First-Line Treatment Options for Patients with Stage IV Non-Small Cell Lung Cancer with Driver Alterations Patients with stage IV non-small cell lung cancer Nonsquamous cell carcinoma and squamous cell carcinoma Activating EGFR mutation other Sensitizing (L858R/exon 19 MET exon 14 skipping than exon 20 insertion mutations, EGFR exon 20 mutation ALK rearrangement ROS1 rearrangement BRAF V600E mutation RET rearrangement NTRK rearrangement mutations KRAS alterations HER2 alterations NRG1 alterations deletion) EGFR mutation T790M, L858R or Ex19Del PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options Emerging target; no Emerging target; no Emerging target; no Platinum doublet † † † Osimertinib monotherapy S Afatinib monotherapy M M Alectinib S Entrectinib M Dabrafenib/trametinib M Capmatinib M Selpercatinib M Entrectinib M conclusions available conclusions available conclusions available chemotherapy ± bevacizumab Gefitinib with doublet Standard treatment based on Standard treatment based on Standard treatment based on M M M Brigatinib S Crizotinib M M Tepotinib M Pralsetinib* W Larotrectinib M chemotherapy non-driver mutation guideline non-driver mutation guideline non-driver mutation guideline If alectinib or brigatinib are not available If entrectinib or crizotinib are not available Standard treatment based on Standard treatment based on Standard treatment based on Dacomitinib monotherapy M Osimertinib W M M M Ceritinib S Ceritinib W non-driver mutation guideline non-driver mutation guideline non-driver mutation guideline Monotherapy with afatinib M Crizotinib S Lortlatinib W Standard treatment based on Erlotinib/ramucirumab M M non-driver mutation guideline Erlotinib/bevacizumab M Monotherapy with erlotinib M Strength of Recommendation Monotherapy with gefitinib M S Strong M Moderate W Weak Monotherapy with icotinib M Notes. *Provisionally included pending confirmatory data † For alterations without targeted therapy options, refer to the non-driver mutation guideline (Hanna NH, Schneider BJ, Temin S, et al: Therapy for Stage IV Non–Small-Cell Lung Cancer PS 3 This algorithm is derived from recommendations in Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. This is a tool based on an ASCO Guideline and is not intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients. This tool does not purport to suggest any particular course of medical treatment. Use of the guideline and this tool are voluntary. Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. Journal of Clinical Monotherapy with osimertinib, Oncology 38:1608-1632, 2020). New active targeted therapies are anticipated soon. W gefitinib, or erlotinib www.asco.org/thoracic-cancer-guidelines ©American Society of Clinical Oncology 2021. All rights reserved. Abbreviations. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; NRG1, Neuregulin 1; NTRK, neurotrophic For licensing opportunities, contact [email protected] tropomyosin receptor kinase; PS, performance status Second- and Third-Line Treatment Options for Patients with Stage IV Non-Small Cell Lung Cancer with Driver Alterations Patients with stage IV non-small cell lung cancer Nonsquamous cell carcinoma and squamous cell carcinoma Activating EGFR mutation other MET abnormalities other than exon Sensitizing (L858R/exon 19 BRAF mutation other than MET exon 14 skipping than exon 20 insertion mutations, EGFR exon 20 mutation ALK rearrangement ROS1 rearrangement BRAF V600E mutation 14 skipping mutations or previously RET rearrangement NTRK rearrangement KRAS alterations HER2 alterations NRG1 alterations deletion) EGFR mutation T790M, L858R or Ex19Del BRAF V600E mutations treated with MET-targeted therapy Treatment Options Treatment Options Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options Treatment Options Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS 0-2 Treatment Options PS of 0-2 who have had previous EGFR- targeted Previously received alectinib or brigatinib Previously received ROS1-targeted therapy Previously received or been ineligible for first-line Previously received MET-targeted therapy Previously received RET-targeted therapy Previously received a NTRK inhibitor Previously received BRAF/MEK targeted therapy therapy (who did not receive osimertinib) & chemotherapy with or without immunotherapy Emerging target; no Emerging target; no Emerging target; no Standard treatment based on † † † subsequently have an EGFR T790M resistance mutation M conclusions available conclusions available conclusions available non-driver mutation guideline Standard treatment based on Standard treatment based on Standard treatment based on Standard treatment based on Standard treatment based on M Lorlatinib M M M Capmatinib M M M non-driver mutation guideline non-driver mutation guideline non-driver mutation guideline non-driver mutation guideline non-driver mutation guideline Osimertinib monotherapy S Previously received non-targeted therapy Previously received crizotinib Patients who did not previously receive BRAF-targeted therapy Did not previously receive RET targeted therapy Did not previously receive a NTRK inhibitor Patients with any EGFR mutation who have progressed on Tepotinib M EGFR TKIs with no T790M mutation OR whose disease Alectinib S Entrectinib M has progressed on osimertinib Dabrafenib/trametinib M Selpercatinib M Entrectinib M Standard treatment based on M Brigatinib S Crizotinib M Dabrafenib alone W non-driver mutation guideline Pralsetinib* W Larotrectinib M Ceritinib S Ceritinib M Vemurafenib W Previously received crizotinib in the first-line & either Previously received chemotherapy, immunotherapy, and alectinib, brigatinib, or ceritinib in the second-line BRAF targeted therapy setting Standard treatment based on M Lorlatinib M non-driver mutation guideline Strength of Recommendation S Strong M Moderate W Weak Standard treatment based on M non-driver mutation guideline Notes. *Provisionally included pending confirmatory data † For alterations without targeted therapy options, refer to the non-driver mutation guideline This algorithm is derived from recommendations in Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. This is a tool based on an ASCO Guideline and is not intended to substitute for the independent (Hanna NH, Schneider BJ, Temin S, et al: Therapy for Stage IV Non–Small-Cell Lung Cancer professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients. This tool does not purport to suggest any particular course of medical treatment. Use of the guideline and this tool are voluntary. Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. Journal of Clinical Oncology 38:1608-1632, 2020). New active targeted therapies are anticipated soon. Abbreviations. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; www.asco.org/thoracic-cancer-guidelines ©American Society of Clinical Oncology 2021. All rights reserved. HER2, human epidermal growth factor receptor 2; NRG1, Neuregulin 1; NTRK, neurotrophic For licensing opportunities, contact [email protected] tropomyosin receptor kinase; PS, performance status; TKI, tyrosine kinase inhibitors.