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Scientific Advances in Thoracic Oncology 2016

Open ArchivePublished:June 01, 2017DOI:https://doi.org/10.1016/j.jtho.2017.05.019

      Abstract

      Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

      Keywords

      Introduction

      A very exciting time exists in the field of thoracic malignancies. In the past year, we have witnessed tremendous advances in thoracic cancer research and treatment. In this annual report, now in its second year, we are pleased and excited to bring together leaders in the field to summarize recent major breakthroughs and significant advances in prevention and early detection, molecular diagnostics, pathology, staging, surgery, adjuvant therapy, radiotherapy (RT), molecular targeted therapy, and immunotherapy. Important progress has been made in SCLC and malignant mesothelioma and has also been included. With more novel treatment options, we reviewed the quality and value of such therapy, and lastly, a perspective on emerging trends and future directions in lung cancer research and treatment is provided.

      Prevention and Early Detection

      Cigarettes, E-cigarettes, and Cannabis

      Section Authors: Emily C. A. Stone, M.B.B.S., MMed, K. Michael Cummings, PhD, MPH, James R. Jett, MD

      Cigarettes

      Tobacco cigarettes account for the vast majority of tobacco consumed worldwide and are by far the most lethal type of tobacco product consumed, costing global economies $1 trillion annually through loss of productivity and health care expenditure.
      Global cost of smoking passes $1 trillion.
      Tobacco control interventions such as higher taxes, graphic health warnings, mass media campaigns, and bans have led to a fall in smoking rates in developed countries, but less so in low-income countries where the tobacco industry is building market share. However, when such declines in smoking rates do occur, they result more from reduced youth uptake than from smoking cessation. Smokers are clearly looking for viable options to move away from cigarettes, but until recently few alternatives were available. The rapid uptake of e-cigarettes by smokers over the past decade has posed some interesting challenges for the medical profession. Will these new nicotine delivery products offer smokers an escape from cigarettes? Will nonsmokers (especially the young) be led into smoking? Another issue confronting the lung health field is the movement to legalize cannabis, which appears to be changing how cannabis is perceived and used, which in turn could have important health consequences in the future.

      E-cigarettes

      Electronic cigarettes (e-cigarettes) are a form of electronic nicotine delivery that has emerged as a potential alternative to conventional tobacco cigarettes and as a possible aid to tobacco cessation. A newly published systematic review identifies the need for frequent reevaluation of evidence in a field characterized by rapid change.
      • Glasser A.M.
      • Collins L.
      • Pearson J.L.
      • et al.
      Overview of electronic nicotine delivery systems: a systematic review.
      The regulatory status of the e-cigarette industry, an industry appropriated by global tobacco companies, varies around the world, with restrictions ranging from minimum age of purchase to a ban on sales altogether.
      • Kennedy R.D.
      • Awopegba A.
      • De Leon E.
      • Cohen J.E.
      Global approaches to regulating electronic cigarettes.
      Although it does appear that e-cigarettes can help some smokers quit or reduce their smoking, the evidence is mixed. The recent U.S. surgeon general’s report on e-cigarettes discourages the sale and use of any nicotine-containing product by nonsmokers, especially the young.
      US Department of Health and Human Services
      E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General.
      Conversely, Public Health England cited e-cigarettes as “95% safer” than tobacco cigarettes, identifying their adoption by smokers as a key strategy for tobacco cessation.

      McNeill A, Brose L, Calder R, et al. E-cigarettes: an evidence update; a report commissioned by Public Health England. London, UK: 2015. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/457102/Ecigarettes_an_evidence_update_A_report_commissioned_by_Public_Health_England_FINAL.pdf. Accessed February 13, 2017.

      A 2016 Cochrane review of e-cigarettes for smoking cessation identified two studies that showed an increased chance of smoking cessation with the use of nicotine e-cigarettes compared with nicotine-free e-cigarettes, but acknowledged a lack of evidence for long-term safety.
      • Hartmann-Boyce J.
      • McRobbie H.
      • Bullen C.
      • Begh R.
      • Stead L.F.
      • Hajek P.
      Electronic cigarettes for smoking cessation.
      The likelihood of cigarette cessation was shown to be lower in those using e-cigarettes compared with other methods in a recent small study of patients with cancer.
      • Kalkhoran S.
      • Glantz S.A.
      E-cigarettes and smoking cessation in real-world and clinical settings: a systematic review and meta-analysis.
      A 2014 review of e-cigarettes in patients with lung cancer noted the urgency of smoking cessation after a diagnosis of lung cancer, but advised against recommending e-cigarette uptake after diagnosis, given the lack of safety and efficacy data.
      • Cummings K.M.
      • Dresler C.M.
      • Field J.K.
      • et al.
      E-cigarettes and cancer patients.

      Cannabis

      Cannabis, also known as marijuana, has been legalized in 28 states in the United States for medical purposes. Recreational cannabis use is now permitted in eight states and Washington, DC. A number of states have also decriminalized possession of small amounts for personal use. Similar legalization efforts have occurred in Canada, Uruguay, Germany, Israel, and other countries. Between 2002 and 2014, the prevalence of cannabis use in the past 30 days in the United States increased by 35%. In 2014, 8.4% of those 12 years of age and older reported use of cannabis in the past 30 days and 3.5% reported daily use.
      • Azofeifa A.
      • Mattson M.E.
      • Schauer G.
      • McAfee T.
      • Grant A.
      • Lyerla R.
      National estimates of marijuana use and related indicators—National Survey on Drug Use and Health, United States, 2002-2014.
      Cannabis is most commonly smoked but can be vaped, ingested, or used topically. Cannabinoids enter the bloodstream and reach the brain within seconds to a few minutes when smoked. Oral ingestion of cannabis takes 30 minutes or longer to have its effects in the brain.
      The most recent and most comprehensive review of the health effects of cannabis use was recently published by the National Academies of Sciences, Engineering, and Medicine.
      National Academies of Sciences, Engineering, and Medicine
      The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.
      There is at least moderate evidence that cannabis is beneficial for chronic pain, neuropathic pain, and muscle spasms, especially related to multiple sclerosis.
      • Volkow N.D.
      • Compton W.M.
      • Weiss S.R.
      Adverse health effects of marijuana use.
      • Whiting P.F.
      • Wolff R.F.
      • Deshpande S.
      • et al.
      Cannabinoids for medical use: a systematic review and meta-analysis.
      • Hill K.P.
      Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review.
      • Paice J.A.
      • Portenoy R.
      • Lacchetti C.
      • et al.
      Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline.
      There is also moderate evidence that cannabis improves nausea and vomiting related to chemotherapy. There is less certain evidence that cannabis can increase appetite and prevent weight loss.
      • Whiting P.F.
      • Wolff R.F.
      • Deshpande S.
      • et al.
      Cannabinoids for medical use: a systematic review and meta-analysis.
      • Wilkie G.
      • Sakr B.
      • Rizack T.
      Medical marijuana use in oncology: a review.
      Cannabis use has been found to impair driving ability, increase drowsiness, cause addiction in approximately 10% of users, and increase psychotic episodes and hyperemesis in heavy long-term users.
      National Academies of Sciences, Engineering, and Medicine
      The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.
      • Wilkie G.
      • Sakr B.
      • Rizack T.
      Medical marijuana use in oncology: a review.
      • Hasin D.S.
      • Saha T.D.
      • Kerridge B.T.
      • et al.
      Prevalence of marijuana use disorders in the United States between 2001-2002 and 2012-2013.
      Cannabis smoke contains many of the same toxins as tobacco smoke, such as polycyclic aromatic hydrocarbons. Studies have shown that frequent cannabis use can cause chronic bronchitis (cough, sputum, and wheeze), but there is no established causality with chronic obstructive pulmonary disease.
      • Kempker J.A.
      • Honig E.G.
      • Martin G.S.
      The effects of marijuana exposure on expiratory airflow. A study of adults who participated in the U.S. National Health and Nutrition Examination Study.
      • Tashkin D.P.
      Effects of marijuana smoking on the lung.
      There is also no conclusive evidence that cannabis use increases the risk for lung cancer, although cannabis users often smoke cigarettes, making it difficult to isolate the impact of regular cannabis use on the risks for chronic lung disease.
      • Douglas I.S.
      • Albertson T.E.
      • Folan P.
      • et al.
      Implications of marijuana decriminalization on the practice of pulmonary, critical care, and sleep medicine. a report of the American Thoracic Society Marijuana Workgroup.
      • Zhang L.R.
      • Morgenstern H.
      • Greenland S.
      • et al.
      Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium.
      • Huang Y.H.
      • Zhang Z.F.
      • Tashkin D.P.
      • Feng B.
      • Straif K.
      • Hashibe M.
      An epidemiologic review of marijuana and cancer: an update.
      The best evaluation of the association between smoking cannabis and lung cancer risk, after adjustment for tobacco use, is a pooled analysis of six case-control studies with 2159 patients with lung cancer and 2985 controls that failed to find evidence of an increased risk for lung cancer among long-term cannabis smokers.
      • Zhang L.R.
      • Morgenstern H.
      • Greenland S.
      • et al.
      Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium.
      Given the changing potency and patterns of use of cannabis, including use by non–cigarette smokers, there is an urgent need to conduct research to assess its effects on lung health.
      • Volkow N.D.
      • Compton W.M.
      • Weiss S.R.
      Adverse health effects of marijuana use.

      Lung Cancer Screening

      Section Authors: John K. Field, PhD, FRCPath., Harry J. M. Groen, MD, PhD, James L. Mulshine, MD
      This is a very dynamic time for both computed tomography (CT)-based lung cancer screening research and the process of clinical implementation of routine CT lung cancer screening. Notable improvements in efficient screening detection rates have been reported, thus addressing concerns about high false positivity in screening work-ups. These reports, including the British pilot study UKLS,
      • Field J.K.
      • Duffy S.W.
      • Baldwin D.R.
      • et al.
      The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.
      the NELSON trial group study,
      • Horeweg N.
      • van der Aalst C.M.
      • Vliegenthart R.
      • et al.
      Volumetric computed tomography screening for lung cancer: three rounds of the NELSON trial.
      • Yousaf-Khan U.
      • van der Aalst C.
      • de Jong P.A.
      • et al.
      Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.
      the I-ELCAP study,
      • Henschke C.I.
      • Yip R.
      • Yankelevitz D.F.
      • et al.
      Definition of a positive test result in computed tomography screening for lung cancer: a cohort study.
      and the preliminary experiences with the American College of Radiology LungRADS approach,
      • Pinsky P.F.
      • Gierada D.S.
      • Black W.
      • et al.
      Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment.
      • Li K.
      • Yip R.
      • Avila R.
      • Yankelevitz D.F.
      Size and growth assessment of pulmonary nodules: consequences of the rounding.
      cite false-positive diagnostic detection rates of less than 10%. In addition, the field recognized that nonstandardized terms for characterizing efficiency of the screening process were also confusing. Some investigators consider the finding of lung nodules on a CT scan as being equivalent to a cancer diagnosis, and because lung nodules are common in smokers, this misconception has resulted in the perception of a high false diagnosis rate. From a screening subject perspective, this situation leads to unnecessary distress; however, this situation in lung cancer screening could benefit from education for subjects and those involved in screening about the fact that pulmonary nodules are not equivalent to lung cancer, most pulmonary nodules are benign in origin, and lung cancer is a pathologic diagnosis rather than an imaging diagnosis. A consensus is emerging that working toward more systematic definitions for key parameters for a lung cancer screening is a near-term priority that could reset screening subjects's expectations and reduce anxiety regarding the process.
      • Yousaf-Khan U.
      • van der Aalst C.
      • de Jong P.A.
      • et al.
      Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval.
      • Horeweg N.
      • Scholten E.T.
      • de Jong P.A.
      • et al.
      Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers.
      • Horeweg N.
      • van Rosmalen J.
      • Heuvelmans M.A.
      • et al.
      Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening.
      • Walter J.E.
      • Heuvelmans M.A.
      • de Jong P.A.
      • et al.
      Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial.
      • Yankelevitz D.F.
      • Henschke C.I.
      Advancing and sharing the knowledge base of CT screening for lung cancer.
      • Yip R.
      • Henschke C.I.
      • Yankelevitz D.F.
      • et al.
      The impact of the regimen of screening on lung cancer cure: a comparison of I-ELCAP and NLST.
      • Field J.K.
      • Devaraj A.
      • Duffy S.W.
      • Baldwin D.R.
      CT screening for lung cancer: is the evidence strong enough?.
      • Callister M.E.
      • Baldwin D.R.
      • Akram A.R.
      • et al.
      British Thoracic Society guidelines for the investigation and management of pulmonary nodules.
      • Ten Haaf K.
      • van Rosmalen J.
      • de Koning H.J.
      Lung cancer detectability by test, histology, stage, and gender: estimates from the NLST and the PLCO trials.
      Additional areas of progress include a number of research efforts to effectively integrate tobacco cessation, both as a service and as a research focus, within the process of lung cancer screening.
      • Ostroff J.S.
      • Copeland A.
      • Borderud S.P.
      • Li Y.
      • Shelley D.R.
      • Henschke C.I.
      Readiness of lung cancer screening sites to deliver smoking cessation treatment: current practices, organizational priority, and perceived barriers.
      • Warren G.W.
      • Ostroff J.S.
      • Goffin J.R.
      Lung cancer screening, cancer treatment, and addressing the continuum of health risks caused by tobacco.
      Dr. Jamie Ostroff of Memorial Sloan Kettering Institute is leading an exciting new research effort to address this vital aspect of lung cancer screening research.
      A major Canadian effort buttressed the growing evidence on the cost-efficiency of providing high-quality lung cancer screening services while still providing a public health benefit.
      • Goffin J.R.
      • Flanagan W.M.
      • Miller A.B.
      • et al.
      Cost-effectiveness of lung cancer screening in Canada.
      • Goffin J.R.
      • Flanagan W.M.
      • Miller A.B.
      • et al.
      Biennial lung cancer screening in Canada with smoking cessation-outcomes and cost-effectiveness.
      When conservative assumptions were used, an analysis of screening benefit was favorable relative to its impact on person-years of life saved. However, each nation has to make its own decision relative to the complex array of health priorities in each distinctive national setting.

      Pathology and Staging

      Pathology and Diagnostics

      Section Authors: Yasushi Yatabe, MD, PhD, Lukas Bubendorf, MD, Sanja Dacic, MD, PhD
      The acquisition of appropriate tumor material is crucial for accurate diagnosis and molecular testing of lung cancer. To meet the clinical demand, new methods have been developed. Electromagnetic navigation bronchoscopy using assisted CT allows precise targeting of peripheral nodules,
      • Khan K.A.
      • Nardelli P.
      • Jaeger A.
      • O'Shea C.
      • Cantillon-Murphy P.
      • Kennedy M.P.
      Navigational bronchoscopy for early lung cancer: a road to therapy.
      whereas transbronchial cryobiopsy is a promising tool to obtain large and high-quality specimens.
      • Pastis N.J.
      • Silvestri G.A.
      Could cryo-biopsies lead bronchoscopy into the Ice Age?.
      Several studies have reported that cytologic specimens obtained by endobronchial ultrasound–guided transbronchial needle aspiration or fine-needle aspiration are equally suitable for molecular testing.
      • Roy-Chowdhuri S.
      • Aisner D.L.
      • Allen T.C.
      • et al.
      Biomarker testing in lung carcinoma cytology specimens: a perspective from members of the Pulmonary Pathology Society.
      The upcoming molecular testing guideline has been updated to include newer targetable genes (ROS1, rearranged during transfection proto-oncogene [RET], BRAF, erb-b2 receptor tyrosine kinase 2 [HER2], and MET proto-oncogene, receptor tyrosine kinase [MET]), resistant mutations, and advances in technology, including liquid biopsy and next-generation sequencing; as well as to reaffirm or update the previous recommendations. The draft was published on the College of American Pathologists, International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology websites for open comment,

      International Association for the Study of Lung Cancer. CAP/IASLC/AMP molecular testing guideline: open comment period. https://www.iaslc.org/articles/capiaslcamp-molecular-testing-guideline-open-comment-period. Accessed February 7, 2017.

      and publication of the final recommendations is planned in 2017.
      In addition to the traditional specimens, liquid biopsies (especially circulating tumor cell DNA [ctDNA]) have been increasingly used in clinical practice. Although the liquid biopsy has been investigated for use in relation to various targetable genes in NSCLC, it is mainly used in the detection of EGFR mutations when there is inadequate tumor sample or when the risk associated with biopsy is high. Although plasma EGFR testing has high specificity, the main concerns remain concordance with tissue biopsy results and its relatively low sensitivity, especially for T790M. This situation has improved with the use of advanced next-generation sequencing platforms.
      • Luo J.
      • Shen L.
      • Zheng D.
      Diagnostic value of circulating free DNA for the detection of EGFR mutation status in NSCLC: a systematic review and meta-analysis.
      • Qiu M.
      • Wang J.
      • Xu Y.
      • et al.
      Circulating tumor DNA is effective for the detection of EGFR mutation in non-small cell lung cancer: a meta-analysis.
      • Mao C.
      • Yuan J.Q.
      • Yang Z.Y.
      • Fu X.H.
      • Wu X.Y.
      • Tang J.L.
      Blood as a substitute for tumor tissue in detecting EGFR mutations for guiding EGFR TKIs treatment of nonsmall cell lung cancer: a systematic review and meta-analysis.
      • Qian X.
      • Liu J.
      • Sun Y.
      • et al.
      Circulating cell-free DNA has a high degree of specificity to detect exon 19 deletions and the single-point substitution mutation L858R in non-small cell lung cancer.
      • Reck M.
      • Hagiwara K.
      • Han B.
      • et al.
      ctDNA determination of EGFR mutation status in European and Japanese patients with advanced NSCLC: the ASSESS Study.
      • Rachiglio A.M.
      • Abate R.E.
      • Sacco A.
      • et al.
      Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma.
      The U.S. Food and Drug Administration (FDA) has recently approved the cobas EGFR Mutation Test v2 plasma-based assay as a companion diagnostic for erlotinib.

      US Food and Drug Administration. FDA approves first blood test to detect gene mutation associated with non-small cell lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504488.htm. Accessed February 7 2017.

      If the plasma EGFR results are negative, tissue-based testing should be performed.
      • Tan D.S.
      • Yom S.S.
      • Tsao M.S.
      • et al.
      The International Association for the Study of Lung Cancer consensus statement on optimizing management of EGFR mutation-positive non-small cell lung cancer: status in 2016.
      Saliva and urine have also been used to detect EGFR mutations.
      Clinically, immune checkpoint inhibitors provide an additional treatment option in advanced NSCLC, and programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) is used as a biomarker to select patients who are more likely to respond to such treatment in either the first- or second-line setting.

      Lisberg A, Garon EB. The value of PD-L1 testing in non-small-cell lung cancer [e-pub ahead of print]. JAMA Oncol. http://dx.doi.org/10.1001/jamaoncol.2016.0043, accessed March 21, 2017.

      • Shukuya T.
      • Carbone D.P.
      Predictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in lung cancer.
      However, the development of different PD-L1 IHC assays with individual cutoff values, antibodies, and platforms for the immune checkpoint inhibitors has raised concerns among pathologists and oncologists (Table 1).
      • Kerr K.M.
      • Tsao M.S.
      • Nicholson A.G.
      • et al.
      Programmed death-ligand 1 immunohistochemistry in lung cancer: in what state is this art?.
      • Sholl L.M.
      • Aisner D.L.
      • Allen T.C.
      • et al.
      Programmed death ligand-1 immunohistochemistry—a new challenge for pathologists: a perspective from members of the Pulmonary Pathology Society.
      • Kerr K.M.
      • Hirsch F.R.
      Programmed death ligand-1 immunohistochemistry: friend or foe?.
      To obtain some clarity, the five individual assays have been, and are currently being, compared with one another.
      • Hirsch F.R.
      • McElhinny A.
      • Stanforth D.
      • et al.
      PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project.
      • Scheel A.H.
      • Dietel M.
      • Heukamp L.C.
      • et al.
      Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas.
      • Gaule P.
      • Smithy J.W.
      • Toki M.
      • et al.
      A quantitative comparison of antibodies to programmed cell death 1 ligand 1.
      • Rimm D.
      • Han G.
      • Taube J.M.
      • et al.
      ORAL01.01: a prospective, multi-institutional assessment of four assays for PD-L1 expression in NSCLC by immunohistochemistry: topic: pathology.

      Ratcliffe MJ, Sharpe A, Midha A, et al. Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cut-offs in non-small cell lung cancer [e-pub ahead of print]. Clin Cancer Res. http://dx.doi.org/10.1158/1078-0432.CCR-16-2375, accessed March 21, 2017.

      • Adam J.
      • Rouquette I.
      • Damotte D.
      • et al.
      Multicentric French harmonization study for PD-L1 IHC testing in NSCLC.
      Among these studies, first insights for possible harmonization of different PD-L1 IHC assays were provided with the BluePrint project, which was conducted in collaboration with pharmaceutical companies, diagnostic partners, the American Association for Cancer Research, and the IASLC. Three clones (22C3, 28-8, and SP263) showed similar results in tumor cell staining, whereas the SP142 assay displayed significantly less tumor cell staining. All assays stained immune cells with greater variability than tumor cells.
      • Hirsch F.R.
      • McElhinny A.
      • Stanforth D.
      • et al.
      PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project.
      Recently, tumor mutation burden was focused on as an alternative predictive biomarker for immune checkpoint inhibitor treatment, as a high nonsynonymous mutational load is expected to lead to more tumor-specific T-cell responses though expression of neoantigens.
      • Rizvi N.A.
      • Hellmann M.D.
      • Snyder A.
      • et al.
      Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
      Indeed, the mutation burden enriched the patients who benefit from first-line therapy with nivolumab, and the combination of mutation burden plus high PD-L1 expression appeared to be more predictive.
      • Peters S.
      • Creelan B.
      • Hellmann M.D.
      • et al.
      Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage IV or recurrent non-small cell lung cancer: an exploratory analysis of CheckMate 026.
      Table 1Immune Checkpoint Inhibitors and PD-L1 IHC Assays in NSCLC
      CharacteristicPharmaceutical Company
      BMSMerckRocheAstraZenecaPfizer
      DrugNivolumabPembrolizumabAtezolizumabDurvalumabAvelumab
      Antibody cloneDako 28-8Dako 22C3Ventana SP142Ventana SP263Dako 73-10
      US FDA statusComplementaryCompanionComplementaryNot approvedNot approved
      Cell type scoredTCsTCsTCs and TILsTCsTCs
      PD-L1 thresholdAll patients<50% or ≥50%TC1/2/3 or IC1/2/3 ≥1%≥25%≥1%
      Validation trialCM-057: all comers

      CM-026: ≥1%
      KN-001: PD-L1 ≥1%

      KN-010:PD-L1 ≥1%

      KN-024: PD-L1 ≥50%
      BIRCH: TC or IC 2/3

      POPLAR: all comers
      NCT01693562: All comersNCT02395172 (JAVELIN Lung 200) ≥1%
      PD-L1, programmed death ligand 1; IHC, immunohistochemistry; BMS, Bristol-Myers Squibb; US FDA, U.S. Food and Drug Administration; TIL, tumor-infiltrating lymphocyte; IC, immune cell; TC, tumor cell.

      TNM Staging System

      Section Author: Ramon Rami-Porta, MD, Frank C. Detterbeck, MD, Eric Lim, MBChB., MD, MSc
      The eighth edition of the TNM classification of lung cancer
      • Rami-Porta R.
      • Bolejack V.
      • Giroux D.J.
      • et al.
      The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer.
      • Nicholson A.G.
      • Chansky K.
      • Crowley J.
      • et al.
      The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the clinical and pathologic staging of small cell lung cancer in the forthcoming eighth edition of the TNM classification for lung cancer.
      • Detterbeck F.C.
      • Chansky K.
      • Groome P.
      • et al.
      The IASLC Lung Cancer Staging Project: methodology and validation used in the development of proposals for revision of the stage classification of NSCLC in the forthcoming (eighth) edition of the TNM classification of lung cancer.
      includes adenocarcinoma in situ (Tis[AIS]) and minimally invasive adenocarcinoma (T1mi)
      • Travis W.D.
      • Asamura H.
      • Bankier A.A.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer.
      ; incremental categories based on a 1-cm increase in tumor size from T1a–c to T2a–b, with tumors smaller than 5; 5 to no larger than 7 cm and those larger than 7 cm reclassified as T3 and T4, respectively; reclassification of endobronchial location less than 2 cm from the carina and total atelectasis-pneumonitis as T2; and diaphragmatic invasion as T4.
      • Rami-Porta R.
      • Bolejack V.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer.
      Nodal classification and intrathotracic metastasis remain unchanged.
      • Asamura H.
      • Chansky K.
      • Crowley J.
      • et al.
      The International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer.
      Single extrathoracic metastasis is now classified as M1b separately from multiple extrathoracic metastases as M1c.
      • Eberhardt W.E.
      • Mitchell A.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for the revision of the M descriptors in the forthcoming eighth edition of the TNM classification of lung cancer.
      Amendments were made to stage grouping,
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.
      as well as to classification of lung cancers with multiple lesions.
      • Detterbeck F.C.
      • Nicholson A.G.
      • Franklin W.A.
      • et al.
      The IASLC Lung Cancer Staging Project: summary of proposals for revisions of the classification of lung cancers with multiple pulmonary sites of involvement in the forthcoming eighth edition of the TNM classification.
      • Detterbeck F.C.
      • Franklin W.A.
      • Nicholson A.G.
      • et al.
      The IASLC Lung Cancer Staging Project: background data and proposed criteria to distinguish separate primary lung cancers from metastatic foci in patients with two lung tumors in the forthcoming eighth edition of the TNM classification for lung cancer.
      • Detterbeck F.C.
      • Bolejack V.
      • Arenberg D.A.
      • et al.
      The IASLC Lung Cancer Staging Project: background data and proposals for the classification of lung cancer with separate tumor nodules in the forthcoming eighth edition of the TNM classification for lung cancer.
      • Detterbeck F.C.
      • Marom E.M.
      • Arenberg D.A.
      • et al.
      The IASLC Lung Cancer Staging Project: background data and proposals for the application of TNM Staging rules to lung cancer presenting as multiple nodules with ground glass or lepidic features or a pneumonic type of involvement in the forthcoming eighth edition of the TNM classification.
      Overall survival (OS) by clinical stage according to the seventh and eigth editions is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Overall survival by clinical stage according to the seventh edition (A) and eighth edition (B) of the TNM staging system using the entire database available for the eighth edition. Survival is weighted by type of database submission: registry versus other.
      • Goldstraw P.
      • Chansky K.
      • Crowley J.
      • et al.
      The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer.
      MST, median survival time.
      The revised TNM classification for mesothelioma includes combination of T1a and T1b into the new T1 category,
      • Pass H.
      • Giroux D.
      • Kennedy C.
      • et al.
      The IASLC Mesothelioma Staging Project: improving staging of a rare disease through international participation.
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      collapse of N1 and N2 into the category N1, and reclassification of N3 as N2.
      • Rice D.
      • Chansky K.
      • Nowak A.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the N descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      The M categories remain unchanged and stage grouping has been modified for improved stratification.
      • Rusch V.W.
      • Chansky K.
      • Kindler H.L.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for the M descriptors and for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for mesothelioma.
      The TNM classification of thymic epithelial malignancies was a joint effort of the IASLC and the International Thymic Malignancies Interest Group.
      • Detterbeck F.C.
      • Asamura H.
      • Crowley J.
      • et al.
      The IASLC/ITMIG Thymic Malignancies Staging Project: development of a stage classification for thymic malignancies.
      The T component is classified according to the involved organs.
      • Nicholson A.G.
      • Detterbeck F.C.
      • Marino M.
      • et al.
      The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposals for the T component for the forthcoming (8th) edition of the TNM classification of malignant tumors.
      Nodal involvement is divided into N1 (anterior [perithymic] nodes) and N2 (deep intrathoracic or supraclavicular nodes).
      • Kondo K.
      • Van Schil P.
      • Detterbeck F.C.
      • et al.
      The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposals for the N and M components for the forthcoming (8th) edition of the TNM classification of malignant tumors.
      • Bhora F.Y.
      • Chen D.J.
      • Detterbeck F.C.
      • et al.
      The ITMIG/IASLC Thymic Epithelial Tumors Staging Project: a proposed lymph node map for thymic epithelial tumors in the forthcoming 8th edition of the TNM classification of malignant tumors.
      Stages I, II, IIIA, and IIIB are based on increasing local organ invasion, with stage IVA, including N1 and M1a (separate pleural or pericardial nodules) and stage IVB including N2 and M1b (intrapulmonary or distant organ metastasis).
      • Detterbeck F.C.
      • Stratton K.
      • Giroux D.
      • et al.
      The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM classification of malignant tumors.
      For esophageal and esophagogastric junction cancers (cancers with their epicenter within the proximal 2 cm of the cardia),
      • Rice T.W.
      • Ishwaran H.
      • Ferguson M.K.
      • Blackstone E.H.
      • Goldstraw P.
      Cancer of the esophagus and esophagogastric junction: an eighth edition staging primer.
      tumors were staged clinically,
      • Rice T.W.
      • Apperson-Hansen C.
      • DiPaola L.M.
      • et al.
      Worldwide Esophageal Cancer Collaboration: clinical staging data.
      pathologically,
      • Rice T.W.
      • Chen L.Q.
      • Hofstetter W.L.
      • et al.
      Worldwide Esophageal Cancer Collaboration: pathologic staging data.
      or pathologically after induction treatment.
      • Rice T.W.
      • Lerut T.E.
      • Orringer M.B.
      • et al.
      Worldwide Esophageal Cancer Collaboration: neoadjuvant pathologic staging data.
      This edition included subdivision of T4 into T4a and T4b depending on invaded organ; differentiation of clinical and pathologic stages for squamous and adenocarcinoma; introduction of pathologic stages after induction for both cancers; and introduction of prognostic subgroups based on anatomic extent, location, and differentiation grade.
      • Rice T.W.
      • Ishwaran H.
      • Kelsen D.P.
      • et al.
      Recommendations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals.
      • Rice T.W.
      • Ishwaran H.
      • Hofstetter W.L.
      • et al.
      Recommendations for pathologic staging (pTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals.
      • Rice T.W.
      • Ishwaran H.
      • Blackstone E.H.
      • et al.
      Recommendations for clinical staging (cTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals.

      Therapy

      Surgery

      Section Authors: Hisao Asamura, MD, Jessica Donington, MD

      Minimally Invasive Lobectomy

      Over the past 2 decades, video-assisted thoracic surgery (VATS) has become a common surgical technique. Along with it came improvements in operative and visual instruments. Although definition of VATS has been conflicting, VATS generally means operating by using thoracoscopy with a minimal number of small incisions and without rib spreading. Treatment of lung cancer by VATS has been performed under the assumption that it has an oncologic outcome equivalent to that of open thoracotomy but is a less invasive method. However, scientifically supported comparisons between VATS and open thoracotomy with randomized controlled trials have been scarcely reported. Some studies using large national or regional databases have reported that VATS had a lower incidence of postoperative complications or shorter length of hospital stay by 1 to 2 days, but there is uncertainty as to whether this is clinically meaningful.
      • Falcoz P.E.
      • Puyraveau M.
      • Thomas P.A.
      • et al.
      Video-assisted thoracoscopic surgery versus open lobectomy for primary non-small-cell lung cancer: a propensity-matched analysis of outcome from the European Society of Thoracic Surgeon database.
      • Pages P.B.
      • Delpy J.P.
      • Orsini B.
      • et al.
      Propensity score analysis comparing videothoracoscopic lobectomy with thoracotomy: a French nationwide study.
      • Wang B.Y.
      • Huang J.Y.
      • Lin C.H.
      • et al.
      Thoracoscopic lobectomy produces long-term survival similar to that with open lobectomy in cases of non-small cell lung carcinoma: a propensity-matched analysis using a population-based cancer registry.
      • Yang C.F.
      • Sun Z.
      • Speicher P.J.
      • et al.
      Use and outcomes of minimally invasive lobectomy for stage I non-small cell lung cancer in the National Cancer Data Base.
      On the other hand, some reports concluded that a higher incidence of nodal upstaging has been observed in thoracotomy than in VATS, indicating the possibility of insufficient nodal evaluation in VATS.
      • Martin J.T.
      • Durbin E.B.
      • Chen L.
      • et al.
      Nodal upstaging during lung cancer resection is associated with surgical approach.
      • Medbery R.L.
      • Gillespie T.W.
      • Liu Y.
      • et al.
      Nodal upstaging is more common with thoracotomy than with VATS During lobectomy for early-stage lung cancer: an analysis from the National Cancer Data Base.
      Of note, these conclusions were derived from retrospective studies; therefore, they always harbor hidden biases that may affect the outcome.
      A randomized controlled trial from Denmark concluded that VATS was associated with less postoperative pain and better quality of life (QOL) compared with thoracotomy for the first year after surgery.
      • Bendixen M.
      • Jorgensen O.D.
      • Kronborg C.
      • Andersen C.
      • Licht P.B.
      Postoperative pain and quality of life after lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung cancer: a randomised controlled trial.
      This study focused on the self-reported scoring systems of pain and QOL as outcomes. Further randomized studies that compare VATS to thoracotomy would be required to definitively demonstrate the prognostic equivalence and any differences in QOL or postoperative complications for these two surgical modalities.
      Robot-assisted thoracic surgery (RATS) is defined as a surgical procedure that utilizes a robotic system for all or mostly all of the crucial aspects of the operation. In a recent retrospective study, RATS was reported to be equivalent to VATS in all measures of quality for treatment of lung cancer.
      • Louie B.E.
      • Wilson J.L.
      • Kim S.
      • et al.
      Comparison of video-assisted thoracoscopic surgery and robotic approaches for clinical stage I and stage II non-small cell lung cancer using the Society of Thoracic Surgeons Database.
      To date, no randomized trials have reported the comparative data between RATS and VATS/thoracotomy for lung cancer.
      • Veronesi G.
      • Novellis P.
      • Voulaz E.
      • Alloisio M.
      Robot-assisted surgery for lung cancer: state of the art and perspectives.
      The extent of parenchymal resection remains an area of evolution. There are several situations where sublobar resection should be considered as primary treatment for early-stage NSCLC. In patients with limited pulmonary reserve or with poor physical conditions, sublobar resection, either as segmentectomy or wedge resection, can be reasonably selected as a surrogate for lobectomy. In cases of multiple primary NSCLCs, sublobar resections should be considered as well. Of course, there are anatomic limitations for such resection; however, there is no doubt that such surrogate resections could be selected.

      Surgical Quality

      The importance of surgical quality measures (QMs) in NSCLC was highlighted in 2016. Two independent studies from the National Cancer Database found that compliance with basic QMs was associated with improved OS after NSCLC resections. A study examining stage I NSCLC looked at (1) anatomic resection, (2) operation within 8 weeks of diagnosis, (3) R0 resection, and (4) more than 10 lymph nodes sampled. Whereas 99% of resections met at least one QM, only 22% satisfied all four. Median OS varied from 31 to 89 months for those who met no QMs as opposed to four QMs.
      • Samson P.
      • Crabtree T.
      • Broderick S.
      • et al.
      Quality measures in clinical stage I non-small cell lung cancer: improved performance is associated with improved survival.
      Similarly, in clinical stage IIIA, adherence to four QMs (neoadjuvant therapy, lobectomy or more extensive procedure, R0 resection, and >10 lymph nodes sampled) was examined and only 12.8% of stage IIIA resections satisfied all QMs. Median OS varied from 12 to 43.5 months for those who met no QMs compared with for those who met four.
      • Samson P.
      • Crabtree T.
      • Morgensztern D.
      • et al.
      Surgical quality measures in stage IIIA non–small cell lung cancer are associated with improved survival.
      Compliance with QMs was associated with age, insurance type, hospital volume, and comorbidity score but remained a strong independent predictor of survival in both studies. The benefit of thorough thoracic lymphadenectomy in early-stage NSCLC was further emphasized with multiple meta-analysis and population-based studies demonstrating improved OS when greater numbers of lymph nodes were resected and examined.
      • Stiles B.M.
      • Kamel M.K.
      • Nasar A.
      • et al.
      The importance of lymph node dissection accompanying wedge resection for clinical stage IA lung cancer†.
      • Samayoa A.X.
      • Pezzi T.A.
      • Pezzi C.M.
      • et al.
      Rationale for a minimum number of lymph nodes removed with non–small cell lung cancer resection: correlating the number of nodes removed with survival in 98,970 patients.
      • Li Q.
      • Zhan P.
      • Yuan D.
      • et al.
      Prognostic value of lymph node ratio in patients with pathological N1 non-small cell lung cancer: a systematic review with meta-analysis.
      • Liang W.
      • He J.
      • Shen Y.
      • et al.
      Impact of examined lymph node count on precise staging and long-term survival of resected non-small-cell lung cancer: a population study of the US SEER Database and a Chinese multi-institutional registry.
      • Tamura M.
      • Matsumoto I.
      • Saito D.
      • Yoshida S.
      • Takata M.
      • Takemura H.
      Lymph node ratio as a prognostic factor in patients with pathological N2 non-small cell lung cancer.

      Adjuvant Therapy in Completely Resected NSCLC

      Section Authors: Heather Wakelee, MD, and Yi-Long Wu, MD
      Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II and IIIA NSCLC and is commonly used for patients with larger (at least 4 cm) stage IB tumors. In 2016 we learned from a subset analysis of the E1505 trial that the four platinum-based doublets utilized (cisplatin with either vinorelbine, gemcitabine, docetaxel, or pemetrexed) had comparable efficacy but differing toxicity profiles.
      • Wakelee H.A.
      • Dahlberg S.E.
      • Keller S.M.
      • et al.
      E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC—outcomes based on chemotherapy subsets.
      Further data to support the 4-cm cutoff to recommend adjuvant chemotherapy came from a propensity score–matched analysis performed in the Republic of Korea that divided stage IB patients into those with tumors 3 cm or smaller with visceral pleural invasion, tumors 3 to 4 cm in size, and tumors 4 to 5 cm in size. The study reported that the only group with a clear differential benefit from adjuvant chemotherapy was that with tumors 4 to 5 cm in size.
      • Jeon J.H.
      • Moon D.H.
      • Yang H.C.
      • Moon S.K.
      • Jong M.L.
      Selection for adjuvant chemotherapy in stage IB non-small cell lung cancer: a propensity score-matched analysis.
      A Chinese study that utilized carboplatin/docetaxel and randomized nearly 200 patients to preoperative or postoperative therapy was presented at the IASLC World Conference on Lung Cancer 2016.
      • Yang X.-N.
      • Zhong W.-Z.
      • Ben X.-S.
      • et al.
      Randomized Controlled study comparing adjuvant versus neo-adjuvant chemotherapy in resectable stage IB to IIIA NSCLC.
      Both disease-free survival and OS trended in favor of the adjuvant approach, but the trial was too small to draw any definitive conclusions and leaves us with continued questions about the ideal strategy. Recent studies with strategies including the addition of bevacizumab in E1505 and the use of the MAGE-A3 vaccine in MAGRIT failed to demonstrate any improvement in survival with these approaches.
      • Wakelee H.A.
      • Dahlberg S.E.
      • Keller S.M.
      • et al.
      E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC—outcomes based on chemotherapy subsets.
      • Vansteenkiste J.F.
      • Cho B.C.
      • Vanakesa T.
      • et al.
      Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Encouraging data from retrospective and nonrandomized trials of adjuvant EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant NSCLC have led to randomized trials, including the phase III RADIANT trial of adjuvant erlotinib or placebo.
      • Kelly K.
      • Altorki N.K.
      • Eberhardt W.E.
      • et al.
      Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial.
      In the EGFR-mutated subset (n = 161) disease-free survival favored erlotinib (hazard ratio [HR] = 0.61 [not significant]); OS did not trend favorably but was immature. Table 2 includes multiple ongoing trials of adjuvant EGFR TKI (and adjuvant anaplastic lymphoma kinase [ALK] TKI) therapy for patients with resected early-stage NSCLC with tumors harboring the appropriate molecular marker. With approvals in advanced-stage disease, multiple programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors are now being studied in the adjuvant setting.
      Table 2Ongoing Phase III Targeted and Immunotherapy Adjuvant Trials
      TrialPatient Population
      All include stage II to IIIA, all PD-1/PD-L1 studies open to stage IB (4 cm) to IIIA after adjuvant chemotherapy.
      Adjuvant TherapyPrimary End Point(s)Estimated Enrollment
      C-TONG 1104

      NCT01405079
      EGFR deletion 19 or exon 21 L858R mutationGefitinib vs. vinorelbine/cisplatinDFS220
      GASTO1002

      NCT01996098
      EGFR deletion 19 or exon 21 L858R mutationChemotherapy then Icotinib vs. observationDFS477
      BD-IC-IV-59

      NCT02125240
      EGFR deletion 19 or exon 21 L858R mutationChemotherapy, then Icotinib vs. placeboDFS300
      WJOG6401L

      IMPACT
      EGFR deletion 19 or exon 21 L858R mutationGefitinib vs. cisplatin/vinorelbineDFS230
      ADAURA

      NCT02511106
      EGFR deletion 19 or exon 21 L858R mutation with or without T790MChemotherapy or no chemotherapy, then osimertinib vs. placeboDFS700
      ALCHEMIST

      A081105

      NCT02193282
      EGFR deletion 19 or exon 21 L858R mutationErlotinib vs. placeboOS450
      ALCHEMIST

      E4512

      NCT02201992
      ALK-positive by FISHCrizotinib vs. placeboOS378
      ALCHEMIST/ANVIL

      NCT02595944
      EGFR/ALK wildtype, regardless of PD-L1 statusChemotherapy, then nivolumab vs. observationOS/DFS714
      Impower010

      NCT02486718
      Regardless of PD-L1 statusChemotherapy, then atezolizumab vs. placeboDFS1127
      BR31

      NCT02273375
      Regardless of PD-L1 statusChemotherapy or no chemotherapy, then durvalumab vs. placeboDFS1100
      Keynote-091

      NCT02504372
      Regardless of PD-L1 statusChemotherapy or no chemotherapy, then pembrolizumab vs. placeboDFS1380
      DFS, disease-free survival; OS, overall survival; ALK, ALK receptor tyrosine kinase gene; FISH, fluorescence in situ hybridization; PD-L1, programmed death ligand 1; PD-1, programmed cell death 1.
      a All include stage II to IIIA, all PD-1/PD-L1 studies open to stage IB (4 cm) to IIIA after adjuvant chemotherapy.

      Advances in RT

      Section Authors: Kristin Higgins, MD, Suresh Senan, MD

      Locally Advanced Stage III Disease

      The standard of care for locally advanced NSCLC remains concurrent platinum-based chemotherapy and radiation to 60 to 66 Gy.
      • Bradley J.D.
      • Paulus R.
      • Komaki R.
      • et al.
      Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
      The PROCLAIM study evaluated two concurrent chemotherapy schemes, pemetrexed-cisplatin versus cisplatin-etoposide, with thoracic radiation therapy (TRT) in stage IIIA/IIIB nonsquamous NSCLC. Survival with pemetrexed-cisplatin-TRT was not superior, although grade 3 or lower neutropenia occurred less frequently in the pemetrexed arm.
      • Senan S.
      • Brade A.
      • Wang L.H.
      • et al.
      PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer.
      A randomized study comparing intensity-modulated RT (IMRT) with passively scattered proton therapy reported no differences in the primary study end point of treatment failure (defined as either local progression or grade 3 or higher radiation pneumonitis).
      • Liao Z.X.
      • Lee J.J.
      • Komaki R.
      • et al.
      Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer.
      Secondary analyses of the RTOG 0617 study found less high-grade pneumonitis, lower cardiac doses with use of IMRT versus three-dimensional conformal radiation therapy,
      • Chun S.G.
      • Hu C.
      • Choy H.
      • et al.
      Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial.
      and also less clinically meaningful decline in QOL with IMRT.
      • Movsas B.
      • Hu C.
      • Sloan J.
      • et al.
      Quality of life analysis of a radiation dose-escalation study of patients with non-small-cell lung cancer: a secondary analysis of the radiation therapy oncology group 0617 randomized clinical trial.

      SBRT for Early-Stage and Oligometastatic Disease

      The impact of stereotactic body RT (SBRT) for peripheral early-stage NSCLC is reflected in a Surveillance, Epidemiology, and End Results analysis showing that RT utilization rates for stage IA NSCLC increased from 13% to 29% between 2004 and 2012, with significant improvements in OS in the RT cohort.
      • Haque W.
      • Szeja S.
      • Tann A.
      • Kalra S.
      • Teh B.S.
      Changes in treatment patterns and overall survival in patients with early-stage non-small cell lung cancer in the United States after the incorporation of stereotactic ablative radiation therapy: a population-based analysis.
      A systematic review reported only limited changes in health-related QOL after SBRT.
      • Chen H.
      • Louie A.V.
      • Boldt R.G.
      • Rodrigues G.B.
      • Palma D.A.
      • Senan S.
      Quality of life after stereotactic ablative radiotherapy for early-stage lung cancer: a systematic review.
      For patients with centrally located lung tumors, both a prospective trial
      • Bezjak A.
      • Paulus R.
      • Gaspar L.E.
      • et al.
      Efficacy and toxicity analysis of NRG Oncology/RTOG 0813 trial of stereotactic body radiation therapy (SBRT) for centrally located non-small cell lung cancer (NSCLC).
      and a literature overview
      • Tekatli H.
      • Senan S.
      • Dahele M.
      • Slotman B.J.
      • Verbakel W.F.
      Stereotactic ablative radiotherapy (SABR) for central lung tumors: plan quality and long-term clinical outcomes.
      suggested that the toxicity rates of SBRT were acceptable, but the HILUS trial reported significant rates of fatal hemoptysis.
      • Lindberg K.
      • Bergström P.
      • Brustugun O.T.
      • et al.
      The Nordic HILUS-Trial—first report of a phase II trial of SBRT of centrally located lung tumors.
      Mature data from prospective trials of SBRT for central tumors are awaited. In stage IV oligometastatic NSCLC (one to three metastatic lesions), a randomized phase II trial in patients not progressing after first-line systemic therapy demonstrated a significant improvement in progression-free survival (PFS) with local consolidative therapy (chemoradiotherapy or resection of all lesions) compared with standard therapy (11.9 months versus 3.9 months, log-rank p = 0.0054).
      • Gomez D.R.
      • Blumenschein Jr., G.R.
      • Lee J.J.
      • et al.
      Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.

      Use of WBRT in NSCLC

      Brain metastases will develop in up to 50% of patients with NSCLC.
      • Law A.
      • Karp D.D.
      • Dipetrillo T.
      • Daly B.T.
      Emergence of increased cerebral metastasis after high-dose preoperative radiotherapy with chemotherapy in patients with locally advanced nonsmall cell lung carcinoma.
      • Barnholtz-Sloan J.S.
      • Sloan A.E.
      • Davis F.G.
      • Vigneau F.D.
      • Lai P.
      • Sawaya R.E.
      Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.
      In selected patients, surgery or radiosurgery offers the best results. However, patients with large-volume metastatic brain disease have traditionally been treated with whole brain RT (WBRT). In the QUARTZ trial, 538 patients with brain metastases from NSCLC who were ineligible for surgery or radiosurgery were randomized to WBRT (20 Gy in five fractions) or best supportive care.
      • Mulvenna P.
      • Nankivell M.
      • Barton R.
      • et al.
      Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial.
      The primary outcome measure was quality-adjusted life-years, and no differences in OS, QOL, or dexamethasone use were observed between the two groups. This study provides evidence that poor prognosis patients with brain metastases from NSCLC do not benefit from WBRT. However, the QUARTZ data are not applicable to younger patients, those with limited extracranial disease, and those for whom radiosurgery remains an option.

      ALK

      Section Authors: Benjamin Solomon, M.B.B.S., PhD, Dong-Wan Kim, MD, PhD

      New-Generation TKIs

      Currently, ceritinib and alectinib are approved by the U.S. FDA as subsequent treatment options after crizotinib failure in ALK-positive patients. Several recent trials have provided clinical data on these drugs in the crizotinib-naive setting. In the ASCEND-4 study, which was a phase 3 study comparing ceritinib with chemotherapy, the median PFS was 16.6 months for ceritinib compared with 8.1 months for chemotherapy (HR = 0.55, 95% confidence interval [CI]: 0.42–0.73, p < 0.00001).
      • Soria J.C.
      • Tan D.S.
      • Chiari R.
      • et al.
      First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.
      The randomized phase 3 J-ALEX study compared alectinib, 300 mg twice daily, and crizotinib in Japanese patients without prior ALK inhibitor treatment. Alectinib was significantly superior to crizotinib, with PFS not reached versus 10.8 months, respectively (HR = 0.34).
      • Hida T.
      • Nokihara H.
      • Kondo M.
      • et al.
      Alectinib versus crizotinib in patients with ALK positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial.
      Results from a global phase 3 study (ALEX study) comparing alectinib, 600 mg twice daily, and crizotinib will likely be reported soon. Lorlatinib and brigatinib showed efficacy in patients with brain metastasis and/or resistant mutations, including G1202R.
      • Solomon B.J.
      • Bauer T.M.
      • Felip E.
      • et al.
      Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC).
      • Kim D.-W.
      • Tiseo M.
      • Ahn M.-J.
      • et al.
      Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): first report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA).
      Phase 3 trials comparing these agents with crizotinib are ongoing.

      ALK Resistance and Sequencing of Therapies

      Resistance to first- and second-generation ALK TKIs may occur through ALK-dependent mechanisms (primarily ALK kinase secondary mutations or amplification) or ALK-independent mechanisms, including activation of oncogenic bypass tracts or cell lineage change (small cell or epithelial-to-mesenchymal transformations).
      • Camidge D.R.
      • Doebele R.C.
      Treating ALK-positive lung cancer—early successes and future challenges.
      • Lin J.J.
      • Riely G.J.
      • Shaw A.T.
      Targeting ALK: precision medicine takes on drug resistance.
      Recently, Gainor et al. extensively characterized mutations in post-TKI biopsy specimens and identified differences in the frequency and type of secondary mutations occurring in patients progressing while receiving crizotinib compared with second-generation ALK TKIs.
      • Gainor J.F.
      • Dardaei L.
      • Yoda S.
      • et al.
      Molecular mechanisms of resistance to first- and second-generation ALKiInhibitors in ALK-rearranged lung cancer.
      Secondary ALK mutations were present in 20% to 30% of patients progressing while taking crizotinib compared with in more than 50% of patients progressing during treatment with a second-generation ALK TKI. Mutations such as L1196M and G1269A were frequent in post–crizotinib treatment biopsy specimens; they were less common after treatment with second-generation ALK TKIs. In contrast, G1202R, which was found in only 2% of post–crizotinib treatment specimens, was the most frequent mutation after treatment with second-generation TKIs. Interestingly, the mutation profile of tumors changes with time and with the influence of sequential ALK TKIs.
      • Gainor J.F.
      • Dardaei L.
      • Yoda S.
      • et al.
      Molecular mechanisms of resistance to first- and second-generation ALKiInhibitors in ALK-rearranged lung cancer.
      • Shaw A.T.
      • Friboulet L.
      • Leshchiner I.
      • et al.
      Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F.
      Although the empirical use of sequential ALK TKIs such as crizotinib followed by ceritinib or alectinib has resulted in long-term disease control and excellent survival, characterization of resistance mechanisms by using serial tumor biopsy specimens has potential to guide selection of multiple, sequential lines of ALK inhibitor therapy.
      • Gainor J.F.
      • Tan D.S.
      • De Pas T.
      • et al.
      Progression-free and overall survival in ALK-positive NSCLC patients treated with sequential crizotinib and ceritinib.
      • Watanabe S.
      • Hayashi H.
      • Okamoto K.
      • et al.
      Progression-free and overall survival of patients with ALK rearrangement-positive non-small cell lung cancer treated sequentially with crizotinib and alectinib.
      For example, the I1171 mutation that is associated with resistance to crizotinib and alectinib may be sensitive to ceritinib; alternatively, the G1202R mutation that is associated with resistance to crizotinib, alectinib, and ceritinib may be sensitive to the third-generation ALK TKI lorlatinib.
      • Solomon B.J.
      • Bauer T.M.
      • Felip E.
      • et al.
      Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC).

      EGFR

      Section Authors: Melissa Johnson, MD, James C. H. Yang, MD, PhD, Lecia V. Sequist, MD
      The optimal treatment for patients with EGFR mutations continued to be refined in 2016. Key research findings centered around comparing first-line EGFR TKIs, solidifying the role of the newly approved osimertinib for acquired resistance, developing novel EGFR TKIs, and using plasma to genotype EGFR.
      The LUX-Lung 7 trial compared first-line afatinib to geftinib among patients with EGFR mutation. A slight PFS benefit for afatinib (HR = 0.73, 95% CI: 0.57–0.95, p = 0.017) was seen, but the median PFS was 11 months in both arms.
      • Park K.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.
      Furthermore the OS was similar in both treatment arms, including analyses within exon 19 deletion and L858R.
      • Paz-Ares L.
      • Tan E.H.
      • O'Byrne K.
      • et al.
      Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.
      At this time, whether there are clear differences between the first-line EGFR TKIs is unclear; therefore, afatinib, erlotinib, and gefitinib are all reasonable options.
      In November 2015, osimertinib became the first U.S. FDA–approved T790M mutant–specific, wild-type–sparing (third-generation) EGFR TKI. This year we saw mature results from two large single-arm phase II studies of osimertinib, 80 mg daily, in patients with T790M-mediated acquired resistance. The AURA extension and AURA2 trials showed overall response rates (ORRs) of 62% and 58%, disease control rates (DCRs) of 90% and 92%, and PFS times of 12.3 and 9.9 months, respectively.
      • Goss G.
      • Tsai C.M.
      • Shepherd F.A.
      • et al.
      Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.
      • Yang J.
      • Ahn M.
      • Kim D.
      • et al.
      Pretreated T790M-positive advanced non–small-cell lung cancer: AURA study phase II extension component.
      The phase III AURA3 trial randomized 419 EGFR-mutant patients with T790M after failure of first-line EGFR TKIs to osimertinib or platinum/pemetrexed; the PFS times were 10.1 and 4.4 months, respectively (HR = 0.30, 95% CI: 0.23–0.41, p < 0.001).
      • Mok T.S.
      • Wu Y.L.
      • Ahn M.J.
      • et al.
      Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer.
      Osimertinib may also have unique central nervous system activity.
      • Ballard P.
      • Yates J.W.
      • Yang Z.
      • et al.
      Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.
      EGFR-mutant patients (EGFR T790M not required) with leptomeningeal disease were treated with osimertinib, 160 mg (BLOOM study).
      • Yang J.C.-H.
      • Kim D.-W.
      • Kim S.-W.
      • et al.
      Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): updated results from BLOOM, a phase I study.
      Nine of 20 patients had radiographic responses; improvements in neurologic examination findings and declining levels of ctDNA in the cerebrospinal fluid were also reported. Promising PFS was seen with first-line osimertinib in patients with EGFR-mutant NSCLC,
      • Ramalingam S.
      • Yang J.C.H.
      • Lee C.K.
      • et al.
      Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two phase I expansion cohorts.
      and the results of a phase III study comparing osimertinib to erlotinib/gefitinib (FLAURA) are greatly anticipated.
      The need for tissue rebiopsy to determine T790M status can be a barrier to appropriate treatment selection. Plasma detection and semiquantitation of the activating EGFR and T790M mutation is a useful tool to predict the efficacy of osimertinib,
      • Oxnard G.R.
      • Thress K.S.
      • Alden R.S.
      • et al.
      Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer.
      and an assay for T790M in ctDNA was U.S. FDA–approved in 2016 as a companion diagnostic to osimertinib. Novel techniques for T790M detection in both plasma and urine have been studied,
      • Liao B.C.
      • Lin C.C.
      • Lee J.H.
      • Yang J.C.
      Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors.
      and minimally invasive assays are expected to gain prominence in the future.
      Updates regarding several other novel EGFR TKIs were published in 2016.
      • Reckamp K.L.
      • Melnikova V.O.
      • Karlovich C.
      • et al.
      A highly sensitive and quantitative test platform for detection of NSCLC EGFR mutations in urine and plasma.
      Olmutinib was approved in the Republic of Korea, but global development has been halted. EGF816
      • Tan D.S.-W.
      • Yang J.C.-H.
      • Leighl N.B.
      • et al.
      Updated results of a phase 1 study of EGF816, a third-generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC) harboring T790M.
      and ASP8273
      • Yu H.A.
      • Spira A.I.
      • Horn L.
      • et al.
      Antitumor activity of ASP8273 300 mg in subjects with EGFR mutation-positive non-small cell lung cancer: interim results from an ongoing phase 1 study.
      are active in T790M-positive patients. Rociletinib development has ceased owing to low activity in T790M-positive patients.
      • Chuang J.C.
      • Salahudeen A.A.
      • Wakelee H.A.
      Rociletinib, a third generation EGFR tyrosine kinase inhibitor: current data and future directions.
      • Sequist L.V.
      • Soria J.C.
      • Camidge D.R.
      Update to rociletinib data with the RECIST confirmed response rate.
      A novel EGFR TKI, AZD3759, has increased central nervous system penetration but does not inhibit T790M.
      • Yang Z.
      • Guo Q.
      • Wang Y.
      • et al.
      AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases.
      • Ahn M.-J.
      • Kim D.-W.
      • Kim T.M.
      • et al.
      Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM).
      Finally, although immune therapy checkpoint inhibitors have had a huge impact in advanced NSCLC in 2016, the studies to date show little if any benefit for EGFR mutation-positive patients.
      • Herbst R.S.
      • Baas P.
      • Kim D.W.
      • et al.
      Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      • 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.

      ROS1

      Section Authors: Alice Shaw, MD, PhD, Myung-Ju Ahn, MD, PhD
      Resistance to crizotinib develops in almost all patients with ROS1-rearranged NSCLC. Although the mechanisms of acquired resistance are incompletely understood, several case series of repeat biopsies with supporting preclinical studies have identified missense mutations within the ROS1 kinase domain, such as G2032R,
      • Awad M.M.
      • Katayama R.
      • McTigue M.
      • et al.
      Acquired resistance to crizotinib from a mutation in CD74-ROS1.
      D2033N,
      • Drilon A.
      • Somwar R.
      • Wagner J.P.
      • et al.
      A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer.
      S1986Y/F,
      • Facchinetti F.
      • Loriot Y.
      • Kuo M.S.
      • et al.
      Crizotinib-resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1- and ALK-rearranged lung cancers.
      and L2155S,
      • Song A.
      • Kim T.M.
      • Kim D.W.
      • et al.
      Molecular changes associated with acquired resistance to crizotinib in ROS1-Rearranged non-small cell lung cancer.
      which can mediate crizotinib resistance. The ROS1 G2032R mutation, which is located at the solvent front of the kinase hinge, confers high-level resistance to crizotinib and appears to be the most common resistance mechanism in crizotinib-treated patients.
      • Gainor J.F.
      • Friboulet L.
      • Yoda S.
      • et al.
      Frequency and spectrum of ROS1 resistance mutations in ROS1-positive lung cancer patients progressing on crizotinib.
      Preclinical studies suggest that cabozantinib,
      • Katayama R.
      • Kobayashi Y.
      • Friboulet L.
      • et al.
      Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.
      foretinib,
      • Davare M.A.
      • Vellore N.A.
      • Wagner J.P.
      • et al.
      Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors.
      and lorlatinib
      • Zou H.Y.
      • Friboulet L.
      • Kodack D.P.
      • et al.
      PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models.
      may be able to overcome this resistance mutation. The ROS1 D2033N resistance mutation was identified in a patient with CD74 molecule gene (CD74)-ROS1 fusion who relapsed while taking crizotinib. Like G2032R, D2033N is located at the solvent front of the kinase hinge. Notably, this patient was highly responsive to the multitargeted inhibitor cabozantinib, experiencing a rapid and durable clinical response.
      • Drilon A.
      • Somwar R.
      • Wagner J.P.
      • et al.
      A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer.
      Recently, a dual ROS1 kinase domain mutation, S1986Y and S1986F, was discovered in a ROS1-positive patient who had relapsed while receiving crizotinib. This patient subsequently responded to lorlatinib.
      • Facchinetti F.
      • Loriot Y.
      • Kuo M.S.
      • et al.
      Crizotinib-resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1- and ALK-rearranged lung cancers.
      Finally, the novel resistance mutation, L2155S, was identified in crizotinib-resistant HCC78 cell lines harboring the solute carrier family 34 member 2 gene (SLC34A2)-ROS1 fusion.
      • Song A.
      • Kim T.M.
      • Kim D.W.
      • et al.
      Molecular changes associated with acquired resistance to crizotinib in ROS1-Rearranged non-small cell lung cancer.
      Whether this ROS1 mutation will emerge in patients exposed to crizotinib remains to be determined. To date, the lorlatinib phase 1/2 trial represents the largest study to examine patients with crizotinib-resistant, ROS1-positive NSCLC. Preliminary data suggest that lorlatinib can induce responses in some patients, but ROS1 mutation status in these responders has not been reported.
      • Solomon B.J.
      • Bauer T.M.
      • Felip E.
      • et al.
      Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC).
      A newer next-generation ROS1 inhibitor, TPX-0005, will soon enter phase 1 clinical testing. TPX-0005 has been specifically designed to overcome the solvent front mutations in ALK and ROS1, including ROS1 G2032R.
      • Zhai D.
      • Deng W.
      • Huang Z.
      • Rogers E.
      • Cui J.J.
      The novel, rationally-designed, ALK/SRC inhibitor TPX-0005 overcomes multiple acquired resistance mechanisms to current ALK inhibitors.
      In addition to secondary mutations within ROS1, several different off-target mechanisms of resistance have also been reported in crizotinib-resistant tumors, including a KIT proto-oncogene receptor tyrosine kinase gene (KIT) D816G activating mutation
      • Dziadziuszko R.
      • Le A.T.
      • Wrona A.
      • et al.
      An activating KIT mutation induces crizotinib resistance in ROS1-positive lung cancer.
      and EGFR pathway activation.
      • Davies K.D.
      • Mahale S.
      • Astling D.P.
      • et al.
      Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer.
      Further studies of crizotinib-resistant tumor specimens are needed to fully define the spectrum of on-target and off-target resistance mechanisms in ROS1-positive NSCLC. Elucidating these mechanisms may inform the rational development of new treatment strategies for crizotinib-resistant, ROS1-positive NSCLC.

      Other Targets

      Section Authors: Daniel B. Costa, MD, PhD, Jyoti D. Patel, MD
      Although in 2016 approval of TKIs matched to a driver was restricted to tumors with genomic aberrations in EGFR, ALK and ROS1,
      • Rosell R.
      • Carcereny E.
      • Gervais R.
      • et al.
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
      • Mok T.S.
      • Wu Y.L.
      • Thongprasert S.
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      • Sequist L.V.
      • Yang J.C.
      • Yamamoto N.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      • Kwak E.L.
      • Bang Y.J.
      • Camidge D.R.
      • et al.
      Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
      • Shaw A.T.
      • Kim D.W.
      • Nakagawa K.
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Solomon B.J.
      • Mok T.
      • Kim D.W.
      • et al.
      First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
      • Shaw A.T.
      • Ou S.H.
      • Bang Y.J.
      • et al.
      Crizotinib in ROS1-rearranged non-small-cell lung cancer.
      other putative driver events could predict for response to targeted therapies in advanced NSCLC, particularly in lung adenocarcinoma (Table 3
      • Hyman D.M.
      • Puzanov I.
      • Subbiah V.
      • et al.
      Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations.
      • Planchard D.
      • Kim T.M.
      • Mazieres J.
      • et al.
      Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial.
      • Planchard D.
      • Besse B.
      • Groen H.J.
      • et al.
      Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.
      • Drilon A.E.
      • Camidge D.R.
      • Ou S.-H.I.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      • Camidge D.R.
      • Ou S.-H.I.
      • Shapiro G.
      • et al.
      Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC).
      • Drilon A.
      • Rekhtman N.
      • Arcila M.
      • et al.
      Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.
      • Yoh K.
      • Seto T.
      • Satouchi M.
      • et al.
      Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
      • Lee S.-H.
      • Lee J.-K.
      • Ahn M.-J.
      • et al.
      A phase II study of vandetanib in patients with non-small cell lung cancer harboring RET rearrangement.
      • Velcheti V.
      • Hida T.
      • Reckamp K.L.
      • et al.
      Phase 2 study of lenvatinib (LN) in patients (Pts) with RET fusion-positive adenocarcinoma of the lung.
      • Cascone T.
      • Subbiah V.
      • Hess K.R.
      • et al.
      Significant systemic and CNS activity of RET inhibitor vandetanib combined with mTOR inhibitor everolimus in patients with advanced NSCLC with RET fusion.
      • Kris M.G.
      • Camidge D.R.
      • Giaccone G.
      • et al.
      Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.
      • Mazieres J.
      • Peters S.
      • Lepage B.
      • et al.
      Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.
      • Besse B.
      • Soria J.C.
      • Yao B.
      • et al.
      LBA39_PR. Neratinib (N) with or without temsirolimus (Tem) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: an international randomized phase II study.
      • Farago A.F.
      • Le L.P.
      • Zheng Z.
      • et al.
      Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer.
      ).
      Table 3Driver Oncogene Mutations, Inhibitors, Response, and ClinicalTrials.gov Registration for Other Targets in Lung Cancer
      Driver OncogenePrevalence of Lung AdenocarcinomaInhibitor(s)ORRNCT No.
      BRAF

      V600E mutation
      1%–2%Vemurafenib42% (n = 19)
      • Hyman D.M.
      • Puzanov I.
      • Subbiah V.
      • et al.
      Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations.
      NCT01524978
      Dabrafenib35% (n = 84)
      • Planchard D.
      • Kim T.M.
      • Mazieres J.
      • et al.
      Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial.
      NCT01336634
      Dafrafenib + trametinib
      Approved by European Union and FDA in 2017 and pending review for formal regulatory approval elsewhere.
      63% (n = 57)
      • Planchard D.
      • Besse B.
      • Groen H.J.
      • et al.
      Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.
      NCT01336634
      BRAF

      non-V600E mutations
      1%–2%TrametinibNRNCT02465060
      MET

      exon 14 skipping
      3%–4%Crizotinib44% (n = 18)
      • Drilon A.E.
      • Camidge D.R.
      • Ou S.-H.I.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      NCT00585195
      CrizotinibNRNCT02465060
      CrizotinibNRNCT02664935
      CapmatinibNRNCT01324479
      TepotinibNRNCT02864992
      SavolitinibNRNCT02897479
      GlesatinibNRNCT02544633
      CabozantinibNRNCT01639508
      MerestinibNRNCT02920996
      MET

      high-level amplification
      1%Crizotinib66% (n = 6)
      • Camidge D.R.
      • Ou S.-H.I.
      • Shapiro G.
      • et al.
      Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC).
      NCT00585195
      CapmatinibNRNCT01324479
      GlesatinibNRNCT02544633
      CabozantinibNRNCT01639508
      RET

      rearrangements
      1%–2%Cabozantinib28% (n = 25)
      • Drilon A.
      • Rekhtman N.
      • Arcila M.
      • et al.
      Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.
      NCT01639508
      Vandetanib47% (n = 19)
      • Yoh K.
      • Seto T.
      • Satouchi M.
      • et al.
      Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
      UMIN10095 (Japan)
      Vandetanib17% (n = 18)
      • Lee S.-H.
      • Lee J.-K.
      • Ahn M.-J.
      • et al.
      A phase II study of vandetanib in patients with non-small cell lung cancer harboring RET rearrangement.
      NCT01823068
      Lenvatinib16% (n = 25)
      • Velcheti V.
      • Hida T.
      • Reckamp K.L.
      • et al.
      Phase 2 study of lenvatinib (LN) in patients (Pts) with RET fusion-positive adenocarcinoma of the lung.
      NCT01877083
      SunitinibNRNCT01829217
      ApatinibNRNCT02540824
      PonatinibNRNCT01813734
      AlectinibNRNCT02314481
      AlectinibNRUMIN20628 (Japan)
      Vandetanib + everolimus83% (n = 6)
      • Cascone T.
      • Subbiah V.
      • Hess K.R.
      • et al.
      Significant systemic and CNS activity of RET inhibitor vandetanib combined with mTOR inhibitor everolimus in patients with advanced NSCLC with RET fusion.
      NCT01582191
      ERBB2 (HER2)

      exon 20 mutations
      2%Dacomitinib12% (n = 26)
      • Kris M.G.
      • Camidge D.R.
      • Giaccone G.
      • et al.
      Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.
      NCT00818441
      Afatinib33% (n = 3)
      • Mazieres J.
      • Peters S.
      • Lepage B.
      • et al.
      Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.
      NCT02369484
      AfatinibNRNCT02465060
      Ado-trastuzumab emtansineNRNCT02675829
      Neratinib0% (n = 13)
      • Besse B.
      • Soria J.C.
      • Yao B.
      • et al.
      LBA39_PR. Neratinib (N) with or without temsirolimus (Tem) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: an international randomized phase II study.
      NCT01827267
      Neratinib + temsirolimus21% (n = 14)
      • Besse B.
      • Soria J.C.
      • Yao B.
      • et al.
      LBA39_PR. Neratinib (N) with or without temsirolimus (Tem) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: an international randomized phase II study.
      NCT01827267
      AP32788NRNCT02716116
      NTRK1/2/3

      rearrangements
      <1%EntrectinibNRNCT02568267
      EntrectinibNR
      • Farago A.F.
      • Le L.P.
      • Zheng Z.
      • et al.
      Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer.
      NCT02097810
      LarotrectinibNRNCT02122913
      LarotrectinibNRNCT02576431
      Plx7486NRNCT01804530
      Ds6051bNRNCT02279433
      AltiratinibNRNCT02228811
      SitravatinibNRNCT02219711
      CabozantinibNRNCT01639508
      MerestinibNRNCT02920996
      FGFR1/2/3

      mutations or rearrangements
      <1%AZD4547NRNCT02465060
      AZD4547NRNCT02154490
      AZD4547NRNCT02664935
      ErdafitinibNRNCT02699606
      LucitanibNRNCT02109016
      NintedanibNRNCT02299141
      BGJ398NRNCT02160041
      ORR, overall response rate; NCT No., ClinicalTrials.gov identifier; NR, not reported/ongoing trial; MET, MNNG HOS Transforming gene; RET, ret proto-oncogene; ERBB2, erb-b2 receptor tyrosine kinase 2 gene; NTRK1/2/3, neurotrophic receptor tyrosine kinase 1/2/3 gene; FGFR1/2/3, fibroblast growth factor receptor 1/2/3 gene.
      a Approved by European Union and FDA in 2017 and pending review for formal regulatory approval elsewhere.
      The genotype/inhibitor duo closest to receiving approval by the U.S. FDA and other worldwide regulatory agencies is the BRAF V600E mutation (found in ∼1% to 2% of adenocarcinomas) with dabrafenib plus trametinib, as the ORR of this BRAF plus MEK inhibitor combination is higher than 60% and is associated with prolonged disease control.
      • Hyman D.M.
      • Puzanov I.
      • Subbiah V.
      • et al.
      Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations.
      • Planchard D.
      • Kim T.M.
      • Mazieres J.
      • et al.
      Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial.
      • Planchard D.
      • Besse B.
      • Groen H.J.
      • et al.
      Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.
      • Nguyen-Ngoc T.
      • Bouchaab H.
      • Adjei A.A.
      • Peters S.
      BRAF alterations as therapeutic targets in non-small-cell lung cancer.
      The European Union approved the aforementioned combination in April 2017 and the FDA in June 2017.
      Another promising treatable target is MET proto-oncogene receptor tyrosine kinase, which is also known as hepatocyte growth factor receptor. MET can be activated as a primary oncogenic driver in NSCLC by two independent mechanisms: high-level MET gene amplification (in ∼1% of adenocarcinomas) and MET exon 14 alterations (in ∼3%–4% of adenocarcinomas and >10% of sarcomatoid carcinomas).
      • Reungwetwattana T.
      • Liang Y.
      • Zhu V.
      • Ou S.I.
      The race to target MET exon 14 skipping alterations in non-small cell lung cancer: the why, the how, the who, the unknown, and the inevitable.
      • Liu X.
      • Jia Y.
      • Stoopler M.B.
      • et al.
      Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations.
      • Collisson E.A.
      • Campbell J.D.
      • et al.
      Cancer Genome Atlas Research Network
      Comprehensive molecular profiling of lung adenocarcinoma.
      • Paik P.K.
      • Drilon A.
      • Fan P.D.
      • et al.
      Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.
      • Awad M.M.
      • Oxnard G.R.
      • Jackman D.M.
      • et al.
      MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression.
      • Jorge S.E.
      • Schulman S.
      • Freed J.A.
      • et al.
      Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation.
      • Heist R.S.
      • Shim H.S.
      • Gingipally S.
      • et al.
      MET exon 14 skipping in non-small cell lung cancer.
      Crizotinib, the U.S. FDA–approved ALK/ROS1/MET TKI, induces responses in close to half of patients with advanced cancers with MET alterations,
      • Drilon A.E.
      • Camidge D.R.
      • Ou S.-H.I.
      • et al.
      Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC).
      • Camidge D.R.
      • Ou S.-H.I.
      • Shapiro G.
      • et al.
      Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC).
      • Heist R.S.
      • Sequist L.V.
      • Borger D.
      • et al.
      Acquired resistance to crizotinib in NSCLC with MET exon 14 skipping.
      and there are ongoing clinical trials of multiple other multitargeted MET TKIs (see Table 3).
      The activity of TKI monotherapy in other subgroups of lung cancer is less clear.
      • Bunn Jr., P.A.
      Karnofsky Award 2016: a lung cancer journey, 1973 to 2016.
      • Shea M.
      • Costa D.B.
      • Rangachari D.
      Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches.
      The oncogene rearranged during transfection (RET) is seen in approximately 1% to 2% of patients with NSCLC; however, the ORR is less than 30% with the currently available multitargeted RET TKIs.
      • Drilon A.
      • Rekhtman N.
      • Arcila M.
      • et al.
      Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.
      • Yoh K.
      • Seto T.
      • Satouchi M.
      • et al.
      Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.
      • Lee S.-H.
      • Lee J.-K.
      • Ahn M.-J.
      • et al.
      A phase II study of vandetanib in patients with non-small cell lung cancer harboring RET rearrangement.
      • Velcheti V.
      • Hida T.
      • Reckamp K.L.
      • et al.
      Phase 2 study of lenvatinib (LN) in patients (Pts) with RET fusion-positive adenocarcinoma of the lung.
      • Drilon A.
      Targeted therapy outcomes in RET-rearranged lung cancers: drug or driver?.
      • Gautschi O.
      • Wolf J.
      • Milia J.
      • et al.
      Targeting RET in patients with RET-rearranged lung cancers: results from a global registry.
      ErbB2 receptor tyrosine kinase 2 (ERBB2 or HER2) exon 20 mutations occur in approximately 2% of lung adenocarcinomas. Currently available ERBB TKIs and monoclonal antibodies are minimally active and seldom reach an ORR higher than 20%.
      • Kris M.G.
      • Camidge D.R.
      • Giaccone G.
      • et al.
      Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.
      • Mazieres J.
      • Peters S.
      • Lepage B.
      • et al.
      Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.
      • Besse B.
      • Soria J.C.
      • Yao B.
      • et al.
      LBA39_PR. Neratinib (N) with or without temsirolimus (Tem) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations: an international randomized phase II study.
      • Costa D.B.
      • Jorge S.E.
      • Moran J.P.
      • et al.
      Pulse afatinib for ERBB2 exon 20 insertion-mutated lung adenocarcinomas.
      • Mazieres J.
      • Barlesi F.
      • Filleron T.
      • et al.
      Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort.
      More specific TKIs and rational combination approaches
      • Cascone T.
      • Subbiah V.
      • Hess K.R.
      • et al.
      Significant systemic and CNS activity of RET inhibitor vandetanib combined with mTOR inhibitor everolimus in patients with advanced NSCLC with RET fusion.
      may hold the promise of eventually leading to regulatory approval of precision therapies in these tumors (see Table 3).
      The drug development platform for driver oncogenes with a prevalence less than 1% in lung cancer, such as neurotrophic receptor tyrosine kinase (NTRK) or fibroblast growth factor receptor (FGFR) rearrangements,
      • Farago A.F.
      • Le L.P.
      • Zheng Z.
      • et al.
      Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer.
      • Amatu A.
      • Sartore-Bianchi A.
      • Siena S.
      NTRK gene fusions as novel targets of cancer therapy across multiple tumour types.
      • Desai A.
      • Adjei A.A.
      FGFR signaling as a target for lung cancer therapy.
      • Nogova L.
      • Sequist L.V.
      • Perez Garcia J.M.
      • et al.
      Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study.
      is more challenging (see Table 3) and may require large umbrella or basket trials that capture different molecular subgroups of lung cancer, such as Lung-MAP (NCT02154490) and the U.K. National Lung Matrix (NCT02664935), or that involve multiple cancer primaries binned by molecular alterations, such as NCI-MATCH (NCT02465060).
      • Abrams J.
      • Conley B.
      • Mooney M.
      • et al.
      National Cancer Institute's precision medicine initiatives for the new National Clinical Trials Network.

      Immunotherapy

      Section Authors: Leora Horn, MD, MSc, Scott Gettinger, MD, Solange Peters, MD, PhD
      In 2016 the first anti–PD-L1 antibody, atezolizumab, received approval as a second-line treatment option for patients with metastatic NSCLC that provides a significant improvement in OS compared with docetaxel (13.8 versus 9.6 months, HR = 0.73, p = 0.0003).
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • et al.
      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
      Contrary to the data on nivolumab in patients with nonsquamous NSCLC,
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      the data on atezolizumab demonstrated a significant benefit in patients with tumors that were negative for PD-L1 expression. However, this may be due to the differential sensitivity between the complimentary diagnostic antibody approved for atezolizumab (SP142) and both the companion diagnostic approved for pembrolizumab (22C3) and the complimentary diagnostic approved for nivolumab (28-8).
      • Hirsch F.R.
      • McElhinny A.
      • Stanforth D.
      • et al.
      PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project.
      Pembrolizumab became the first checkpoint inhibitor to be approved as a first-line treatment option for patients with newly diagnosed stage IV NSCLC, with a superior PFS (10.3 versus 6.0, HR = 0.50, p < 0.001), OS (HR = 0.60, p = 0.005), health-related QOL, and time to deterioration for dyspnea, cough, and chest pain compared with platinum-based chemotherapy in patients with tumors that were EGFR and ALK negative and strongly PD-L1–positive (≥50%).
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      • Brahmer J.R.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • et al.
      Health-related quality of life for pembrolizumab vs chemotherapy in advanced NSCLC with PD-L1 TPS ≥50%: data from KEYNOTE-024.
      A similarly designed study did not show efficacy when nivolumab was compared with chemotherapy; however, in this first-line study, patients with tumors expressing PD-L1 at a lower level of expression (>1% of tumor cells) were enrolled.
      • Socinski M.
      • Creelan B.
      • Horn L.
      • et al.
      NSCLC, metastaticCheckMate 026: a phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)−positive NSCLC.
      First-line avelumab demonstrated efficacy similar to that of currently approved agents, with a 21.2% RR and PFS of 4.2 months (95% CI: 2.8–5.6) in an unselected cohort of patients with NSCLC.
      • Jerusalem G.
      • Chen F.
      • Spigel D.
      • et al.
      JAVELIN solid tumor: safety and clinical activity of avelumab (anti-PD-L1) as first-line treatment in patients with advanced NSCLC.

      Benefit with EGFR/ALK Positivity

      The role of immunotherapy, and in particular, immune checkpoint inhibitors, in EGFR mutant and ALK-rearranged NSCLC, has yet to be determined. Retrospective subset analyses from several trials suggest lower rates of response to PD-1 axis inhibitors, without better outcome than standard second-line chemotherapy.
      • Lee C.K.
      • Man J.
      • Lord S.
      • et al.
      Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis.
      • Barlesi F.
      • Park K.
      • Ciardiello F.
      • et al.
      Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC.
      • Gainor J.F.
      • Shaw A.T.
      • Sequist L.V.
      • et al.
      EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.
      That said, some patients benefit from such therapy, as demonstrated in the CheckMate 012 trial. One arm of this trial, 20 patients with EGFR-mutant NSCLC and acquired resistance to EGFR TKI therapy as last therapy were treated with erlotinib and nivolumab; four experienced prolonged tumor regression.
      • Rizvi N.A.
      • Chow L.Q.M.
      • Borghaei H.
      • et al.
      Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC.
      Combination therapy was tolerated well; however, increased toxicity, particularly pneumonitis, has been suggested with other TKI and PD-L1 axis inhibitor combinations.
      • Ahn M.J.
      • Yang J.
      • Yu H.
      • et al.
      Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial.
      Additional arms on the CheckMate 012 trial evaluated combination therapy with nivolumab and ipilimumab; among eight patients with EGFR-mutant NSCLC, four achieved response.
      • Hellmann M.D.
      • Rizvi N.A.
      • Goldman J.W.
      • et al.
      Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.
      Less clinical information exists concerning ALK rearranged NSCLC, although preclinical studies suggest intrinsic PD-L1 upregulation in such tumors, and responsiveness to PD-1 axis inhibition.
      • Hong S.
      • Chen N.
      • Fang W.
      • et al.
      Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients.
      Currently, whether high tumor PD-L1 expression trumps EGFR or ALK status is uncertain. One retrospective analysis suggested this may not to be the case, with poor outcome with pembrolizumab among 19 patients with high PD-L1–expressing EGFR-mutant NSCLC.
      • Hui R.
      • Gandhi L.
      • Costa E.C.
      • et al.
      Long-term OS for patients with advanced NSCLC enrolled in the KEYNOTE-001 study of pembrolizumab (pembro).

      Immunotherapy: Novel Combinations and Future Directions

      Immune escape is a critical gateway to malignancy. Although the recent clinical developments in immunotherapy for lung cancer have improved the outcome of patients with metastatic disease, further improvements are still required. So what approaches can be taken to improve outcomes? Combination therapy with nivolumab, every 2 weeks, and ipilimumab, every 12 or 6 weeks, has demonstrated promising results with increasing response rates (RRs) compared with nivolumab alone, 47%, 38%, and 23%, respectively, and durable responses, albeit with a higher number of grade 3 and grade 4 adverse events.
      • Hellmann M.D.
      • Rizvi N.A.
      • Goldman J.W.
      • et al.
      Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.
      Combination strategies with both anti–PD-1 or anti–PD-L1 inhibitors and anti–cytotoxic T-lymphocyte associated protein 4 are being explored further in phase II and III clinical trials (NCT02477826, NCT02659059, NCT02542293, and NCT02453282). To further build on successes of the PD-1/PD-L1 blockade and take advantage of the multiple negative feedback mechanisms that regulate the adaptive immune response, numerous clinical trials of immunotherapy combinations are in progress. New modulatory monoclonal antibodies are currently being tested in phase I or II in NSCLC or solid tumors, including lymphocyte activation gene 3 (NCT01968109/NCT02460224), hepatitis A virus cellular receptor 2 (NCT02817633/NCT02608268), tumor necrosis factor superfamily member 4 (NCT02318394/NCT02410512), tumor necrosis factor receptor superfamily member 18 (NCT02583165/NCT02697591), and indoleamine 2,3-dioxygenase inhibitors (NCT02460367). Finally, a small phase II trial demonstrated superior RRs (55% versus 29%) and PFS times (median 13.0 months versus 8.9 months [HR = 0.53, 95% CI: 0.31–0.91, p = 0.0205]) for patients treated with pembrolizumab plus pemetrexed and carboplatin compared with chemotherapy alone, with a similar incidence of grade 3 or higher adverse events.
      • Langer C.J.
      • Gadgeel S.M.
      • Borghaei H.
      • et al.
      Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.
      This led to the U.S. FDA giving accelerated approval for pembrolizumab in combination with pemetrexed and carboplatin for the first-line treatment of metastatic nonsquamous NSCLC irrespective of PD-L1 expression. Multiple trials comparing this approach are ongoing.
      The second approach is designing studies that target specific defects in the cancer-immune interaction. Currently mutational burden,
      • Rizvi N.A.
      • Hellmann M.D.
      • Snyder A.
      • et al.
      Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
      tumor-infiltrating lymphocytes,
      • Brambilla E.
      • Le Teuff G.
      • Marguet S.
      • et al.
      Prognostic effect of tumor lymphocytic infiltration in resectable non-small-cell lung cancer.
      and high PD-L1
      • Grigg C.
      • Rizvi N.A.
      PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction?.
      expression in the tumor microenvironment are associated with sensitivity to immune checkpoint inhibition. Therefore, research efforts should be directed at mapping the state of the cancer immune interaction in a comprehensive manner.
      • Blank C.U.
      • Haanen J.B.
      • Ribas A.
      • Schumacher T.N.
      Cancer Immunology. The “cancer immunogram”.
      A third approach is to create publicly available, open source inventories of large numbers of tissue and blood samples from patients before initiation of immunotherapy and subject such samples to genomics (whole exome sequencing and RNA sequencing), multiplex IHC, flow cytometry, and proteomics analyses, with the results coupled to clinical outcomes. These studies will aid in the characterization of predictors of response and progression. On the basis of these signatures, clinical trials should be performed to test combinations that have been shown to overcome the specific defect in the cancer-immune interaction present in that particular patient population.
      Another approach is to treat in earlier disease stages with the aim of increasing cure rates. Early results from melanoma studies suggest that the general immune state of stage III disease patients is better than that of stage IV patients, resulting in a higher RR and more toxicities.
      • Blank C.U.
      • van Akkooi A.
      • Rozeman L.
      • et al.
      (Neo-)adjuvant ipilimumab + nivolumab (IPI + NIVO) in palpable stage 3 melanoma—the OpACIN trial. Society for Melanoma Research 2016 Congress [abstract].
      Interestingly, pathologic responses have also been observed after neoadjuvant anti–PD-1 in early NSCLC.
      • Forde P.M.
      • Smith K.N.
      • Chaft J.E.
      • et al.
      NSCLC, early stage neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small-cell lung cancer.
      Earlier-stage patients may require a shorter treatment duration than stage IV patients. Immunotherapy is being actively studied in the neoadjuvant (NCT02259621/NCT02998528) and the adjuvant (NCT02504372/NCT02273375) settings in NSCLC.
      Finally, as pricing of new immuno-oncology drugs is unlikely to change soon, the aforementioned future directions will certainly lead to a much more cost-effective utilization of our resources, as chances for best outcome will be optimal.

      SCLC

      Section Authors: Corinne Faivre-Finn, MD, PhD, Charles M. Rudin, MD, PhD

      RT for SCLC

      The optimal timing and schedule of thoracic radiation in the management of limited-stage (LS) SCLC continues to provoke debate. Since the publication of Intergroup 0096 in 1999, there has been controversy about the standard chemoradiotherapy regimen in LS disease.
      • Turrisi 3rd, A.T.
      • Kim K.
      • Blum R.
      • et al.
      Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.
      • Komaki R.
      • Khalid N.
      • Langer C.J.
      • et al.
      Penetration of recommended procedures for lung cancer staging and management in the United States over 10 years: a quality research in radiation oncology survey.
      At the American Society of Clinical Oncology 2016 annual meeting, the CONVERT trial was presented.

      Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial [e-pub ahead of print]. Lancet Oncol, accessed July 8, 2017.

      This multicenter, international, randomized, phase III trial aimed to establish a standard chemoradiotherapy regimen in LS SCLC. Patients were randomized 1:1 to receive either 45 Gy in 30 twice-daily fractions over 3 weeks or 66 Gy in 33 once-daily fractions over 6.5 weeks starting on day 22 of cycle 1 of chemotherapy, followed by prophylactic cranial irradiation. The study enrolled 547 patients, who were recruited from 73 centers in seven European countries and Canada between 2008 and 2013. Once-daily RT did not result in superior survival or worse toxicity than twice-daily RT (2-year survival of 56% compared with 51% [HR for death in the once-daily group = 1.18, p = 0.14]). The survival for both regimens was higher than previously reported and radiation toxicities were lower than expected, likely because of the use of modern RT techniques. The implications of CONVERT are important. As CONVERT was not an equivalence trial and because the only study to date that has shown superiority for one RT regimen over another in LS SCLC is the Intergroup 0096 trial (which showed no major differences in toxicity), twice-daily RT should continue to be regarded as the standard of care. However, once-daily RT at a dose of 66 Gy in 33 fractions can certainly be considered an alternative regimen if 45 Gy in 30 fractions twice daily cannot be delivered because of patient choice, departmental logistics, or other factors. Given the importance of keeping the overall treatment time short, future studies could investigate dose-escalated twice-daily or hypofractionated RT concurrently with chemotherapy.
      For patients with extensive-stage SCLC with residual intrathoracic disease who have responded after induction chemotherapy, addition of thoracic RT reduces the risk for intrathoracic recurrence and improves 2-year survival
      • Slotman B.J.
      • van Tinteren H.
      • Praag J.O.
      • et al.
      Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial.
      ; however, the primary end point of 1-year survival was not met. A survey of routine practice presented at the European Society for Radiotherapy and Oncology 2016 conference showed that since publication of the CREST trial there has been a dramatic increase in the use of TRT (from 25% to 81%).
      • Haslett K.
      • De Ruysscher D.
      • Dziadziuszko R.
      • et al.
      OC-0140: management of patients with extensive-stage small-cell lung cancer: a European survey of practice.
      Subsequently, a subanalysis of CREST investigating the prognostic importance of the number and sites of metastases was presented at the ASTRO 2016 annual meeting.
      • Slotman B.J.
      • Faivre-Finn C.
      • van Tinteren H.
      • et al.
      Identifying patients with extensive-stage small cell lung cancer (ES-SCLC) most likely to benefit from intensive radiation therapy.
      It suggested that future studies evaluating more intensive thoracic and extrathoracic RT in extensive-stage SCLC focus on patients with fewer than three metastases that are not in the liver or bone.

      Advances in Novel Systemic Therapies for SCLC

      Several new approaches to systemic treatment of SCLC have recently emerged and have been the subject of recent reviews.
      • Bunn Jr., P.A.
      • Minna J.D.
      • Augustyn A.
      • et al.
      Small cell lung cancer: can recent advances in biology and molecular biology be translated into improved outcomes?.
      • Rudin C.M.
      • Poirier J.T.
      Small-cell lung cancer in 2016: shining light on novel targets and therapies.
      These will be touched on here only briefly, but they include combination immunotherapy approaches that have shown substantial efficacy in other diseases, as well as a novel antibody drug conjugate against a cell surface determinant, DLL3, which is relatively unique to SCLC.
      In the immunotherapy domain, several of the same PD-1–directed T-cell checkpoint inhibitors already discussed in relation to NSCLC, including both pembrolizumab and nivolumab, have demonstrated initial activity in SCLC.
      • Antonia S.J.
      • Lopez-Martin J.A.
      • Bendell J.
      • et al.
      Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.
      • Ott P.
      • Felip E.
      • Hiret S.
      • et al.
      Pembrolizumab in patients with extensive-stage small cell lung cancer: updated survival results from KEYNOTE-028.
      Early data with the combination of nivolumab plus ipilimumab appear particularly promising. In a 216-patient randomized phase II study of nivolumab versus various schedules of nivolumab and ipilimumab, the combination arms demonstrated RRs of 19% to 23% and DCRs of 36% to 42%.
      • Antonia S.J.
      • Lopez-Martin J.A.
      • Bendell J.
      • et al.
      Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.
      The toxicities observed were similar to those reported in other diseases. On the basis of these data, the combination of nivolumab and ipilimumab has been included as a treatment option for recurrent SCLC in the most recent National Comprehensive Cancer Network treatment guidelines for SCLC, and confirmatory trials are ongoing.
      DLL3 is an inhibitory Notch ligand that is normally confined to intracellular compartments but is markedly up-regulated and becomes aberrantly cell surface–expressed in most SCLC.
      • Saunders L.R.
      • Bankovich A.J.
      • Anderson W.C.
      • et al.
      A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
      Rovalpituzumab teserine, or Rova-T, is an antibody drug conjugate directed against DLL3 that demonstrated remarkable preclinical efficacy against SCLC in vivo
      • Saunders L.R.
      • Bankovich A.J.
      • Anderson W.C.
      • et al.
      A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
      and promising activity in a first-in-human phase I clinical trial in patients with recurrent metastatic SCLC.
      • Rudin C.M.
      • Pietanza M.C.
      • Bauer T.M.
      • et al.
      Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.
      Early data suggest that high-level expression of the target, DLL3, may serve as a predictive biomarker for the activity of this agent, as a 38% RR (10 of 26) and DCR of 88% (23 of 26) were observed in two-thirds of patients with DLL3 expressed in more than 50% of the cells. Larger confirmatory trials of Rova-T in SCLC are ongoing.

      Mesothelioma

      Section Authors: Anne Tsao, MD, Paul Baas, MD, PhD
      In the past year, the field of mesothelioma treatment has seen a dramatic increase in therapeutic clinical trials. Several basket trials in immunotherapy with mesothelioma cohorts have reported on the preliminary results of monotherapy PD-1/PD-L1 inhibitors (Table 4).
      • Alley E.
      • Lopez J.
      • Santoro A.
      • et al.
      Long-term overall survival for patients with malignant pleural mesothelioma on pembrolizumab enrolled in KEYNOTE-028.
      • Kindler H.
      • Karrison T.
      • Carol Tan Y.-H.
      • et al.
      Phase II trial of pembrolizumab in patients with malignant mesothelioma (MM): interim analysis.
      • Quispel-Janssen J.
      • Zago G.
      • Schouten R.
      • et al.
      A phase II study of nivolumab in malignant pleural mesothelioma (nivomes): with translational research (TR) biopies.
      • Hassan R.
      • Thomas A.
      • Patel M.R.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity, and PD-L1 expression.
      In general, the reported RRs vary between 9% and 28%, with DCRs of 50% to 77% in unselected patients with mesothelioma. As in NSCLC, checkpoint inhibitors seem to be more active in PD-L1 IHC–positive patients, but the association is not strong. Unfortunately, the cytotoxic T-lymphocyte associated protein inhibitor tremelimumab did not show any benefit over placebo in the DETERMINE trial (NCT01843374).
      • Kindler H.L.
      • Scherpereel A.
      • Calabrò L.
      • et al.
      Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): results from the global, double-blind, placebo-controlled DETERMINE study.
      Although there is a preliminary modest signal with PD-1/PD-L1 inhibitors, there is still a critical need to understand the biology and develop novel combination therapies. Combination regimens such as ipilimumab-nivolumab and platinum-pemetrexed combinations with PD-1/PD-L1 inhibitors are being investigated in the frontline and salvage settings (Table 5). Other approaches encompass neoadjuvant trials with atezolizumab or adjuvant trials with a Wilms’ tumor 1 vaccine, galinpepimut-S.
      • Zauderer M.G.
      • Dao T.
      • Rusch V.W.
      • et al.
      Randomized phase II study of adjuvant WT1 vaccine (SLS-001) for malignant pleural mesothelioma (MPM) after multimodality therapy.
      Table 4Selected Monotherapy Immunotherapy Trials and Preliminary Reported Results
      AgentNCT No.TypeSettingORRDCRPFSOSPD-L1 IHC status
      Pembrolizumab (KEYNOTE-028)
      • Alley E.
      • Lopez J.
      • Santoro A.
      • et al.
      Long-term overall survival for patients with malignant pleural mesothelioma on pembrolizumab enrolled in KEYNOTE-028.
      02054806PD-1 inhibitorSecond line28%76%5.8 mo18 moAll patients were PD-L1 IHC–positive
      Pembrolizumab
      • Kindler H.
      • Karrison T.
      • Carol Tan Y.-H.
      • et al.
      Phase II trial of pembrolizumab in patients with malignant mesothelioma (MM): interim analysis.
      02399371PD-1 inhibitorSecond line21%77%6.2 moNRDid not correlate with response
      Nivolumab (NivoMes trial)
      • Quispel-Janssen J.
      • Zago G.
      • Schouten R.
      • et al.
      A phase II study of nivolumab in malignant pleural mesothelioma (nivomes): with translational research (TR) biopies.
      02497508PD-1 inhibitor1 prior therapy24%50%3.6 moNRTrend for a correlations with OR
      Avelumab (JAVELIN)
      • Hassan R.
      • Thomas A.
      • Patel M.R.
      • et al.
      Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity, and PD-L1 expression.
      01772004PD-L1 inhibitorSalvage, any line9.4%57%4.3 moNRTrend to correlate with median PFS
      NCT No., ClinicalTrials.gov identifier; ORR, overall response rate; DCR, disease control rate; PFS, progression-free s