Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing non-oncogene-addicted mNSCLC.•ESMO-MCBS scores are given to describe the levels of evidence for treatment choices.•ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies.•Recommendations are based on available scientific data and the authors’ collective expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach. Details on incidence and epidemiology are covered in the Supplementary Material Section 1, available at https://doi.org/10.1016/j.annonc.2022.12.013. Details on diagnostic procedures are covered in the Supplementary Material Section 2, available at https://doi.org/10.1016/j.annonc.2022.12.013. Diagnosis of tumour type allows prognostication and triage for biomarker testing (see the Supplementary Material Section 3 and Supplementary Figure S1, available at https://doi.org/10.1016/j.annonc.2022.12.013). In stage IV lung cancer, usually only small biopsy and/or cytology samples are available, more frequently from sites within the thorax, and usually acquired through endoscopy or facilitated by imaging. Lung cancer may be diagnosed at various metastatic sites. Systematic collaboration and frequent communication between pathologists and interventionalists are recommended to maximise diagnostic yield of samples, e.g. rapid onsite evaluation of samples. Pathological diagnosis and subtyping are carried out according to the World Health Organization (WHO) guidelines (2021).1The World Health Organisation Classification of Thoracic Tumours5th ed. WHO Classification of Tumours Editorial Board 2021. Vol 5. IARC Press, Lyon2021Google Scholar Terminology specifically for use when diagnosing small samples is given in Table 1. Biopsy site, clinical information and tumour morphology should allow for primary lung cancer to be appropriately diagnosed in most cases. Clinical information is vital to prevent waste of limited tumour tissue in inappropriate pursuit of alternative, non-pulmonary origins of a tumour. This and other techniques for sparing tissue during diagnosis preserve material for biomarker testing. All handling, processing and preparation must allow for and facilitate biomarker testing, including molecular techniques. For further information, please refer to the ESMO Clinical Practice Guideline (CPG) on oncogene-addicted metastatic non-small-cell lung carcinoma (mNSCLC; available at: https://www.esmo.org/guidelines/guidelines-by-topic/lung-and-chest-tumours).2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google ScholarTable 1Usage of terminology for diagnosing small samplesWHO recommended terminology for small sample lung cancer diagnosisaAbridged from source reference.1 This adaptation covers most eventualities but refer to the source for full recommendations.1Comment on usageSmall-cell carcinomaUsually a morphological diagnosis. Neuroendocrine IHC may help but is not mandatorySquamous-cell carcinomaMorphological features clearly presentNon-small-cell carcinoma, probably/favour squamousUndifferentiated morphology but P40 IHC positiveAdenocarcinomaMorphological features clearly presentNon-small-cell carcinoma, probably/favour adenocarcinomaUndifferentiated morphology but TTF1 IHC positiveNon-small-cell carcinoma, not otherwise specified (NSCC NOS)Undifferentiated tumour; IHC not predictive (TTF1 and P40 negative or not done)Non-small-cell carcinoma with neuroendocrine morphology and positive neuroendocrine markersb‘High-grade neuroendocrine carcinoma’ can be useful in some cases. (possible large-cell neuroendocrine carcinoma where appropriate)Neuroendocrine IHC positive but not SCLC by morphologyAny of the above (with pleomorphic features)When significant pleomorphism or sarcomatoid/spindle cell morphology is presentSalivary-type carcinomasRare—largely a morphological diagnosisAdapted with permission from the WHO.1The World Health Organisation Classification of Thoracic Tumours5th ed. WHO Classification of Tumours Editorial Board 2021. Vol 5. IARC Press, Lyon2021Google ScholarIHC, immunohistochemistry; NSCC, non-squamous-cell carcinoma; NOS, not otherwise specified; SCLC, small-cell lung carcinoma; TTF1, thyroid transcription factor-1; WHO, World Health Organization.a Abridged from source reference.1The World Health Organisation Classification of Thoracic Tumours5th ed. WHO Classification of Tumours Editorial Board 2021. Vol 5. IARC Press, Lyon2021Google Scholar This adaptation covers most eventualities but refer to the source for full recommendations.1The World Health Organisation Classification of Thoracic Tumours5th ed. WHO Classification of Tumours Editorial Board 2021. Vol 5. IARC Press, Lyon2021Google Scholarb ‘High-grade neuroendocrine carcinoma’ can be useful in some cases. Open table in a new tab Adapted with permission from the WHO.1The World Health Organisation Classification of Thoracic Tumours5th ed. WHO Classification of Tumours Editorial Board 2021. Vol 5. IARC Press, Lyon2021Google Scholar IHC, immunohistochemistry; NSCC, non-squamous-cell carcinoma; NOS, not otherwise specified; SCLC, small-cell lung carcinoma; TTF1, thyroid transcription factor-1; WHO, World Health Organization. Triage of cases based on non-squamous non-small-cell carcinoma subtype for molecular profiling (including the use of cell-free DNA) for driver oncogene targets is discussed in the ESMO CPG on oncogene-addicted mNSCLC.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar All stage IV NSCLC cases (squamous and non-squamous) are recommended for programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) testing. PD-L1 expression >50% [≥50% of at least 100 tumour cells (TCs) showing membrane expression] is a required selection criterion for use of pembrolizumab or cemiplimab monotherapy in the first line while PD-L1 ≥1% on TCs is required for nivolumab plus ipilimumab in the first line [not European Medicines Agency (EMA) approved] and pembrolizumab in the second line. PD-L1 ≥50% on TCs or ≥10% on tumour-infiltrating immune cells (ICs) is a required selection criterion for atezolizumab monotherapy in the first line.3Tsao M. Kerr K. Dacic S. et al.IASLC Atlas of PD-L1 testing in Lung Cancer. Aurora, CO: IASLC Press, 2017Google Scholar,4Lantuejoul S. Sound-Tsao M. Cooper W.A. et al.PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee.J Thorac Oncol. 2020; 15: 499-519Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Several anti-PD-L1 assays (22C3, SP263, SP142, 28-8, 73-10) are available and were used in clinical trials.3Tsao M. Kerr K. Dacic S. et al.IASLC Atlas of PD-L1 testing in Lung Cancer. Aurora, CO: IASLC Press, 2017Google Scholar, 4Lantuejoul S. Sound-Tsao M. Cooper W.A. et al.PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee.J Thorac Oncol. 2020; 15: 499-519Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 5Tsao M.S. Kerr K.M. Kockx M. et al.PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project.J Thorac Oncol. 2018; 13: 1302-1311Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar These IHC clones, plus others, have also been used in laboratory-developed tests for clinical PD-L1 testing. All such tests will not necessarily give the same results. Comparative studies have shown that trial-validated 22C3, SP263 and 28-8 assays are effectively interchangeable; SP142 and 73-10 assays differ significantly.3Tsao M. Kerr K. Dacic S. et al.IASLC Atlas of PD-L1 testing in Lung Cancer. Aurora, CO: IASLC Press, 2017Google Scholar, 4Lantuejoul S. Sound-Tsao M. Cooper W.A. et al.PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee.J Thorac Oncol. 2020; 15: 499-519Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 5Tsao M.S. Kerr K.M. Kockx M. et al.PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project.J Thorac Oncol. 2018; 13: 1302-1311Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar Regardless of the method of PD-L1 testing, rigorous internal and external quality assurance is essential to ensure accurate results. Both biopsy- and cytology-type samples are suitable for PD-L1 IHC testing, provided they are suitably prepared for IHC, there is adequate tumour (at least 100 assessable TCs) and prior validation is undertaken.6Gosney J.R. Boothman A.M. Ratcliffe M. et al.Cytology for PD-L1 testing: a systematic review.Lung Cancer. 2020; 141: 101-106Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar For further information see the Supplementary Material Section 3, available at https://doi.org/10.1016/j.annonc.2022.12.013. PD-L1 IHC scores should be reported within a minimum of three ranges (<1%, 1%-49%, ≥50%) but reporting in 10% intervals is strongly recommended. More detailed information for PD-L1 testing in lung cancer is available in the dedicated International Association for the Study of Lung Cancer (IASLC) Atlas.3Tsao M. Kerr K. Dacic S. et al.IASLC Atlas of PD-L1 testing in Lung Cancer. Aurora, CO: IASLC Press, 2017Google Scholar,4Lantuejoul S. Sound-Tsao M. Cooper W.A. et al.PD-L1 testing for lung cancer in 2019: perspective from the IASLC pathology committee.J Thorac Oncol. 2020; 15: 499-519Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Amongst other NSCLC immunotherapy biomarkers, the SP142 assay for atezolizumab scores PD-L1 in both TCs and ICs. The value of IC PD-L1 expression beyond this registrational setting, notably as a single predictive biomarker in NSCLC, is not established. The presence or absence of various IC types may be important, but data showing clinical utility are lacking. Therefore, this is not currently a recommended practice outside of trials and academic study. Tumour mutational burden as a surrogate predictor of tumour immunogenicity is capable of enriching NSCLC populations for response but compelling evidence for adoption of this complex biomarker, as well as its standardisation, is lacking. Mutations in, for example, STK11 and KEAP1 are associated with a poor prognosis, and exploratory subgroup analysis of clinical trials suggest they are, especially in KRAS-mutated tumours, associated with lower immune checkpoint inhibitor (ICI) efficacy. The predictive value should be confirmed in prospective trials.7Di Federico A. De Giglio A. Parisi C. et al.STK11/LKB1 and KEAP1 mutations in non-small cell lung cancer: prognostic rather than predictive?.Eur J Cancer. 2021; 157: 108-113Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,8Ricciuti B. Arbour K.C. Lin J.J. et al.Diminished efficacy of programmed death-(Ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status.J Thorac Oncol. 2022; 17: 399-410Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar •Preferably, a metastatic lesion is biopsied for diagnostic as well as staging purposes [IV, B].•Bronchoscopy is a technique ideally suited to central lesions and can be used with bronchial washing, brushing, and bronchial and transbronchial biopsy [IV, A].•Endobronchial ultrasound (EBUS) and/or endoscopic ultrasound (EUS) allows for evaluation of regional lymph nodes [IV, A].•Transthoracic fine-needle aspiration and/or core biopsy, under imaging guidance [typically computed tomography (CT)], is indicated in case of mid to peripheral lesions [IV, A].•In the presence of a pleural effusion, thoracentesis could represent both a diagnostic tool and a symptomatic treatment [IV, A].•When less invasive techniques (EBUS, EUS, transthoracic fine-needle aspiration, core biopsy) cannot allow for accurate diagnosis, more invasive, surgical approaches (mediastinoscopy, mediastinotomy, thoracoscopy, etc.) in the diagnostic work-up should be considered [IV, B].•Systematic collaboration and constant communication between pathologists and interventionalists are encouraged to improve diagnostic yields. This may include use of rapid onsite sample evaluation (ROSE) [IV, A].•Adequate tissue material for histological diagnosis and molecular testing should be obtained to allow for individual treatment decisions. This may require re-biopsy, where possible, when initial sampling is inadequate [IV, A].•Pathological diagnosis should be made according to the 2021 WHO classification of lung tumours [IV, A].•Specific subtyping of all NSCLCs is necessary for therapeutic decision making and should be carried out wherever possible. IHC stains should be used to reduce the NSCLC-not otherwise specified rate to fewer than 10% of cases diagnosed [IV, A].•PD-L1 IHC should be systematically determined in advanced NSCLC [I, A].•If cytology samples are used for clinical PD-L1 testing, individual laboratories should validate their assays in their own cytology preparations against tissue biopsy samples of the same tumour [IV, A].•PD-L1 testing is required for pembrolizumab, atezolizumab and cemiplimab monotherapy and nivolumab plus ipilimumab [Food and Drug Administration (FDA) approved, not EMA approved] in the first line, and pembrolizumab in the second line [I, A]. Details on staging and risk assessment are covered in the Supplementary Material Section 4, available at https://doi.org/10.1016/j.annonc.2022.12.013. •A complete history including a precise smoking history and comorbidities, weight loss, Eastern Cooperative Oncology Group performance status (ECOG PS) and physical examination must be recorded [IV, A].•Standard tests including routine haematology, renal and hepatic functions and bone biochemistry tests are required; additional endocrine and serological tests are necessary if receiving ICIs [IV, A].•Contrast-enhanced CT scan of the chest and (upper) abdomen including the liver and the adrenal glands should be carried out at diagnosis [IV, A].•Imaging of the central nervous system should be considered at diagnosis for all patients with metastatic disease [IV, B] and is required for patients with neurological symptoms or signs [IV, A].•If bone metastases are clinically suspected, bone imaging is required [IV, B].•Bone scintigraphy, ideally coupled with CT, can be used for detection of bone metastasis [IV, B]. [18F]2-fluoro-2-deoxy-D-glucose (FDG)–positron emission topography (PET)–CT is the most sensitive modality in detecting bone metastasis [III, B].•FDG–PET–CT and brain imaging are recommended in patients with suspected oligometastatic (≤5 metastases) disease [IV, A].•NSCLC must be staged according to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM (tumour–node–metastasis) 8th edition staging manual and must be grouped into the stage categories shown in Supplementary Tables S1 and S2, available at https://doi.org/10.1016/j.annonc.2022.12.013 [IV, A]. In the presence of a solitary metastatic site on imaging studies, efforts should be made to obtain a cytological or histological confirmation of stage IV disease [IV, A].•Response evaluation is recommended after two to three cycles of systemic therapy, using the same initial radiographic investigation that demonstrated tumour lesions [IV, B]. Follow-up with PET is not routinely recommended, due to its high sensitivity and relatively low specificity [IV, C].•Measurements and response assessment should follow Response Evaluation Criteria in Solid Tumours (RECIST) v1.19Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (20167) Google Scholar [IV, A].•In the case of ICI therapy, RECIST should formally be used. Immune-related RECIST (irRECIST),10Bohnsack O. Hoos A. Ludajic K. Adaptation and modification of the immune related response criteria (IRRC): IrRECIST.J Clin Oncol. 2014; 32 (15_suppl):e22121Crossref Google Scholar immunotherapy RECIST (iRECIST)11Seymour L. Bogaerts J. Perrone A. et al.iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.Lancet Oncol. 2017; 18: e143-e152Abstract Full Text Full Text PDF PubMed Scopus (1406) Google Scholar and immune-modified RECIST (imRECIST)12Hodi F.S. Ballinger M. Lyons B. et al.Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): refining guidelines to assess the clinical benefit of cancer immunotherapy.J Clin Oncol. 2018; 36: 850-858Crossref PubMed Scopus (247) Google Scholar have not been validated, but may have a role in the overall assessment of therapy [IV, C]. See Figures 1 and 2 and treatment algorithms for systemic treatment without contraindications for the use of ICIs for squamous-cell carcinoma and non-squamous non-small-cell carcinoma, respectively. Contraindications for the use of ICIs are discussed in the ESMO CPG on management of toxicities from immunotherapy.13Haanen J. Obeid M. Spain L. et al.Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2022; 33: 1217-1238Abstract Full Text Full Text PDF PubMed Scopus (123) Google ScholarFigure 2Treatment algorithm for stage IV NSqNSCC after negative findings on molecular tests and without contraindication for immunotherapy.Show full captionPurple: general categories or stratification; white: other aspects of management; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments.BSC, best supportive care; ChT, chemotherapy; CPG, Clinical Practice Guideline; ECOG, Eastern Cooperative Oncology Group; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICI, immune checkpoint inhibitor; LRT, local radical therapy; MCBS, ESMO-Magnitude of Clinical Benefit Scale; NSqNSCC, non-squamous non-small-cell carcinoma; mNSCLC, metastatic non-small-cell lung cancer; NSCLC, non-small-cell lung cancer; PD-L1, programmed death-ligand 1; PS, performance status; TC, tumour cell.aPlease see the ESMO CPG on oncogene-addicted mNSCLC for MET/EGFR ex20ins/KRAS/NTRK/HER2 testing necessary for second-line treatment options and the decision rationale for platinum-doublet ChT, immunotherapy monotherapy or chemo-immunotherapy.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google ScholarbIf positive molecular test, please refer to the ESMO CPG on oncogene-addicted mNSCLC.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google ScholarcESMO-MCBS v1.1109Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-magnitude of clinical benefit scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms).dIf oligoprogression, consider local therapy and continue systemic therapy.eSelection of type of ChT also dependent on first-line therapy.fFDA approved, not EMA approved.gRe-challenge with PD-L1 might be considered if ICI was discontinued previously, but not for progressive disease or severe toxicity.hOther options are pemetrexed if not given in first line [I, B], docetaxel [I, B], nintedanib–docetaxel [II, B], ramucirumab–docetaxel [I, B; MCBS 1].View Large Image Figure ViewerDownload Hi-res image Download (PPT) Purple: general categories or stratification; white: other aspects of management; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments. BSC, best supportive care; ChT, chemotherapy; CPG, Clinical Practice Guideline; ECOG, Eastern Cooperative Oncology Group; EMA, European Medicines Agency; FDA, Food and Drug Administration; ICI, immune checkpoint inhibitor; LRT, local radical therapy; MCBS, ESMO-Magnitude of Clinical Benefit Scale; NSqNSCC, non-squamous non-small-cell carcinoma; mNSCLC, metastatic non-small-cell lung cancer; NSCLC, non-small-cell lung cancer; PD-L1, programmed death-ligand 1; PS, performance status; TC, tumour cell. aPlease see the ESMO CPG on oncogene-addicted mNSCLC for MET/EGFR ex20ins/KRAS/NTRK/HER2 testing necessary for second-line treatment options and the decision rationale for platinum-doublet ChT, immunotherapy monotherapy or chemo-immunotherapy.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar bIf positive molecular test, please refer to the ESMO CPG on oncogene-addicted mNSCLC.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar cESMO-MCBS v1.1109Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-magnitude of clinical benefit scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms). dIf oligoprogression, consider local therapy and continue systemic therapy. eSelection of type of ChT also dependent on first-line therapy. fFDA approved, not EMA approved. gRe-challenge with PD-L1 might be considered if ICI was discontinued previously, but not for progressive disease or severe toxicity. hOther options are pemetrexed if not given in first line [I, B], docetaxel [I, B], nintedanib–docetaxel [II, B], ramucirumab–docetaxel [I, B; MCBS 1]. The treatment strategy for a patient with newly diagnosed, mNSCLC without an oncogenic driver includes consideration of histology, tumour genotype, PD-L1 expression, PS, comorbidities and the patient’s preferences (Supplementary Figure S3, available at https://doi.org/10.1016/j.annonc.2022.12.013). Furthermore, consideration should be given by the multidisciplinary tumour board (MTB) for whether a patient has oligometastatic disease and is eligible for therapy with radical intent (please refer to the ‘Special populations, Oligometastases’ subsection for further information). In general, systemic therapy should be offered to all patients with stage IV NSCLC with an ECOG PS of 0-2. For treatment options for those with a PS of 2, please refer to the ‘Special populations, PS and beyond’ subsection for further information. Treatment for those with a contraindication for ICI is discussed under ‘First-line treatment with contraindications for use of immunotherapy’ (Figures 3 and 4).Figure 4Treatment algorithm for stage IV NSqNSCC after negative findings on molecular tests and with contraindication for immunotherapy.Show full captionPurple: general categories or stratification; white: other aspects of management; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments.BSC, best supportive care; ChT, chemotherapy; CPG, Clinical Practice Guideline; ECOG, Eastern Cooperative Oncology Group; EMA, European Medicines Agency; FDA, Food and Drug Administration; LRT, local radical therapy; MCBS, ESMO-Magnitude of Clinical Benefit Scale; mNSCLC, metastatic non-small-cell lung cancer; NSCLC, non-small-cell lung cancer; NSqNSCC, non-squamous non-small-cell carcinoma; PS, performance status.aPlease see the ESMO CPG on oncogene-addicted mNSCLC for MET/EGFR ex20ins/KRAS/NTRK/HER2 testing necessary for second-line treatment options and the decision rationale for platinum-doublet ChT, immunotherapy monotherapy or chemo-immunotherapy.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google ScholarbIf positive molecular test please refer to the ESMO CPG on oncogene-addicted mNSCLC.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google ScholarcESMO-MCBS v1.1109Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-magnitude of clinical benefit scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms).dIn NSCLC other than predominantly squamous-cell histology.eSelection of type of ChT also dependent on first-line therapy.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Purple: general categories or stratification; white: other aspects of management; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments. BSC, best supportive care; ChT, chemotherapy; CPG, Clinical Practice Guideline; ECOG, Eastern Cooperative Oncology Group; EMA, European Medicines Agency; FDA, Food and Drug Administration; LRT, local radical therapy; MCBS, ESMO-Magnitude of Clinical Benefit Scale; mNSCLC, metastatic non-small-cell lung cancer; NSCLC, non-small-cell lung cancer; NSqNSCC, non-squamous non-small-cell carcinoma; PS, performance status. aPlease see the ESMO CPG on oncogene-addicted mNSCLC for MET/EGFR ex20ins/KRAS/NTRK/HER2 testing necessary for second-line treatment options and the decision rationale for platinum-doublet ChT, immunotherapy monotherapy or chemo-immunotherapy.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar bIf positive molecular test please refer to the ESMO CPG on oncogene-addicted mNSCLC.2Hendriks L.E. Kerr K.M. Menis J. et al.Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023; 34: 339-357Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar cESMO-MCBS v1.1109Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-magnitude of clinical benefit scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms). dIn NSCLC other than predominantly squamous-cell histology. eSelection of type of ChT also dependent on first-line therapy. A combination of platinum-based chemotherapy (ChT) plus programmed cell death protein 1 (PD-1)/PD-L1 blockade is the most common treatment approach for a patient with newly diagnosed stage IV NSCLC (monotherapy ICI for patients with PD-L1 ≥50% is discussed in the First-line treatment of patients with PS 0-1, tumour PD-L1 ≥50% and without contraindication for ICI subsection below). Several combination regimens have successfully demonstrated improved overall survival (OS) compared with ChT alone. These have included platinum-based ChT plus: pembrolizumab (non-squamous non-small-cell carcinoma and squamous-cell carcinoma),14Gandhi L. Rodriguez-Abreu D. Gadgeel S. et al.Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.N Engl J Med. 2018; 378: 2078-2092Crossref PubMed Scopus (4195) Google Scholar,15Paz-Ares L. Luft A. Vicente D. et al.Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.N Engl J Med. 2018; 379: 2040-2051Crossref PubMed Scopus (2367) Google Scholar atezolizumab with or without bevacizumab (non-squamous non-small-cell carcinoma only),16Socinski M.A. Jotte R.M. Cappuzzo F. et al.Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.N Engl J Med. 20