Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: D. Planchard, S. Popat, K. Kerr, S. Novello, E.F. Smit, C. Faivre-Finn, T.S. Mok, M. Reck, P.E. Van Schil, M.D. Hellmann, S. Peters
Journal: Annals of Oncology (2018)

Primary lung cancer remains the most common malignancy after non-melanocytic skin cancer, and deaths from lung cancer exceed those from any other malignancy worldwide [1.IARC. Cancer Incidence, Mortality and Prevalence Worldwide GLOBOCAN 2012. http://gco.iarc.fr/Google Scholar]. In 2012, lung cancer was the most frequently diagnosed cancer in males with an estimated 1.2 million incident cases worldwide. Among females, lung cancer was the leading cause of cancer death in more developed countries and the second leading cause of cancer death in less developed countries [1.IARC. Cancer Incidence, Mortality and Prevalence Worldwide GLOBOCAN 2012. http://gco.iarc.fr/Google Scholar]. The highest incidence is found in Central/Eastern Europe and Asia with age-standardised incidence rates of 53.5 and 50.4 per 100 000, respectively. European projections for 2017 indicate a 10.7% drop in 5 years with an incidence of 33.3/100 000 in males and a rise of 5.1% and an incidence of 14.6/100 000 in females [2.Malvezzi M. Carioli G. Bertuccio P. et al.European cancer mortality predictions for the year 2017, with focus on lung cancer.Ann Oncol. 2017; 28: 1117-1123Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar]. Contrary to the United States, the death rate in females is increasing in Europe [3.Jemal A. Ward E.M. Johnson C.J. et al.Annual Report to the Nation on the Status of Cancer, 1975-2014, Featuring Survival.J Natl Cancer Inst. 2017; 109 (djx 0130)Crossref Scopus (592) Google Scholar]. The number of lung cancer-related deaths in Europe for 2017 is estimated to represent the leading cause of cancer deaths in both genders, accounting for 24% in males and 15% in females, respectively [2.Malvezzi M. Carioli G. Bertuccio P. et al.European cancer mortality predictions for the year 2017, with focus on lung cancer.Ann Oncol. 2017; 28: 1117-1123Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar]. Non-small cell lung cancer (NSCLC) accounts for 80%–90% of lung cancers, while small cell lung cancer (SCLC) has been decreasing in frequency in many countries over the past two decades [4.Jemal A. Bray F. Center M.M. et al.Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90Crossref PubMed Scopus (28678) Google Scholar]. During the last 25 years, the distribution of histological types of NSCLC has changed: in the United States, squamous cell carcinoma (SCC), formerly the predominant histotype, decreased, while adenocarcinoma has increased in both genders. In Europe, similar trends have occurred in men, while in women, both SCC and adenocarcinoma are still increasing [5.Forman D. Bray F. Brewster D. Cancer Incidence in Five Continents. IARC Press, Lyon2013Google Scholar]. The World Health Organization (WHO) estimates that lung cancer is the cause of 1.59 million deaths globally per year, with 71% of them caused by smoking. Tobacco smoking remains the main cause of lung cancer and the geographical and temporal patterns of the disease largely reflect tobacco consumption during the previous decades. Both smoking prevention and smoking cessation can lead to a reduction in a large fraction of lung cancers [6.Ordonez-Mena J.M. Schottker B. Mons U. et al.Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium.BMC Med. 2016; 14: 62Crossref PubMed Google Scholar]. In countries with active tobacco control measures, the incidence of lung cancer has begun to decline in men and is reaching a plateau for women [1.IARC. Cancer Incidence, Mortality and Prevalence Worldwide GLOBOCAN 2012. http://gco.iarc.fr/Google Scholar, 7.Malvezzi M. Bertuccio P. Levi F. et al.European cancer mortality predictions for the year 2013.Ann Oncol. 2013; 24: 792-800Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 8.Jemal A. Ma J. Rosenberg P.S. et al.Increasing lung cancer death rates among young women in southern and midwestern States.J Clin Oncol. 2012; 30: 2739-2744Crossref PubMed Scopus (55) Google Scholar, 9.Hashim D. Boffetta P. La Vecchia C. et al.The global decrease in cancer mortality: trends and disparities.Ann Oncol. 2016; 27: 926-933Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar]. Several other factors have been described as lung cancer risk factors, including exposure to asbestos, arsenic, radon and non-tobacco-related polycyclic aromatic hydrocarbons. Hypotheses about indoor air pollution (e.g. coal-fuelled stoves and cooking fumes) are made for the relatively high burden of non-smoking-related lung cancer in women in some countries [10.Malhotra J. Malvezzi M. Negri E. et al.Risk factors for lung cancer worldwide.Eur Respir J. 2016; 48: 889-902Crossref PubMed Google Scholar]. There is evidence that lung cancer rates are higher in cities than in rural settings but many confounding factors other than outdoor air pollution may be responsible for this pattern. About 500 000 deaths annually are attributed to lung cancer in lifetime never-smokers [1.IARC. Cancer Incidence, Mortality and Prevalence Worldwide GLOBOCAN 2012. http://gco.iarc.fr/Google Scholar]. Absence of any history of tobacco smoking characterises 19% of female compared with 9% of male lung carcinoma in the United States [11.Novello S. Stabile L. Siegfried J. Gender-related Differences in Lung Cancer. The IASLC Multidisciplinary Approach to Thoracic Oncology. IASLC Press, Aurora, CO2014Google Scholar, 12.McCarthy W. Meza R. Jeon J. Moolgavkar S. Chapter 6: Lung cancer in never smokers: epidemiology and risk prediction models.Risk Anal. 2012; 32: S69.Crossref PubMed Scopus (0) Google Scholar]. An increase in the proportion of NSCLC in never-smokers has been observed, especially in Asian countries [13.Toh C.K. Gao F. Lim W.T. et al.Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity.J Clin Oncol. 2006; 24: 2245-2251Crossref PubMed Scopus (271) Google Scholar]. These new epidemiological data have resulted in ‘non-smoking-associated lung cancer’ being considered a distinct disease entity, where specific molecular and genetic tumour characteristics have been identified [14.Couraud S. Souquet P.J. Paris C. et al.BioCAST/IFCT-1002: epidemiological and molecular features of lung cancer in never-smokers.Eur Respir J. 2015; 45: 1403-1414Crossref PubMed Scopus (40) Google Scholar]. Use of non-cigarette tobacco products such as cigars and pipes has been increasing. A pooled analysis highlighted the increased risk, particularly for lung and head and neck cancers, in smokers (former and current) of cigars and pipes [15.Malhotra J. Borron C. Freedman N.D. et al.Association between Cigar or pipe smoking and cancer risk in men: a pooled analysis of five Cohort studies.Cancer Prev Res (Phila). 2017; 10: 704-709Crossref PubMed Scopus (0) Google Scholar]. Familial risk of lung cancer has been reported in several registry-based studies after careful adjustment for smoking [16.Lorenzo Bermejo J. Hemminki K. Familial lung cancer and aggregation of smoking habits: a simulation of the effect of shared environmental factors on the familial risk of cancer.Cancer Epidemiol Biomarkers Prev. 2005; 14: 1738-1740Crossref PubMed Scopus (0) Google Scholar]. A recent study estimated the heritability of lung cancer at 18% but many of the genetic components remain unidentified. Genome-wide association studies (GWAS) have identified lung cancer susceptibility loci including CHRNA3, CHRNA5, TERT, BRCA2, CHECK2 and the human leukocyte antigen (HLA) region [17.Mucci L.A. Hjelmborg J.B. Harris J.R. et al.Familial risk and heritability of cancer among twins in Nordic Countries.JAMA. 2016; 315: 68-76Crossref PubMed Scopus (301) Google Scholar, 18.Timofeeva M.N. Hung R.J. Rafnar T. et al.Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.Hum Mol Genet. 2012; 21: 4980-4995Crossref PubMed Scopus (147) Google Scholar, 19.Wang Y. McKay J.D. Rafnar T. et al.Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer.Nat Genet. 2014; 46: 736-741Crossref PubMed Scopus (179) Google Scholar]. Another trial, including data from 29 266 cases and 56 450 controls from European descent, found 18 susceptibility loci reaching genome-wide significance, among which 10 were previously unknown. Interestingly, while four of the latter were associated with overall lung cancer risk, six were associated with lung adenocarcinoma only [20.McKay J.D. Hung R.J. Han Y. et al.Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017; 49: 1126-1132Crossref PubMed Scopus (160) Google Scholar]. Changes in the therapeutic scenario in the last 15 years have emphasised the need for a multidisciplinary approach in lung cancer. Data show that high-volume centres and multidisciplinary teams are more efficient at managing patients with lung cancer than low-volume or non-multidisciplinary centres, by providing more complete staging, better adherence to guidelines and increased survival [21.Freeman R.K. Van Woerkom J.M. Vyverberg A. Ascioti A.J. The effect of a multidisciplinary thoracic malignancy conference on the treatment of patients with lung cancer.Eur J Cardiothorac Surg. 2010; 38: 1-5Crossref PubMed Scopus (76) Google Scholar, 22.Forrest L.M. McMillan D.C. McArdle C.S. Dunlop D.J. An evaluation of the impact of a multidisciplinary team, in a single centre, on treatment and survival in patients with inoperable non-small-cell lung cancer.Br J Cancer. 2005; 93: 977-978Crossref PubMed Scopus (148) Google Scholar]. Multidisciplinary tumour boards influence providers’ initial plans in 26%–40% of cases [23.Schmidt H.M. Roberts J.M. Bodnar A.M. et al.Thoracic multidisciplinary tumor board routinely impacts therapeutic plans in patients with lung and esophageal cancer: a prospective cohort study.Ann Thorac Surg. 2015; 99: 1719-1724Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. The absolute need to reach a proper and precise morphological and biological definition often requires challenging tissue sampling, with most treatment decisions depending on the information obtained from the specimen collected at diagnosis. Bronchoscopy is a technique ideally suited to large, central lesions and offers the advantage of minimal morbidity. Bronchoscopy can be used for bronchial washing, brushing, bronchial and transbronchial biopsy, with a diagnostic yield of 65%–88% [24.Ost D.E. Ernst A. Lei X. et al.Diagnostic yield and complications of bronchoscopy for peripheral lung lesions. Results of the AQuIRE Registry.Am J Respir Crit Care Med. 2016; 193: 68-77Crossref PubMed Google Scholar, 25.Rivera M.P. Mehta A.C. Wahidi M.M. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e142S-e165SAbstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 26.van der Drift M.A. van der Wilt G.J. Thunnissen F.B. Janssen J.P. A prospective study of the timing and cost-effectiveness of bronchial washing during bronchoscopy for pulmonary malignant tumors.Chest. 2005; 128: 394-400Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. By combining direct bronchoscopic airway visualisation with ultrasound-guided biopsy of the lesion, endobronchial ultrasound (EBUS) provides a diagnostic yield of 75%–85% in large, centrally located lesions [27.Herth F. Becker H.D. Ernst A. Conventional vs endobronchial ultrasound-guided transbronchial needle aspiration: a randomized trial.Chest. 2004; 125: 322-325Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 28.Paone G. Nicastri E. Lucantoni G. et al.Endobronchial ultrasound-driven biopsy in the diagnosis of peripheral lung lesions.Chest. 2005; 128: 3551-3557Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. Fibre optic bronchoscopy allows for the evaluation of regional lymph nodes by EBUS and/or endoscopic ultrasound (EUS). EBUS-guided transbronchial needle aspiration (TBNA) is less invasive and at least as accurate as mediastinoscopy [29.Adams K. Shah P.L. Edmonds L. Lim E. Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis.Thorax. 2009; 64: 757-762Crossref PubMed Scopus (291) Google Scholar]. Several studies have shown that cytological specimens obtained by EBUS-TBNA are suitable for molecular testing for epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homologue (KRAS) and anaplastic lymphoma kinase (ALK) status [30.Nakajima T. Kimura H. Takeuchi K. et al.Treatment of lung cancer with an ALK inhibitor after EML4-ALK fusion gene detection using endobronchial ultrasound-guided transbronchial needle aspiration.J Thorac Oncol. 2010; 5: 2041-2043Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 31.Nakajima T. Yasufuku K. Nakagawara A. et al.Multigene mutation analysis of metastatic lymph nodes in non-small cell lung cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration.Chest. 2011; 140: 1319-1324Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 32.Rekhtman N. Brandt S.M. Sigel C.S. et al.Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing.J Thorac Oncol. 2011; 6: 451-458Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 33.Sakairi Y. Nakajima T. Yasufuku K. et al.EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration.Clin Cancer Res. 2010; 16: 4938-4945Crossref PubMed Scopus (140) Google Scholar]; however, collection of samples suitable for broader molecular diagnostic testing should be encouraged. In case of peripheral lesions, transthoracic percutaneous fine needle aspiration and/or core biopsy, under imaging guidance [typically computed tomography (CT)] is proposed [34.Chan E.Y. Gaur P. Ge Y. et al.Management of the solitary pulmonary nodule.Arch Pathol Lab Med. 2017; 141: 927-931Crossref PubMed Scopus (8) Google Scholar]. Needle biopsy is associated with a diagnostic accuracy of > 88% yield, a sensitivity of 90% and a false-negative rate of 22% [25.Rivera M.P. Mehta A.C. Wahidi M.M. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: e142S-e165SAbstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 35.Choi S.H. Chae E.J. Kim J.E. et al.Percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center.AJR Am J Roentgenol. 2013; 201: 964-970Crossref PubMed Scopus (0) Google Scholar, 36.Fontaine-Delaruelle C. Souquet P.J. Gamondes D. et al.Negative predictive value of transthoracic core-needle biopsy: a multicenter study.Chest. 2015; 148: 472-480Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 37.Lee S.M. Park C.M. Lee K.H. et al.C-arm cone-beam CT-guided percutaneous transthoracic needle biopsy of lung nodules: clinical experience in 1108 patients.Radiology. 2014; 271: 291-300Crossref PubMed Scopus (118) Google Scholar, 38.Takeshita J. Masago K. Kato R. et al.CT-guided fine-needle aspiration and core needle biopsies of pulmonary lesions: a single-center experience with 750 biopsies in Japan.AJR Am J Roentgenol. 2015; 204: 29-34Crossref PubMed Scopus (43) Google Scholar]. The most significant disadvantage of transthoracic needle biopsy is a procedural risk of pneumothorax, ranging from 17% to 50% [37.Lee S.M. Park C.M. Lee K.H. et al.C-arm cone-beam CT-guided percutaneous transthoracic needle biopsy of lung nodules: clinical experience in 1108 patients.Radiology. 2014; 271: 291-300Crossref PubMed Scopus (118) Google Scholar, 38.Takeshita J. Masago K. Kato R. et al.CT-guided fine-needle aspiration and core needle biopsies of pulmonary lesions: a single-center experience with 750 biopsies in Japan.AJR Am J Roentgenol. 2015; 204: 29-34Crossref PubMed Scopus (43) Google Scholar]. In the presence of a pleural effusion, thoracentesis could represent both a diagnostic tool and a palliative treatment. If fluid cytology examination is negative, image-guided pleural biopsy or surgical thoracoscopy should be carried out. More invasive, surgical approaches [mediastinoscopy, mediastinotomy, thoracoscopy, video-assisted thorascopic surgery (VATS), secondary lesion resection etc.] in the diagnostic workup are considered when the previously described techniques cannot allow for an accurate diagnosis. Histological diagnosis of NSCLC is crucial to many treatment decisions and should be as exact and detailed as the samples and available technology allow. Diagnosis should be based upon the criteria laid out in the WHO classification [39.Travis W.D. Brambilla E. Burke A.P. et al.WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.4th edition. IARC Press, Lyon, France2015Google Scholar]. This classification details the complete diagnostic approach for surgically resected tumours but, importantly, also provides guidance for assessing and reporting small biopsy and cytology samples where complete morphological criteria for specific diagnosis may not be met [39.Travis W.D. Brambilla E. Burke A.P. et al.WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.4th edition. IARC Press, Lyon, France2015Google Scholar, 40.Travis W.D. Brambilla E. Noguchi M. et al.Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification.Arch Pathol Lab Med. 2013; 137: 668-684Crossref PubMed Scopus (251) Google Scholar, 41.Travis W.D. Brambilla E. Noguchi M. et al.International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.J Thorac Oncol. 2011; 6: 244-285Abstract Full Text Full Text PDF PubMed Scopus (3131) Google Scholar]. Most patients with NSCLC present with advanced stage unresectable disease, therefore all treatment-determining diagnoses must be made on small biopsy and/or cytology-type samples. Sampling may be carried out of the primary tumour or any accessible metastases, taken under direct vision or more usually with image-guided assistance, which greatly increases the diagnostic yield (hit rate). Sampling metastatic disease may facilitate staging, as well as diagnosis. These diagnostic samples frequently have limited tumour material and must therefore be handled accordingly; ensuring processing is suitable for all likely diagnostic procedures and that material is used sparingly at each step, since many diagnostic tests may be required [42.Dietel M. Bubendorf L. Dingemans A.M. et al.Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group.Thorax. 2016; 71: 177-184Crossref PubMed Scopus (89) Google Scholar]. Immunohistochemistry (IHC) has become a key technique in primary diagnosis as well as in predictive biomarker assessment. In those cases of NSCLC where specific subtyping is not possible by morphology alone, a limited panel of IHC is recommended to determine the subtype [39.Travis W.D. Brambilla E. Burke A.P. et al.WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.4th edition. IARC Press, Lyon, France2015Google Scholar, 40.Travis W.D. Brambilla E. Noguchi M. et al.Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification.Arch Pathol Lab Med. 2013; 137: 668-684Crossref PubMed Scopus (251) Google Scholar]. Thyroid transcription factor 1 (TTF1) positivity is associated with probable diagnosis of adenocarcinoma, p40 positivity with probable diagnosis of SCC; if neither are positive the diagnosis remains NSCLC-not otherwise specified (NOS). IHC staining should be used to reduce the NSCLC-NOS rate to < 10% of cases diagnosed [IV, A]. Pathologists are urged to conserve tissue at every stage of diagnosis, to use only two tissue sections for IHC NSCLC subtyping and to avoid excessive IHC investigation, which may not be clinically relevant. After morphological diagnosis, the next consideration is therapy-predictive biomarker testing. This practice will be driven by the availability of treatments and will vary widely between different geopolitical health systems [43.Lindeman N.I. Cagle P.T. Beasley M.B. et al.Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.J Thorac Oncol. 2013; 8: 823-859Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar, 44.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 45.Lindeman N. Cagle P. Aisner D. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.Arch Pathol Lab Med. 2018; 142: 321-346Crossref PubMed Scopus (257) Google Scholar]. Contemporary practice has now evolved into two testing streams, one for the detection of targetable, usually addictive, oncogenic alterations and the other for immuno-oncology therapy biomarker testing. A personalised medicine synopsis table is shown in Table 1.Table 1A personalised medicine synopsis table for metastatic NSCLCBiomarkerMethodUseLoE, GoREGFR mutationAny appropriate, validated method, subject to external quality assuranceTo select those patients with EGFR-sensitising mutations most likely to respond to EGFR TKI therapyI, AALK rearrangementAny appropriate, validated method, subject to external quality assurance. FISH is the historical standard but IHC is now becoming the primary therapy-determining test, provided the method is validated against FISH or some other orthogonal test approach. NGS is an emerging technologyTo select those patients with ALK gene rearrangements most likely to respond to ALK TKI therapyI, AROS1 rearrangementFISH is the trial-validated standard. IHC may be used to select patients for confirmatory FISH testing but currently lacks specificity. NGS is an emerging technology. External quality assurance is essentialTo select those patients with ROS1 gene rearrangements most likely to respond to ROS1 TKI therapyII, ABRAF mutationAny appropriate, validated method, subject to external quality assuranceTo select those patients with BRAF V600-sensitising mutations most likely to respond to BRAF inhibitor, with or without MEK inhibitor therapyII, APD-L1 expressionIHC to identify PD-L1 expression at the appropriate level and on the appropriate cell population(s) as determined by the intended drug and line of therapy. Only specific trial assays are validated. Internal and external quality assurance are essentialTo enrich for those patients more likely to benefit from anti-PD-1 or anti-PD-L1 therapy. For pembrolizumab, testing is a companion diagnostic for nivolumab and atezolizumab, testing is complementaryI, AALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridisation; GoR, grade of recommendation; IHC, immunohistochemistry; LoE, level of evidence; MEK, mitogen-activated protein kinase kinase; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor. Open table in a new tab ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridisation; GoR, grade of recommendation; IHC, immunohistochemistry; LoE, level of evidence; MEK, mitogen-activated protein kinase kinase; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor. Several molecular drivers for oncogene addiction represent strong predictive biomarkers and excellent therapeutic targets. They are generally mutually exclusive of each other [43.Lindeman N.I. Cagle P.T. Beasley M.B. et al.Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.J Thorac Oncol. 2013; 8: 823-859Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar, 44.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 45.Lindeman N. Cagle P. Aisner D. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.Arch Pathol Lab Med. 2018; 142: 321-346Crossref PubMed Scopus (257) Google Scholar]. These tumours are much more common in never- (never smoked or who smoked < 100 cigarettes in lifetime), long-time ex- (> 10 years) or light-smokers (< 15 pack-years) but they can also be found in patients who smoke. The vast majority of oncogene-addicted lung cancers are adenocarcinomas. Patients, in general, tend to be younger, while female gender and East Asian ethnicity particularly enriches for EGFR-mutant tumours. Nonetheless, guidelines suggest that all patients with advanced, possible, probable or definite, adenocarcinoma should be tested for oncogenic drivers [43.Lindeman N.I. Cagle P.T. Beasley M.B. et al.Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.J Thorac Oncol. 2013; 8: 823-859Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar, 44.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 45.Lindeman N. Cagle P. Aisner D. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.Arch Pathol Lab Med. 2018; 142: 321-346Crossref PubMed Scopus (257) Google Scholar, 46.Kalemkerian G.P. Narula N. Kennedy E.B. et al.Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update.J Clin Oncol. 2018; 36: 911-919PubMed Google Scholar]. Molecular testing is not recommended in SCC, except in those rare circumstances when SCC is found in a never-, long-time ex- or light-smoker (< 15 pack-years) [IV, A]. Testing for EGFR mutations and rearrangements involving the ALK and ROS1 genes are now considered mandatory in most European countries. BRAF V600E mutations are rapidly approaching this status as first-line BRAF/MEK inhibitors are more widely approved, while HER2 (human epidermal growth factor receptor 2) and MET exon 14 mutations and fusion genes involving RET and NTRK1 (neurotropic tropomyosin receptor kinase 1) are evolving targets/biomarkers [43.Lindeman N.I. Cagle P.T. Beasley M.B. et al.Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.J Thorac Oncol. 2013; 8: 823-859Abstract Full Text Full Text PDF PubMed Scopus (588) Google Scholar, 44.Kerr K.M. Bubendorf L. Edelman M.J. et al.Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer.Ann Oncol. 2014; 25: 1681-1690Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 45.Lindeman N. Cagle P. Aisner D. et al.Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the