb/Eli Lilly and Co; serving on the advisory board or as a consultant for Bristol-Myers Squibb, Eli Lilly and Co, Genentech, Celgene, Pfizer, Merck, Merck-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia, Amgen, Abbvie, Axiom, PharmaMar, Takeda, Huya Bio, Gerson Lehrman Group, and Daiichi; serving on the data safety and monitoring board for the University of Pennsylvania CAR T Program, Takeda, and Incyte; and owning shares in Sonnetbio and Rgenix outside the submitted work. Dr Edelman reported receiving institutional support from Merck, Apexigen, Nektar, and Bristol-Myers Squibb; serving on the advisory board of and receiving institutional support from Windmil; owning stock in Biomarker Strategies; serving on the scientific advisory board of Flame and Syndax; serving on the data safety and monitoring board of AstrasZeneca and Takeda; serving on the advisory and data safety and monitoring boards of GlaxoSmithKline; and serving on the advisory boards of Armo and BerGen Bio outside the submitted work.
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Borghaei H, Edelman MJ. Biomarker Testing in Lung Cancer—What Does It Mean? JAMA Netw Open. 2020;3(6):e207171. doi:10.1001/jamanetworkopen.2020.7171
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