Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy

The following ESMO Clinical Practice Guideline has been recently updated with new treatment recommendations:Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.1Postmus P.E. Kerr K.M. Oudkerk M. et al.Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (928) Google ScholarEupdateView the ESMO eUpdate here: https://www.esmo.org/guidelines/lung-and-chest-tumours/early-stage-and-locally-advanced-non-metastatic-non-small-cell-lung-cancer/eupdate-early-and-locally-advanced-non-small-cell-lung-cancer-nsclc-treatment-recommendations2.Pathology/molecular biologyDiagnosisThe original Table 1 is updated.Table 1Work-up for diagnosis and stagingMandatoryOptionalGeneralMedical historyaTests needed for clinical staging.Physical examinationaTests needed for clinical staging.Assessing comorbidityPSImagingCT thorax and upper abdomenaTests needed for clinical staging.X-ray thoraxbX-ray could be used as a first test in case of suspicious of lung cancer. However, a CT scan is recommended for those patients with risk factors or high clinical suspicious and a negative X-ray.PET-CTaTests needed for clinical staging.Bone scintigraphyMRI braincSee text.Contrast-enhanced CT brainLaboratoryBlood cell countsRenal functionLiver enzymesBone parametersdOptional, at physician's discretion upon suspicion. Bone scan or PET-CT to be carried out in case of suspicion for bone metastases.Cardiopulmonary functionFVC, FEV1, DLCOECGIf indicated: CPETEjection fraction, CAGTissue procurementBronchoscopycSee text.,eDepending on site and size of tumour with biopsy/aspiration/brush/washing.EBUS/EUS mediastinal nodesaTests needed for clinical staging.MediastinoscopyCT-guided biopsyGenomic profilingEGFR mutation statusALK fusion statusOther biomarkersPD-L1 expression (for unresectable NSCLC)PD-L1 expression (for completely resected NSCLC)CAG, coronary angiography; CPET, cardiopulmonary exercise testing; CT, computed tomography; DLCO, diffusing capacity of the lungs for carbon monoxide; EBUS, endoscopic bronchial ultrasound; ECG, electrocardiogram; EUS, endoscopic ultrasound; FEV1, forced expiratory volume in 1 second; FVC, forced expiratory vital capacity; MRI, magnetic resonance imaging; NSCLC, non-small-cell lung cancer; PD-L1, programmed death-ligand 1; PET-CT, positron emission tomography computed tomography; PS, performance status.a Tests needed for clinical staging.b X-ray could be used as a first test in case of suspicious of lung cancer. However, a CT scan is recommended for those patients with risk factors or high clinical suspicious and a negative X-ray.c See text.d Optional, at physician's discretion upon suspicion. Bone scan or PET-CT to be carried out in case of suspicion for bone metastases.e Depending on site and size of tumour with biopsy/aspiration/brush/washing. Open table in a new tab Staging and risk assessmentLocoregional stagingThe original Figure 1 is updated.Treatment of early stages (stages I-IIIA)The original section ‘Treatment of early stages (stages I-II)’ is renamed ‘Treatment of early stages (stages I-IIIA)’. The original recommendations are updated and a new treatment algorithm provided (Figure 6). The ESMO-MCBS table is updated to include osimertinib (Table 6).Figure 6Systemic treatment algorithm for early-stage (stage IB-IIIA) and unresectable locally advanced (stage III) NSCLC.Show full captionFor resection criterion, check Figure 2. Purple: general categories or stratification (symptom); red: surgery; dark green: radiotherapy; blue: systemic anticancer therapy; turquoise: combination of treatments or other systemic treatments; white: other aspects of management.ChT, chemotherapy; ESMO, European Society for Medical Oncology; MCBS, Magnitude of Clinical Benefit Scale; N+, node-positive; PD-L1, programmed death-ligand 1; PORT, post-operative radiotherapy; RT, radiotherapy.a For stage IB, adjuvant ChT in primary tumours ≥4 cm [II, B].b Only in adenocarcinoma tumours.c ESMO-MCBS v1.1 score for new therapy/indication approved by the EMA since 1 January 2016 and the Food and Drug Administration (FDA) since 1 January 2020. The score has been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee (https://www.esmo.org/guidelines/esmo-mcbs/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).d Primary endpoint of ADAURA trial was DFS in stage II-IIIA according to 7th TNM (T> 5 cm or N+). Adjuvant osimertinib in stage IB (3 cm < T ≤ 5 cm) ​was a secondary endpoint. Stage was a stratification factor. Therefore, indication for osimertinib in T ≤ 5 cm N0 will follow local recommendations/physician’s discretion [I, B].View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 6ESMO-MCBS table for new therapies/indications in early and locally advanced NSCLCTherapyDurvalumabDisease settingConsolidation therapy in patients with stage III NSCLC who did not have disease progression after ≥2 cycles of platinum-based CRTTrialA study of durvalumab as consolidation therapy in patients with locally advanced, unresectable NSCLC (stage III) who have not progressed following definitive, platinum-based, concurrent chemoradiation therapy (PACIFIC)10Antonia S.J. Villegas A. Daniel D. et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (2331) Google Scholar, 11Antonia S.J. Villegas A. Daniel D. et al.Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1511) Google Scholar, 12Hui R. Ozguroglu M. Villegas A. et al.Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study.Lancet Oncol. 2019; 20: 1670-1680Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 13Gray J.E. Villegas A. Daniel D. et al.Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC-update from PACIFIC.J Thorac Oncol. 2020; 15: 288-293Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 14Faivre-Finn C. Vicente D. Kurata T. et al.Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial.J Thorac Oncol. 2021; 16: 860-867Abstract Full Text Full Text PDF PubMed Scopus (176) Google ScholarPhase IIINCT02125461Control (median)PlaceboPFS ITT across all PD-L1 categories control: 5.6 monthsOS control: 29.1 months2-year OS control: 55.3%4-year OS control: 36.3%Absolute survival gainPFS ITT across all PD-L1 categories gain: 11.6 monthsOS gain: 18.4 months2-year OS gain: 11%4-year OS gain: 13.3%HR (95% Cl)PFS HR: 0.55 (0.44-0.67)OS HR: 0.71 (0.57-0.88)QoL/toxicityNo benefit observedESMO-MCBS scoreaESMO-MCBS v1.1.15 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/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).4bEMA approval is limited to PD-L1 >1%, based on post hoc subgroup analysis indicating lack of benefit for patients with PD-L1 <1%13; FDA approval is based on ITT and is irrespective of PD-L1. (Form 2a)TherapyOsimertinib – 3 yearsDisease settingAdjuvant treatment after tumour resection EGFR exon 19 deletions or exon 21 (L858R) mutationTrialA study of osimertinib versus placebo in patients with EGFR mutation positive stage IB-IIIA NSCLC following complete tumour resection with or without adjuvant chemotherapy (ADAURA)15Cherny 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 (311) Google ScholarPhase IIINCT02511106Control (median)Placebo2-year DFS control: 52%dApproval was based on all patient data (including stage Ib), which was a secondary outcome (statistically significant after hierarchical testing).Absolute survival gain2-year DFS gain: 37%dApproval was based on all patient data (including stage Ib), which was a secondary outcome (statistically significant after hierarchical testing).HR (95% Cl)DFS HR: 0.20 (0.14-0.30)cHR with 99.12% CI.,dApproval was based on all patient data (including stage Ib), which was a secondary outcome (statistically significant after hierarchical testing).QoL/toxicityESMO-MCBS scoreaESMO-MCBS v1.1.15 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/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).AdApproval was based on all patient data (including stage Ib), which was a secondary outcome (statistically significant after hierarchical testing). (Form 1)CI, confidence interval; CRT, chemoradiotherapy; DFS, disease-free survival; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; FDA, Food and Drug Administration; HR, hazard ratio; ITT, intention to treat; NSCLC, non-small-cell lung cancer; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; QoL, quality of life.a ESMO-MCBS v1.1.15Cherny 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 (311) Google Scholar 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/scale-evaluation-forms-v1.0-v1.1/scale-evaluation-forms-v1.1).b EMA approval is limited to PD-L1 >1%, based on post hoc subgroup analysis indicating lack of benefit for patients with PD-L1 <1%13Gray J.E. Villegas A. Daniel D. et al.Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC-update from PACIFIC.J Thorac Oncol. 2020; 15: 288-293Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar; FDA approval is based on ITT and is irrespective of PD-L1.c HR with 99.12% CI.d Approval was based on all patient data (including stage Ib), which was a secondary outcome (statistically significant after hierarchical testing). Open table in a new tab Systemic therapyAdjuvant treatment with targeted therapiesAdjuvant osimertinib for resected IB-IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R mutationsOsimertinib is approved by both the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as adjuvant therapy after complete tumour resection in patients with stage IB-IIIA NSCLC whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations [I, A; European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: A].Efficacy was demonstrated in a randomised, double-blind, placebo-controlled trial (ADAURA, NCT02511106) in patients with centrally confirmed EGFR exon 19 deletions or exon 21 L858R mutation-positive stage IB-IIIA NSCLC who had complete tumour resection, with or without prior adjuvant chemotherapy (ChT).3Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (514) Google Scholar,4Herbst R.S. Tsuboi M. John T. et al.Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA.J Clin Oncol. 2020; 38: LBA5Crossref Google Scholar A total of 682 patients were randomised (1 : 1) to receive 3 years of osimertinib 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant ChT, if given. The major efficacy outcome measure was disease-free survival (DFS) in patients with stage II-IIIA NSCLC determined by investigator assessment. With a median follow-up for the primary endpoint of 22.1 months in the osimertinib arm and 14.9 months in the placebo arm, the median DFS was not reached [(38.8 months-not evaluable (NE)] in patients on the osimertinib arm compared with 19.6 months (16.6-24.5 months) on the placebo arm [hazard ratio (HR) 0.17, 99.1% confidence interval (CI) 0.11-0.26, P < 0.0001]. DFS in the overall study population was a secondary efficacy outcome measure; the median was not reached (NE-NE) in patients on the osimertinib arm compared with 27.5 months (22.0-35.0 months) on the placebo arm (HR 0.20, 99.1% CI 0.14-0.30, P < 0.0001).3Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (514) Google Scholar,4Herbst R.S. Tsuboi M. John T. et al.Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA.J Clin Oncol. 2020; 38: LBA5Crossref Google Scholar The DFS benefit with osimertinib occurred in patients who received adjuvant ChT (HR 0.16, 95% CI 0.10-0.26), and among those who did not (HR 0.23, 95% CI 0.13-0.40), knowing that ChT administration was not a stratification factor and this decision was left to the investigator.3Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (514) Google ScholarThe recommended osimertinib dose for adjuvant treatment of early-stage NSCLC is 80 mg orally once daily, with or without food, until disease recurrence, or unacceptable toxicity, or for up to 3 years.Neoadjuvant or adjuvant immune checkpoint inhibitorsUnpublished data from phase III clinical trials have reported that in patients with stage IB-IIIA NSCLC, neoadjuvant immune checkpoint inhibitors (ICIs) plus ChT increases the rate of pathological complete response compared with ChT. Likewise, in the same setting, adjuvant ICI with anti-programmed death-ligand 1 (anti-PD-L1) leads to increased DFS versus best supportive care (BSC) for patients with PD-L1-positive tumours.The recent phase III IMpower-010 trial assessed the role of adjuvant atezolizumab 1200 mg every 3 weeks for 16 cycles versus BSC in completely resected stage IB-IIIA NSCLC patients following recovery from surgery and standard adjuvant cisplatin-based ChT.5Felip E. Altorki N. Zhou C. Csőszi T. Vynnychenko I. Goloborodko O. Luft A. Akopov A. Martinez-Marti A. Kenmotsu H. Chen Y.M. Chella A. Sugawara S. Voong D. Wu F. Yi J. Deng Y. McCleland M. Bennett E. Gitlitz B. Wakelee H. IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.Lancet. 2021 Sep 17; S0140-6736(21)02098-5 (Epub ahead of print. Erratum in: Lancet. 2021 Sep 23; PMID: 34555333)https://doi.org/10.1016/S0140-6736(21)02098-5Abstract Full Text Full Text PDF Scopus (171) Google Scholar In hierarchical testing, atezolizumab significantly improved the DFS versus BSC in PD-L1-expressing tumour cells ≥1% (SP263 assay) stage II-IIIA NSCLC [median DFS not reached versus 35.3 months, (HR 0.66, 95% CI 0.50-0.88, P = 0.0039)], as well as in all randomised stage II-IIIA tumours [median DFS 42.3 versus 35.3 months, (HR 0.79, 95% CI 0.64-0.96, P = 0.0205)]. Finally, in the intention-to-treat population, DFS did not cross significance boundary [HR 0.81, 95% CI 0.67-0.99, P = 0.04].5Felip E. Altorki N. Zhou C. Csőszi T. Vynnychenko I. Goloborodko O. Luft A. Akopov A. Martinez-Marti A. Kenmotsu H. Chen Y.M. Chella A. Sugawara S. Voong D. Wu F. Yi J. Deng Y. McCleland M. Bennett E. Gitlitz B. Wakelee H. IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.Lancet. 2021 Sep 17; S0140-6736(21)02098-5 (Epub ahead of print. Erratum in: Lancet. 2021 Sep 23; PMID: 34555333)https://doi.org/10.1016/S0140-6736(21)02098-5Abstract Full Text Full Text PDF Scopus (171) Google Scholar Atezolizumab, however, does not have EMA approval in this setting yet.The primary analysis population from the three-arm CheckMate 816 trial reported that nivolumab plus platinum-based ChT for 3 cycles as neoadjuvant strategy in patients with stage IB-IIIA NSCLC significantly improved the primary endpoint of pathological complete responses compared with ChT alone [24.0% versus 2.2%, odds ratio 13.94, 99% CI 3.49-55.75, P < 0.0001]. This benefit was consistent across disease stages, histologies, tumour mutational burden and PD-L1 expression levels.6Forde PM, Spicer J, Lu S, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial [abstract]. Proceedings of the 112th Annual Meeting of the American Association for Cancer Research. 2021 April 10-15. Philadelphia (PA): AACR; 2021. Abstract nr CT003.Google Scholar There are no data yet, however, on outcome with this strategy from this phase III trial. Therefore, in stage IB-IIIA NSCLC, the immune strategy in the (neo)adjuvant setting using ICIs ± CT is not yet standard. Several large phase III clinical trials are still ongoing with immune strategy in the (neo)adjuvant stage IB-IIIA clinical scenario.Post-operative radiotherapyThe original recommendations are updated.RecommendationsAdjuvant ChT•Adjuvant ChT should be offered to patients with resected TNM (tumour–node–metastasis) 8th edition stage IIB and III NSCLC [I, A] and can be considered in patients with T2bN0, stage IIA resected primary tumour >4 cm [II, B]. Pre-existing comorbidity, time from surgery and post-operative recovery need to be taken into account in this decision taken in a multidisciplinary tumour board [V, A].•For adjuvant ChT, a two-drug combination with cisplatin is preferable [I, A]. In randomised studies, the attempted cumulative cisplatin dose was up to 300 mg/m2, delivered in 3 to 4 cycles.•When cisplatin administration is not feasible, carboplatin is an accepted alternative [IV, B].•Although the most frequently studied regimen is cisplatin-vinorelbine, other combinations such as cisplatin and gemcitabine, or docetaxel or pemetrexed (only in adenocarcinoma tumours) could be also feasible [II, B].•Carboplatin and paclitaxel is a potential ChT option for T2bN0, stage IIA resected primary tumour >4 cm [IV, B].Adjuvant treatment with targeted therapies•Osimertinib is indicated for the adjuvant treatment after complete tumour resection in adult patients with stage IB-IIIA NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R substitution mutations [I, A; ESMO-MCBS v1.1 score: A].Post-operative radiotherapy•Post-operative radiotherapy (PORT) in completely resected early-stage I-IIIA NSCLC is not recommended [I, E].•In case of microscopic residual tumour (R1) resection (positive resection margin, chest wall), PORT should be considered [IV, B].•Even if such patients were not included in randomised, clinical trials, adjuvant ChT should be considered in patients with R1 resection of stage IIA-IIB-III disease [V, A].•In case both ChT and radiotherapy (RT) are administered post-R1 surgery, RT may be administered before ChT [V, C].Treatment of locally advanced stage (stage III)The original recommendations are updated and a new treatment algorithm provided (see Figure 6). The ESMO-MCBS table is updated for durvalumab (see Table 6).Resectable locally advanced NSCLCPORT after resected stage III NSCLCPORT should not be used in patients with NSCLC following complete R0 resection and after (neo)adjuvant ChT, as no statistically significant difference in 3-year DFS was shown in a randomised, controlled trial.The large randomised, controlled LungART trial presented at ESMO 2020 explored the role of modern mediastinal PORT in patients with completely resected NSCLC with histo/cytologically proven N2 nodal involvement. The study randomised 501 patients with completely resected stage IIIA N2 NSCLC to PORT (54 Gy in 27-30 fractions or no PORT). Safety analysis was carried out in 487 patients.7Le Pechoux C. Poural N. Barlesi F. et al.LBA3_PR An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement: primary end-point analysis of lungART (IFCT-0503, UK NCRI, SAKK) NCT00410683.Ann Oncol. 2020; 31: S1178Abstract Full Text Full Text PDF PubMed Google Scholar LungART is the only large, adequately-powered, high-quality, randomised trial in the modern era to be completed in these patients. The trial selected a well-defined, high-risk patient population (52% of patients had ≥2 N2 nodal stations involved), 91% of whom had undergone positron emission tomography (PET) scans, and 95% of whom had undergone systemic ChT. The quality of surgery carried out was clearly specified and also reviewed centrally by a surgical committee.At a median follow-up of 4.8 years, the DFS HR reported in the trial was 0.85 (95% CI 0.67-1.07, P = 0.16), with median DFS times of 30.5 months for PORT and 22.8 months without PORT. Three-year DFS rates were 47.1% and 43.8% with and without PORT, respectively. There was also no evidence that PORT improved overall survival (OS), with 3-year OS rates of 66.5% and 68.5% with and without PORT, respectively. Not only did PORT fail to provide a survival benefit, but it may actually be harmful for patients, with an incidence of late grade 3-4 cardiopulmonary toxicity twice that in patients without PORT (10.8% versus 4.9%).Consequently, PORT cannot be recommended for patients with completely resected stage I-III N2 NSCLC. Its potential utility for locoregional disease control in resected stage III N2 disease (decrease of the rate of mediastinal relapse by 50%) is offset by the risk of over-added cardiopulmonary toxicity. Further analysis is needed to determine whether certain patients, in particular, could benefit. For patients with incompletely resected R1 stage III NSCLC, PORT should be considered, with thorough assessment in a multidisciplinary tumour board.Unresectable locally advanced NSCLCThe phase III PACIFIC trial randomised (2 : 1) 713 patients with unresectable, locally-advanced NSCLC without disease progression within the first 42 days after concurrent chemoradiotherapy, to consolidative durvalumab for 1 year or placebo.8Spigel D.R. Faivre-Finn C. Gray J.E. et al.Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial.J Clin Oncol. 2021; 39: 8511Crossref Google Scholar After a median follow-up of 34.2 months, the median OS for durvalumab was reached (47.5 months versus 29.1 months for placebo, HR 0.72, 95% CI 0.59-0.89), and the estimated 5-year OS rates were 42.9% versus 33.4% for durvalumab versus placebo, respectively. The median PFS was 16.9 months for durvalumab and 5.6 months for placebo (HR 0.55, 95% CI 0.45-0.68) with a 5-year PFS rate of 33.1% versus 19.0%, respectively.8Spigel D.R. Faivre-Finn C. Gray J.E. et al.Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial.J Clin Oncol. 2021; 39: 8511Crossref Google ScholarA post hoc exploratory analysis of the mature survival data requested by licensing European authorities observed that the benefit with durvalumab was not evident in patients with PD-L1 expression <1%. The significance of this observation is disputed.9Peters S. Dafni U. Boyer M. et al.Position of a panel of international lung cancer experts on the approval decision for use of durvalumab in stage III non-small-cell lung cancer (NSCLC) by the Committee for Medicinal Products for Human Use (CHMP).Ann Oncol. 2019; 30: 161-165Abstract Full Text Full Text PDF PubMed Scopus (46) Google ScholarRecommendationsPORT after resected stage III NSCLC•PORT is not beneficial for patients with completely resected stage III N2 NSCLC [I, E] and should only be considered in the setting of residual microscopic or macroscopic disease [IV, B].Unresectable locally advanced NSCLC•The consolidation administration of the ICI durvalumab within 1-42 days after the end of concurrent chemoradiotherapy has demonstrated a survival benefit in unresectable stage III NSCLC and is recommended in patients whose disease has not progressed following platinum-based chemoradiotherapy [I, A] in the intention-to-treat population across all PD-L1 categories and in patients whose tumours express PD-L1 on tumour cells (as per the EMA-approved indication) [I, A; ESMO-MCBS v1.1 score: 4].Follow-up, long-term implications and survivorshipThe original recommendations are updated.Recommendations•NSCLC patients treated with radical intent should be followed for treatment-related complications, detection of treatable relapse or occurrence of second primary lung cancer. Multidisciplinary team assessment is required for feasibility check for treatment of locoregional relapse [III, A].•Surveillance every 6 months for 2 years with a visit including history, physical examination and contrast-enhanced volume chest and abdominal CT scan at least at 12 and 24 months is recommended, with optional [18F]2-fluoro-2-deoxy-D-glucose-PET if required, and thereafter an annual visit including history, physical examination and chest/upper abdominal CT scan in order to detect second primary tumours [III, B]. The following ESMO Clinical Practice Guideline has been recently updated with new treatment recommendations: Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.1Postmus P.E. Kerr K.M. Oudkerk M. et al.Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv1-iv21Abstract Full Text Full Text PDF PubMed Scopus (928) Google Scholar EupdateView the ESMO eUpdate here: https://www.esmo.org/guidelines/lung-and-chest-tumours/early-stage-and-locally-advanced-non-metastatic-non-small-cell-lung-cancer/eupdate-early-and-locally-advanced-non-small-cell-lung-cancer-nsclc-treatment-recommendations2. View the ESMO eUpdate here: https://www.esmo.org/guidelines/lung-and-chest-tumours/early-stage-and-locally-advanced-non-metastatic-non-small-cell-lung-cancer/eupdate-early-and-locally-advanced-non-small-cell-lung-cancer-nsclc-treatment-recommendations2. Pathology/molecular biologyDiagnosisThe original Table 1 is updated.Table 1Work-up for diagnosis and stagingMandatoryOptionalGeneralMedical historyaTests needed for clinical staging.Physical examinationaTests needed for clinical staging.Assessing comorbidityPSImagingCT thorax and upper abdomenaTests needed for clinical staging.X-ray thoraxbX-ray could be used as a first test in case of suspicious of lung cancer. However, a CT scan is recommended for those patients with risk factors or high clinical suspicious and a negative X-ray.PET-CTaTests needed for clinical staging.Bone scintigraphyMRI braincSee text.Contrast-enhanced CT brainLaboratoryBlood cell countsRenal functionLiver enzymesBone parametersdOptional, at physician's discretion upon suspicion. Bone scan or PET-CT to be carried out in case of suspicion for bone metastases.Cardiopulmonary functionFVC, FEV1, DLCOECGIf indicated: CPETEjection fraction, CAGTissue procurementBronchoscopycSee text.,eDepending on site and size of tumour with biopsy/aspiration/brush/washing.EBUS/EUS mediastinal nodesaTests needed for clinical staging.MediastinoscopyCT-guided biopsyGenomic profilingEGFR mutation statusALK fusion statusOther biomarkersPD-L1 expression (for unresectable NSCLC)PD-L1 expression (for completely resected NSCLC)CAG, coronary angiography; CPET, cardiopulmonary exercise testing; CT, computed tomography; DLCO, diffusing capacity of the lungs for carbon monoxide; EBUS, endoscopic bronchial ultrasound; ECG, electrocardiogram; EUS, endoscopic ultrasound; FEV1, forced expiratory volume in 1 second; FVC, forced expiratory vital capacity; MRI, magnetic resonance imaging; NSCLC, non-small-cell lung cancer; PD-L1, programmed death-ligand 1; PET-CT, positron emission tomography computed tomography; PS, performance status.a Tests needed for clinical staging.b X-ray could be used as a first test in case of suspicious of lung cancer. However, a CT scan is recommended for those patients with risk factors or high clinical suspicious and a negative X-ray.c See text.d Optional, at physician's discretion upon suspicion. Bone scan or PET-CT to be carried out in case of suspicion for bone metastases.e Depending on site and size of tumour with biopsy/aspiration/brush/washing. Open table in a new tab DiagnosisThe original Table 1 is updated.Table 1Work-up for diagnosis and stagingMandatoryOptionalGeneralMedical historyaTests needed for clinical staging.Physical examinationaTests needed for clinical staging.Assessing comorbidityPSImagingCT thorax and upper abdomenaTests needed for clinical staging.X-ray thoraxbX-ray could be used as a first test in case of suspicious of lung cancer. However, a CT scan is recommended for those patients with risk factors or high clinical suspicious and a negative X-ray.PET-CTaTests needed for clinical staging.Bone scintigr