Recommendations for first-line treatment of patients: no EGFR photosensitive mutations or ALK gene recombination and a physical status (PS) of 0 to 1 (or PS2 if appropriate): various combinations of cytotoxic chemotherapy are recommended. Preferred platinum-based two-drug therapy is complemented by palliative care and symptom management. If there are no contraindications, cisplatin in combination with bevacizumab, plus paclitaxel, is recommended. For PS2: combination or single agent chemotherapy or palliative therapy alone may be used. For photosensitive EGFR mutations: afatinib, erlotinib or gefitinib are recommended. For ALK gene recombination: crizotinib is recommended. For ROS1 recombination: crizotinib is recommended. For large cell neuroendocrine carcinoma: may combine platinum and etoposide or perform the same treatment as other patients with non-squamous cell carcinoma. First-line cytotoxic chemotherapy should be discontinued in patients with non-responsive stable disease (no change) who have worsening disease or after 4 courses of therapy. For stable or non-responsive disease after 4 courses of first-line therapy that includes pemetrexed: ongoing maintenance therapy with pemetrexed may be used; alternative chemotherapy (replacement therapy) may be used if initial therapy does not include pemetrexed, or termination of chemotherapy may be recommended before disease progression. Recommendations for second-line therapy for patients: For non-squamous cell carcinoma (NSCC): may receive docetaxel, erlotinib, gefitinib, or pemetrexed. For SCC: receive docetaxel, erlotinib, or gefitinib (quality of evidence: high; grade of recommendation: strong). For photosensitive EGFR mutations that do not respond to a first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI): the combination cytotoxic chemotherapy listed in the First-line Therapy section is recommended for patients with NSCC. For photosensitive EGFR mutations that have received a first-line EGFR TKI and have worsened after initial response: switch to chemotherapy or another EGFRTKI as second-line therapy. For ALK recombination and progression after treatment with first-line crizotinib: chemotherapy or cretinoin may be offered. Recommendations for patients on third-line therapy: Patients already receiving erlotinib or gefitinib and with PS 0 to 3: erlotinib may be recommended. Insufficient data to recommend routine third-line cytotoxic agents.