Guideline sources The following summarized guidelines for the evaluation and management of non-small cell lung cancer (NSCLC) are prepared by our editorial team based on guidelines from the American Society of Clinical Oncology (ASCO 2023; 2022; 2020), the European Society for Radiotherapy and Oncology (ESTRO/ASTRO 2023), the European Society of Medical Oncology (ESMO 2022; 2021; 2017), the American Association for Thoracic Surgery (AATS/ESTS 2022), the American College of Chest Physicians (ACCP 2021; 2013), and the U.S. Preventive Services Task Force (USPSTF 2021). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Calculator Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Prognosti https://web.pathway.md/diseases/recomSJPzaod1SYuA 1/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway Guidelines 1. Screening and diagnosis Indications for screening, low-dose CT: As per ACCP 2021 guidelines, obtain annual screening for lung cancer with low-dose CT in asymptomatic individuals aged 55-77 years with a 30 pack-year smoking history and either continuing to smoke or have quit within the past 15 years. B Show 3 more As per USPSTF 2021 guidelines: Obtain annual screening for lung cancer with low-dose CT in individuals aged 50-80 years with a 20 pack-year smoking history and either currently being a smoker or having quit within the past 15 years. B Discontinue screening once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. B As per ESMO 2017 guidelines, consider obtaining screening for lung cancer with low-dose CT in individuals aged 55-74 years being current or former heavy smokers (30 pack-year or 15 years since smoking cessation) and well informed about potential benefits and risks. B Show 2 more Landmark trials: NLST In patients who are at high risk for lung cancer, screening using low-dose CT was superior to screening using CXRs with respect to death from any cause. National Lung Screening Trial Research Team et al. N Engl J Med. 2011 Aug 4. Indications for screening, other modalities: As per ESMO 2017 guidelines, do not obtain other methods for lung cancer screening, such as CXRs, sputum analysis, or biomarkers. D As per ACCP 2013 guidelines: Do not obtain a CXR once or at regular intervals for lung cancer screening in patients at risk for developing lung cancer. D Avoid obtaining sputum cytology at regular intervals for lung cancer screening in patients at risk for developing lung cancer. D Indications for screening (requirements for screening programs): consider developing strategies to determine whether patients have symptoms suggesting the presence of lung cancer https://web.pathway.md/diseases/recomSJPzaod1SYuA 2/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway so that symptomatic patients do not enter screening programs but instead receive appropriate diagnostic testing, regardless of whether the symptomatic patient meets screening eligibility criteria. Show 8 more 2. Classification and risk stratification Staging: As per ESMO 2022 guidelines, use the 8th edition of the AJCC/UICC TNM staging system to stage NSCLC. B Show 2 more As per ESMO 2017 guidelines, use the 8th edition of the AJCC/UICC TNM staging system for detailed locoregional staging and assess the cardiopulmonary fitness of the patient to determine the choice of treatment in NSCLC. B Show 3 more 3. Diagnostic investigations Initial evaluation: obtain a thorough evaluation to provide an initial clinical assessment of tumor stage in patients with known or suspected lung cancer. B Show 2 more 4. Diagnostic procedures Histopathology: report the histologic type, tumor size and location, tumor grade (if appropriate), lymphovascular invasion, pleural involvement, surgical margins, and status and location of lymph nodes by station during pathological evaluation. B Show 5 more 5. Medical management General principles: Consider ensuring timely and efficient delivery of care in patients with known or suspected lung cancer. C Consider using a multidisciplinary team approach in patients with lung cancer requiring multimodality therapy. C Management of early-stage disease (pathological staging): obtain a pretreatment pathological diagnosis before any curative treatment in patients with a clinical stage I lesion. Show 3 more Management of early-stage disease, surgery, indications: https://web.pathway.md/diseases/recomSJPzaod1SYuA 3/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway As per ESMO 2017 guidelines: Offer surgery as the preferred treatment in all patients with stage I-II NSCLC willing to accept procedure-related risks. B Perform surgical resection in patients with a non-centrally located resectable tumor and absence of nodal metastasis on both CT and positron emission tomography. A As per ACCP 2013 guidelines: Perform surgical resection in patients with clinical stage I-II NSCLC without contraindications to operative intervention. B Consider evaluating patients with clinical stage I-II NSCLC by a thoracic surgical oncologist or a multidisciplinary team, even if the patient is considered for nonsurgical therapies, such as percutaneous ablation or stereotactic body radiation therapy. C Manage medically fit patients with clinical stage I-II NSCLC by a board-certified thoracic surgeon focusing on lung cancer. B Management of early-stage disease, surgery, approach: As per ESMO 2017 guidelines: Consider performing open thoracotomy or video-assisted thoracic surgery as appropriate to the surgeon's expertise. B Perform video-assisted thoracic surgery as the approach of choice in patients with stage I tumors. B Updated evidence: VIOLET (lung cancer) In patients with early-stage lung cancer, VATS lobectomy was superior to open lobectomy with respect to improvement in physical function at week 28. Eric Lim et al. NEJM Evid. 2022. As per ACCP 2013 guidelines, prefer a minimally invasive approach, such as video-assisted thoracic surgery (thoracoscopy), over thoracotomy for anatomic pulmonary resection in patients with clinical stage I NSCLC. B Management of early-stage disease, surgery, technique: As per ESMO 2017 guidelines, prefer anatomical resection over wedge resection. A Show 3 more As per ACCP 2013 guidelines, consider performing sleeve or bronchoplastic resection over pneumonectomy in patients with clinical stage I-II central NSCLC if complete resection can be achieved. C Show 6 more Management of early-stage disease, surgery, lymph node dissection: As per ESMO 2017 guidelines, perform lymph node dissection according to the IASLC specifications for staging. B https://web.pathway.md/diseases/recomSJPzaod1SYuA 4/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway As per ACCP 2013 guidelines, perform systematic mediastinal lymph node sampling or dissection during anatomic resection over selective or no sampling for accurate pathologic staging in patients with clinical stage I-II NSCLC. B Show 2 more Management of early-stage disease (primary radiotherapy): offer stereotactic ablative radiotherapy (a biologically equivalent tumor dose of 100 Gy, prescribed to the encompassing isodose) as the non-surgical treatment of choice in patients with stage I NSCLC. Recognize that stereotactic ablative radiotherapy for early-stage peripheral lung tumors is associated with low toxicity in patients with COPD and the elderly. B Management of early-stage disease, adjuvant chemotherapy: As per ASCO 2022 guidelines, do not offer adjuvant cisplatin-based chemotherapy routinely in patients with stage IB (3 < T 4 cm, N0M0) NSCLC. D As per ESMO 2017 guidelines, consider offering adjuvant chemotherapy in patients with R1 resection of stage IIA-IIB disease. B As per ACCP 2013 guidelines, do not offer postoperative chemotherapy in patients with completely resected pathologic stage IA-IB NSCLC unless with a clinical trial. D Management of early-stage disease, adjuvant targeted therapy: As per ASCO 2022 guidelines, offer adjuvant osimertinib in patients with stage IB (3 < T 4 cm, N0M0) NSCLC with sensitizing EGFR (Ex19del or L858R) mutations. A As per ESMO 2021 guidelines, offer adjuvant osimertinib after complete tumor resection in patients with stage IB NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations. A Management of early-stage disease (adjuvant immunotherapy): do not offer adjuvant atezolizumab routinely in patients with stage IB (3 < T 4 cm, N0M0) NSCLC. D Management of early-stage disease, adjuvant radiotherapy: As per ESMO 2017 guidelines, do not offer postoperative radiotherapy in patients with completely resected early-stage NSCLC. D Show 2 more As per ACCP 2013 guidelines, do not offer postoperative radiotherapy in patients with completely resected pathologic stage I NSCLC. D Show 2 more Management of early-stage disease (radiofrequency ablation): consider offering radiofrequency ablation in patients with stage I NSCLC with strong contraindications to surgery and/or stereotactic ablative radiotherapy. C Management of locally advanced disease, imaging for staging: As per ASCO 2022 guidelines: Elicit medical history, perform a physical examination, and obtain contrast-enhanced (if not contraindicated) CT of the chest and upper abdomen to exclude metastatic disease in patients with suspected stage III NSCLC. B https://web.pathway.md/diseases/recomSJPzaod1SYuA 5/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway Obtain FDG positron emission tomography-CT and brain imaging after CT. A As per ESMO 2017 guidelines, obtain contrast-enhanced CT of the chest and upper abdomen followed by a positron emission tomography or a combined positron emission tomography-CT with a CT technique with adequately high resolution for initial staging purposes A to rule out detectable extrathoracic and extracranial metastasis and to assess potential mediastinal lymph node involvement, ideally within 4 weeks before initiating treatment, B in all patients with stage III NSCLC planned for definitive treatment. A Obtain pathological confirmation of single positron emission tomography-positive distant lesions. B Show 3 more As per ACCP 2013 guidelines: Consider obtaining routine brain imaging with head MRI (or CT if MRI is not available) in patients with clinical stage III NSCLC, even in case of negative clinical evaluation. C Consider obtaining CT assessment of the mediastinal stage without invasive confirmation in patients with extensive mediastinal infiltration of tumor and no distant metastases. C Management of locally advanced disease, pathological staging: As per ASCO 2022 guidelines, perform a biopsy from the site that would establish the highest stage when feasible. Take into consideration the potential tissue yield for pathologic analysis and molecular sequencing. B Show 2 more As per ESMO 2017 guidelines, obtain a pretreatment pathological diagnosis before any curative treatment in patients with clinical stages II-III lesions. Show 4 more As per ACCP 2013 guidelines, obtain invasive staging of the mediastinum over staging by imaging alone in patients with discrete mediastinal lymph node enlargement (and no distant metastases) with or without positron emission tomography uptake in mediastinal nodes. B Show 6 more Management of locally advanced disease, general principles of management: As per ASCO 2022 guidelines, arrange a multidisciplinary discussion before initiating any treatment plan in patients with suspected or confirmed stage III NSCLC. B As per ESMO 2017 guidelines, ensure an experienced multidisciplinary team approach for any complex multimodality treatment strategy decision. B As per ACCP 2013 guidelines, decide on the treatment plan for patients with discrete N2 involvement by NSCLC identified preoperatively (IIIA) by a multidisciplinary team. B Management of locally advanced disease, neoadjuvant therapy: As per ASCO 2022 guidelines: Offer systemic neoadjuvant therapy in patients planned for a multimodality approach incorporating surgery. B Offer neoadjuvant chemotherapy or neoadjuvant concurrent chemoradiation in patients with N2 disease planned for surgical resection. A https://web.pathway.md/diseases/recomSJPzaod1SYuA 6/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway Landmark trials: CHECKMATE-816 In patients with stage IB to IIIA resectable non-small cell lung cancer, nivolumab plus chemotherapy was superior to chemotherapy alone with respect to a event-free survival. Patrick M Forde et al. N Engl J Med. 2022 May 26. As per ESMO 2017 guidelines, consider offering resection followed by adjuvant chemotherapy, induction chemotherapy followed by surgery, or induction chemoradiation therapy followed by surgery in patients with single station N2 disease demonstrated by preoperative pathological nodal analysis. C As per ACCP 2013 guidelines: Do not offer neoadjuvant (induction) chemotherapy or chemoradiotherapy followed by surgery in patients with infiltrative stage III (N2, 3) NSCLC and performance status 0-1 planned for curative-intent treatment. D Offer induction therapy followed by surgery or definitive chemoradiotherapy rather than surgery or radiotherapy alone in patients with discrete N2 involvement by NSCLC identified preoperatively (IIIA). A Management of locally advanced disease, surgical resection: As per ASCO 2022 guidelines, consider performing surgery (with or without adjuvant therapy) after induction therapy in patients with stage IIIA (N2) NSCLC meeting all of the following conditions: complete resection (R0) of the primary tumor and involved lymph nodes is deemed possible N3 lymph nodes are deemed to be not involved by multidisciplinary consensus perioperative (90-day) mortality is expected to be low ( 5%). C Show 2 more As per ACCP 2013 guidelines, do not perform primary surgical resection followed by adjuvant therapy in patients with discrete N2 involvement by NSCLC identified preoperatively (IIIA) unless as part of a clinical trial. D Show 2 more Management of locally advanced disease, adjuvant chemotherapy: As per ASCO 2022 guidelines, offer adjuvant platinum-based chemotherapy in patients with resected stage III NSCLC not received neoadjuvant systemic therapy. A As per ASCO 2022 guidelines, offer adjuvant cisplatin-based chemotherapy in all patients with stages IIA-IIIA NSCLC. A As per ESMO 2021 guidelines, offer adjuvant chemotherapy in patients with resected stage IIB- III NSCLC. A Consider offering adjuvant chemotherapy in patients with T2bN0, stage IIA resected primary tumor > 4 cm. B Take into account preexisting comorbidity, time from surgery, and postoperative recovery for this decision taken in a multidisciplinary tumor board. B Show 2 more https://web.pathway.md/diseases/recomSJPzaod1SYuA 7/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway As per ESMO 2017 guidelines, consider offering resection followed by adjuvant chemotherapy, induction chemotherapy followed by surgery, or induction chemoradiation therapy followed by surgery in patients with single station N2 disease demonstrated by preoperative pathological nodal analysis. C Show 2 more As per ACCP 2013 guidelines, offer postoperative platinum-based chemotherapy in patients with completely resected pathologic stage IIA-IIB (N1) NSCLC with good performance status. A Show 2 more Management of locally advanced disease, adjuvant targeted therapy: As per ASCO 2022 guidelines, consider offering adjuvant osimertinib after platinum-based chemotherapy in patients with resected stage III NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation. B As per ASCO 2022 guidelines, offer adjuvant osimertinib after chemotherapy in patients with stages IIA-IIIA NSCLC with sensitizing EGFR mutations, regardless of the PD-L1 status. A As per ESMO 2021 guidelines, offer adjuvant osimertinib after complete tumor resection in patients with stage IIA-IIIA NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations. A Updated evidence: ADAURA In adult patients with postsurgical stage IB, II, or IIIA non-small cell lung cancer who had centrally confirmed epidermal growth factor receptor mutation, osimertinib was superior to placebo with respect to overall survival at 5 years, among patients with stage II to IIIA disease. Masahiro Tsuboi et al. N Engl J Med. 2023 Jun 4. Online ahead of print. Management of locally advanced disease, adjuvant radiotherapy: As per ASCO 2022 guidelines, do not offer routine postoperative radiotherapy in patients with completely resected NSCLC with mediastinal N2 involvement without extracapsular extension received neoadjuvant or adjuvant platinum-based chemotherapy. D As per ESMO 2021 guidelines, do not offer postoperative radiotherapy in patients with completely resected stage III N2 NSCLC. D Consider offering postoperative radiotherapy only in patients with residual microscopic or macroscopic disease. D https://web.pathway.md/diseases/recomSJPzaod1SYuA 8/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway As per ACCP 2013 guidelines: Consider offering sequential adjuvant radiotherapy in patients with resected NSCLC (R0) found to have incidental (occult) N2 disease (IIIA) despite thorough preoperative staging if concern for a local recurrence is high. B Consider offering combined postoperative concurrent chemotherapy and radiotherapy in patients with incompletely resected (R1, 2) NSCLC found to have incidental (occult) N2 disease (IIIA) despite thorough preoperative staging. C Management of locally advanced disease, consolidation immunotherapy: As per ASCO 2022 guidelines, offer consolidation durvalumab for up to 12 months in patients with stage III NSCLC receiving concurrent chemoradiation without disease progression during the initial therapy. A As per ASCO 2022 guidelines, offer adjuvant atezolizumab after cisplatin-based chemotherapy in patients with stages IIA-IIIA NSCLC with PD-L1 1% except for patients with sensitizing EGFR mutations. A As per ESMO 2021 guidelines, offer durvalumab within 1-42 days after the completion of concurrent chemoradiotherapy in patients with unresectable stage III NSCLC (across all PD-L1 categories) if the disease has not progressed following platinum-based chemoradiotherapy. A Management of locally advanced disease, definitive chemoradiotherapy: As per ASCO 2022 guidelines, offer concurrent rather than sequential chemotherapy and radiotherapy in medically or surgically inoperable patients with stage III NSCLC with good performance status. A Show 4 more As per ESMO 2017 guidelines, offer concurrent chemoradiotherapy in patients with unresectable stage IIIA-IIIB NSCLC. Offer sequential chemotherapy followed by definitive radiotherapy if concurrent chemoradiotherapy is not possible. A Show 5 more As per ACCP 2013 guidelines, offer combination platinum-based chemotherapy and radiotherapy (60-66 Gy) in patients with infiltrative stage III (N2, 3) NSCLC and performance status 0-1 planned for curative-intent treatment. Do not offer radiotherapy alone. A Show 4 more Management of locally advanced disease, prophylactic cranial irradiation: As per ESMO 2017 guidelines, do not offer prophylactic cranial irradiation in patients with stage III non-small cancer lung cancer. D As per ACCP 2013 guidelines, avoid offering prophylactic cranial irradiation in patients with infiltrative stage III (N2, 3) NSCLC with a complete response after concurrent chemoradiotherapy. D Management of locally advanced disease (salvage surgery): Consider performing salvage surgery, if feasible, in patients having complications after stereotactic ablative radiotherapy. C https://web.pathway.md/diseases/recomSJPzaod1SYuA 9/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway Consider performing salvage surgery, if feasible, using the same indications as for primary surgery in progressive disease after stereotactic ablative radiotherapy, recognizing that surgery may be more difficult with higher operative risk. C Management of locally advanced disease (palliative therapy): offer palliative radiotherapy in patients with symptomatic infiltrative stage III (N2, 3) NSCLC and either performance status 3-4, comorbidities, or disease too extensive to treat with curative intent. Decide on the fractionation pattern based on the physician's judgment and the patient's needs. B Management of metastatic disease (initial assessment): elicit a complete history, including precise smoking history and comorbidities, weight loss, ECOG performance status, and perform a physical examination in patients with lung cancer. B Show 2 more Management of metastatic disease, imaging for staging: As per ESMO 2022 guidelines, obtain contrast-enhanced CT of the chest and upper abdomen, including the liver and the adrenal glands, at diagnosis. B Show 5 more As per ACCP 2013 guidelines, consider obtaining routine brain imaging with head MRI (or CT if MRI is not available) in patients with clinical stage IV NSCLC, even in case of negative clinical evaluation. C Management of metastatic disease, biopsy and histopathology: As per ESMO 2022 guidelines, stage NSCLC according to the AJCC/UICC TNM 8th edition staging manual. B Show 10 more As per ACCP 2013 guidelines, obtain further evaluation with tissue sampling to pathologically confirm the clinical stage before treatment in patients with an imaging finding (such as by positron emission tomography) suggestive of metastasis. B Management of metastatic disease, molecular testing: As per ESMO 2022 guidelines, obtain immunohistochemistry staining to reduce the NSCLC-not otherwise specified rate to < 10% of cases diagnosed. B Show 3 more As per ESMO 2022 guidelines, obtain molecular tests in patients with advanced nonSCC as well as in unusual cases of SCC, such as young (< 50 years) patients, never (< 100 cigarettes in a lifetime)/former light smokers ( 15 pack-years, all kinds of tobacco) or long-time ex-smokers (quit smoking > 15 years ago, all kinds of tobacco). B Show 4 more Management of metastatic disease (general principles of management): encourage systematic collaboration and constant communication between pathologists and interventionalists to improve diagnostic yields. Consider including the use of rapid onsite sample evaluation. B Show 3 more Management of metastatic disease, first-line therapy, any PD-L1 status: https://web.pathway.md/diseases/recomSJPzaod1SYuA 10/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway As per ESMO 2022 guidelines, offer the following combination regimens with platinum-based chemotherapy and anti-PD-L1 inhibitors as first-line therapy in patients with advanced NSCLC and a performance status of 0-1, regardless of tumor PD-L1 status and without contraindication for immune checkpoint inhibitors: pembrolizumab, pemetrexed, and platinum atezolizumab, bevacizumab, paclitaxel, and carboplatin atezolizumab, carboplatin, and nab-paclitaxel nivolumab-ipilimumab and 2 cycles of chemotherapy. A Show 6 more As per ACCP 2013 guidelines, offer a platinum-based chemotherapy regimen in patients with stage IV NSCLC and a good performance status (ECOG 0-1). A Show 4 more Management of metastatic disease (first-line therapy, PD-L1 < 50%): consider offering cemiplimab plus chemotherapy or durvalumab-tremelimumab plus platinum-based chemotherapy in patients stage IV lung cancer (either non-SCC or SCC), PD-L1 TPS 0-49%, performance status 0-1, and without known EGFR, ALK, or ROS-1 alterations. C Management of metastatic disease (first-line therapy, PD-L1 >= 50%): consider offering pembrolizumab as first-line therapy in patients with advanced NSCLC with a performance status of 0-1, tumor PD-L1 50%, and without contraindication for immune checkpoint inhibitors. Offer atezolizumab (also if immune cells 10%) or cemiplimab as alternatives. B Show 3 more Landmark trials: KEYNOTE-024 In patients with previously untreated advanced non-small cell lung cancer with PD-L expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the ALK gene, pembrolizumab was superior to chemotherapy with respect to median progression-free survival. Reck M et al. N Engl J Med. 2016 Nov 10. Management of metastatic disease (first-line therapy, ineligible for immunotherapy): Consider offering chemotherapy with platinum doublets in all patients with NSCLC, a performance status of 0-2, without major comorbidities, and with contraindications to immune checkpoint inhibitors: B offer 4 cycles of platinum-based doublets followed by less toxic maintenance monotherapy, B or 4 cycles in patients not suitable/eligible for maintenance monotherapy, B up to a maximum of 6 cycles C consider offering carboplatin plus nab-paclitaxel regimen, particularly in patients with greater risk of neurotoxicity, preexisting hypersensitivity to paclitaxel, or contraindications for standard paclitaxel premedication B https://web.pathway.md/diseases/recomSJPzaod1SYuA 11/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway offer platinum-based doublets with a third-generation cytotoxic agent, i.e., gemcitabine, vinorelbine, or taxanes, in patients with squamous-cell carcinoma without major comorbidities and performance status 0-2. B Show 7 more Management of metastatic disease, second- and third-line therapy: As per ESMO 2022 guidelines, offer second-line therapy in patients with advanced NSCLC, a performance status of 0-2, treated with first-line immune checkpoint inhibitors, and without major comorbidities. Choose the type of second-line therapy depending on the agents used in the first line. A Show 8 more Landmark trials: OAK In patients with squamous or non-squamous non-small cell lung cancer who had received one to two previous cytotoxic chemotherapy regimens for stage IIIB or IV non-small cell lung cancer, atezolizumab was superior to docetaxel with respect to overall survival in the intention-to-treat population. Rittmeyer A et al. Lancet. 2017 Jan 21. As per ACCP 2013 guidelines: Offer second-line therapy with erlotinib or docetaxel (or equivalent single-agent such as pemetrexed) in patients with stage IV NSCLC with good performance status (ECOG 0-2). A Offer third-line therapy with erlotinib in patients with stage IV NSCLC with good performance status (ECOG 0-2). B Updated evidence: POPLAR In patients with previously treated non-small cell lung cancer, atezolizumab was superior to atezolizumab with respect to overall survival. Fehrenbacher L et al. Lancet. 2016 Apr 30. Management of metastatic disease, maintenance therapy: As per ESMO 2022 guidelines, adjust the duration of treatment to clinical efficacy and tolerability. B Consider discontinuing immune checkpoint inhibitors after 2 years. B Consider discontinuing maintenance, especially nivolumab plus ipilimumab, after 2 years due to the risk of toxicity. A Landmark trials: PARAMOUNT https://web.pathway.md/diseases/recomSJPzaod1SYuA 12/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway In patients with advanced nonsquamous non-small cell lung cancer who received four cycles of pemetrexed-cisplatin induction therapy, pemetrexed was superior to placebo with respect to overall survival. Paz-Ares LG et al. J Clin Oncol. 2013 Aug 10. As per ACCP 2013 guidelines, consider switching to maintenance pemetrexed in patients with stage IV nonsquamous NSCLC not experiencing disease progression after 4 cycles of platinum- based therapy (not including pemetrexed). C Show 4 more Management of metastatic disease, genotype-driven therapy, EGFR mutation: As per ESMO 2022 guidelines, offer epidermal growth factor receptor TKIs as first-line therapy, irrespective of clinical parameters (including performance status, gender, tobacco exposure, and histology), in all patients with sensitizing EGFR mutation. A Show 13 more Landmark trials: POSEIDON (chemotherapy plus durvalumab and tremelimumab) In adult patients with epidermal growth factor receptor/ALK wild-type metastatic non-small cell lung cancer, tremelimumab plus durvalumab and chemotherapy were superior to chemotherapy with respect to a progression-free survival. Melissa L Johnson et al. J Clin Oncol. 2022 Nov 3. As per ACCP 2013 guidelines, offer an epidermal growth factor receptor TKI (gefitinib or erlotinib) as first-line therapy in patients with stage IV NSCLC and known EGFR mutations. A Updated evidence: FLAURA In patients with untreated epidermal growth factor receptor-mutation-positive advanced non- small cell lung cancer, osimertinib was superior to standard EGFR-TKI with respect to a progression-free survival. Jean-Charles Soria et al. N Engl J Med. 2018 Jan 11. Management of metastatic disease (genotype-driven therapy, BRAF mutation): Offer dabrafenib-trametinib as first-line therapy in patients with advanced NSCLC with BRAF mutation. B Consider offering platinum-based chemotherapy with or without immunotherapy as second-line therapy in never-smoker patients received BRAF-MEK inhibition as first-line therapy. B Consider offering immunotherapy with or without chemotherapy in patients with a smoking history. C Management of metastatic disease, genotype-driven therapy, KRAS G12C mutation: https://web.pathway.md/diseases/recomSJPzaod1SYuA 13/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway As per ASCO 2023 guidelines, consider offering adagrasib monotherapy in patients with advanced NSCLC with KRAS G12C mutation received prior systemic therapy with chemotherapy and anti-programmed death ligand-1 therapy. C As per ESMO 2022 guidelines, follow the first-line recommendations for metastatic NSCLC for patients with KRAS G12C mutation. Consider offering platinum-doublet chemotherapy in patients with progression on first-line monotherapy immune checkpoint inhibitors. B Offer sotorasib in patients failing prior therapy. B Offer adagrasib failing prior therapy. B Updated evidence: CodeBreak 200 In adult patients with KRASG12C-mutated advanced non-small cell lung cancer, who progressed after previous platinum-based chemotherapy and a programmed cell death protein-1 or programmed cell death-ligand 1 inhibitor, sotorasib was superior to docetaxel with respect to median progression-free survival. Adrianus Johannes de Langen et al. Lancet. 2023 Mar 4. Management of metastatic disease (genotype-driven therapy, REF fusion): offer selpercatinib or pralsetinib as first-line therapy in patients with RET fusion-positive NSCLC. B Management of metastatic disease (genotype-driven therapy, ALK rearrangement): offer alectinib, brigatinib, or lorlatinib, A and preferred over crizotinib or ceritinib, B as first-line therapy in patients with advanced NSCLC with ALK rearrangements. A Show 4 more Landmark trials: ALEX In patients with previously untreated, advanced ALK-positive non-small cell lung cancer, alectinib was superior to crizotinib with respect to a progression-free survival. Solange Peters et al. N Engl J Med. 2017 Aug 31. Management of metastatic disease (genotype-driven therapy, ROS1 rearrangement): offer crizotinib or entrectinib as first-line therapy in patients with advanced NSCLC with ROS rearrangements. B Show 3 more Management of metastatic disease (genotype-driven therapy, other genetic alterations): offer platinum-doublet chemotherapy with or without immune checkpoint inhibitors as first-line therapy in patients with MET amplification, NTRK gene fusion, HER2 mutation, or EGFR exon 20 mutation. B Show 4 more https://web.pathway.md/diseases/recomSJPzaod1SYuA 14/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway Management of metastatic disease (salvage surgery): consider offering lung resection with therapeutic intent or a salvage procedure for a primary or metastatic lesion in case of specific complications treatable with salvage surgery in highly selected patients. C Management of metastatic disease, oligometastatic disease: As per ESTRO/ASTRO 2023 guidelines, ensure a patient-centered multidisciplinary team approach for treatment decision-making in patients with oligometastatic NSCLC. E Show 23 more As per ESMO 2022 guidelines: Recognize that patients with oligometastatic disease at diagnosis may experience long-term progression-free survival following systemic therapy and local ablative therapy, such as high- dose radiotherapy or surgery, B but due to limited evidence, prefer inclusion in clinical trials. Recognize that patients with advanced NSCLC and a driver mutation with oligoprogression while on molecular-targeted therapy may benefit from local ablative therapy (high-dose radiotherapy or surgery), including improved long-term disease-free survival, but due to limited data, prefer inclusion in clinical trials. As per ESMO 2022 guidelines, obtain 18F-FDG-positron emission tomography-CT and brain imaging for staging in patients with oligometastatic NSCLC (synchronous, metachronous, oligoprogressive). B Show 2 more Management of metastatic disease (isolated brain metastasis): consider obtaining invasive mediastinal staging and extrathoracic imaging (either whole-body positron emission tomography or abdominal CT plus bone scan) in patients with isolated brain metastasis from NSCLC planned for curative-intent surgical resection. C Show 3 more Management of metastatic disease (isolated adrenal gland metastasis): consider obtaining invasive mediastinal staging and extrathoracic imaging (head CT/MRI plus either whole-body positron emission tomography or abdominal CT plus bone scan) in patients with isolated adrenal metastasis from NSCLC planned for curative-intent surgical resection. C Show 3 more Management of metastatic disease (elderly patients): offer a two-drug combination of monthly carboplatin and weekly paclitaxel in elderly patients (age 70-79 years) with stage IV NSCLC with good performance status and limited comorbidities. A Show 3 more Management of metastatic disease, palliative care: As per ESMO 2022 guidelines, offer early palliative care interventions in parallel with standard oncological care in patients with metastatic lung cancer. A As per ACCP 2013 guidelines, consider offering early palliative care combined with standard oncology care in patients with stage IV lung cancer and/or a high symptom burden. C Show 2 more https://web.pathway.md/diseases/recomSJPzaod1SYuA 15/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway Landmark trials: Early palliative care for metastatic NSLC In patients with newly diagnosed metastatic non-small cell lung cancer, within 8 weeks after diagnosis, early palliative care was superior to standard oncologic care with respect to a FACT-L quality of life scores at 12 weeks. Temel JS et al. N Engl J Med. 2010 Aug 19. Management of metastatic disease (assessment of response, genotype-driven therapy): Obtain response evaluation after 8-12 weeks of genotype-driven treatment using the same radiographic investigation that initially demonstrated the tumor lesions. B Do not obtain routine follow-up positron emission tomography due to its relatively low specificity despite a high sensitivity. B Follow the RECIST for measurements and response assessment. B Recognize that the clinical relevance of the RECIST in evaluating the response remains debatable as patients can derive benefit from continuing the same TKIs after RECIST v1.1 progression. B Management of metastatic disease (assessment of response, non-genotype-driven therapy): obtain an assessment of treatment response after 2-3 cycles of systemic therapy using the same initial radiographic investigation that demonstrated tumor lesions. B Do not obtain routine follow- up positron emission tomography due to its high sensitivity and relatively low specificity. B Show 2 more Symptomatic management (pain control): obtain a thorough assessment of patients with lung cancer experiencing chronic pain. B Show 9 more Symptomatic management (cough): obtain evaluation for other treatable causes of cough, in addition to cancer-related etiologies, in all patients with lung cancer and troublesome cough. B Show 2 more Symptomatic management, hemoptysis: As per ESMO 2022 guidelines, consider performing an endoscopy (endobronchial or by guiding endovascular embolization) for the diagnosis and treatment of hemoptysis. C Show 2 more As per ACCP 2013 guidelines: Secure the airway with a single-lumen endotracheal tube in patients with lung cancer and large-volume hemoptysis. Perform bronchoscopy to identify the source of bleeding, followed by endobronchial management options such as argon plasma coagulation, Nd-YAG laser, and electrocautery for visible central airway lesions. B Perform bronchoscopy to identify the source of bleeding in patients with lung cancer and non- large-volume hemoptysis. Offer endobronchial management options for visible central airway lesions. Offer EBRT for distal or parenchymal lesions. B Symptomatic management, airway obstruction: https://web.pathway.md/diseases/recomSJPzaod1SYuA 16/27 6/30/23, 1:18 AM Non-small cell lung cancer Pathway As per ESMO 2022 guidelines, offer EBRT in patients with hemoptysis and symptomatic airway obstruction. B Show 2 more As per ACCP 2013 guidelines, perform therapeutic bronchoscopy with mechanical debridement, brachytherapy, tumor ablation, or airway stent placement to improve dyspnea, cough, hemoptysis, and overall quality of life in patients with inoperable disease and symptomatic airway obstruction. B Symptomatic management, pleural effusion: As per ESMO 2022 guidelines: Perform talc pleurodesis to improve dyspnea in patients with persisting or recurrent pleural effusions. Consider performing thoracoscopic poudrage over injection of talc slurry in patients with primary lung cancer. B Consider performing placement of an indwelling pleural catheter or talc poudrage for the management of recurrent malignant pleural effusions. C As per ACCP 2013 guidelines, perform tunneled pleural catheter placement or chemical pleurodesis with talc in patients with symptomatic recurrent malignant pleural effusion with documented re-expandable lung. B Show 3 more Symptomatic management (trapped lung): perform indwelling pleural catheter placement or pleuroperitoneal shunting to provide symptomatic relief in patients with a trapped lung by a thickened visceral pleural peel. B Symptomatic management (tracheoesophageal fistulas): perform double stenting of the esophagus and airway or esophageal stenting with self-expanding metallic stents in patients with tracheoesophageal fistulas. B Symptomatic management, superior vena cava syndrome: As per ESMO 2022 guidelines: Consider offering radiotherapy to achieve symptom control in patients with vena cava syndrome. C Consider performing vascular stenting in patients with NSCLC-related superior vena cava compression. C As per ACCP 2013 guidelines, obtain histologic or cytologic methods to confirm the definitive diagnosis of lung cancer before initiating treatment in patients with superior vena cava obstruction from suspected lung cancer. B Show 2 more