TABLE 1.

Approved targeted therapies in oncogene-driven nonsmall cell lung carcinoma

	ASCO [ 173 ]	ESMO# [174] + updated version published 15 September 2020	NCCN¶ [ 167 ] + updated version April 2021
EGFR-sensitising mutations	Afatinib, erlotinib or gefitinib Evidence quality: high Strength of recommendation: strong for each	Erlotinib, gefitinib or afatinib (I, A), or dacomitinib (I, B; MCBS score: 3) None of the four EGFR TKIs is consensually considered as a preferred option (IV, C) Osimertinib (I, A; MCBS score: 4) Erlotinib and bevacizumab (II, B; MCBS score: 3) Erlotinib and ramucirumab (I, B; MCBS score 3) Gefitinib+carboplatin and pemetrexed is a first-line option (I, B; not EMA-approved) Atezolizumab and bevacizumab with carboplatin and paclitaxel may be used after targeted therapies (III, A; not EMA-approved)	Afatinib (other recommended) Erlotinib (other recommended) Dacomitinib (other recommended) Gefitinib (other recommended) Osimertinib (preferred) Erlotinib+ramucirumab Erlotinib+bevacizumab (nonsquamous)
EGFR T790M mutation	Osimertinib Evidence quality: high Strength of recommendation: strong	Osimertinib (I, A; MCBS score: 4)	Osimertinib (category 1)
ALK fusions first-line	Crizotinib Evidence quality: strong Strength of recommendation: high	Crizotinib (I, A; MBCS score: 4), ceritinib (I, B; MCBS score: 4), alectinib (I, A; MCBS: 4), brigatinib (I, B; not EMA-approved), ensartinib (I, A; not EMA-approved) CNS involvement: alectinib (III, A), brigatinib (III, B) or ceritinib (IV, B)	Alectinib (preferred) Ceritinib (other recommended) Brigatinib (other recommended) Crizotinib (useful in certain circumstances) Lorlatinib
ALK fusions subsequent therapy		Ceritinib and alectinib after crizotinib (I, A; MBCS score: 4) Brigatinib after crizotinib (III, A; MCBS score: 3) Lorlatinib in patients who progress after a second-generation ALK TKI (III, A; MCBS score: 3)	Alectinib, brigatinib, lorlatinib, ceritinib
ROS1 rearrangement first-line	Crizotinib (informal consensus) Evidence quality: low Strength of recommendation: weak	Crizotinib (III, A; MBCS score: 3) Ceritinib (III, C; not EMA approved)	Crizotinib (category 2A; preferred) Entrectinib (category 2A; preferred) Ceritinib (category 2A)
ROS1 rearrangement subsequent lines		Lorlatinib (III, B), repotrectinib (III, B), entrectinib (III, B; MCBS score: 3)	Lorlatinib (category 2A) Entrectinib
BRAF V600E mutation positive first-line and subsequent therapy	In patients who have received prior immune checkpoint therapy, dabrafenib alone or in combination with trametinib in third-line is an option (informal consensus) Evidence quality: insufficient Strength of recommendation: moderate	Dabrafenib and trametinib in first- or second-line (III, A; MBCS score: 2)	Dabrafenib and trametinib (category 2A)
NTRK fusion first-line/subsequent therapy		Larotrectinib (III, A; MCBS score: 3), entrectinib (III, B; MCBS score: 3)	Entrectinib (category 2A) Larotrectinib (category 2A)
ERBB2		Trastuzumab deruxtecan (III, B)
MET exon 14 skipping mutation first-line/subsequent therapy		Crizotinib (III, B) Capmatinib (III, B), tepotinib (III, B)	Crizotinib Capmatinib Tepotinib
RET rearrangement positive first-line/subsequent		Not currently routinely recommended and recruitment into open trials is encouraged (II, C) Selpercatinib (III, B), pralsetinib (III, B)	Selpercatinib Pralsetinib Cabozantinib Vandetanib

ASCO: American Society of Clinical Oncology; ESMO: European Society for Medical Oncology; NCCN: National Comprehensive Cancer Network; EGFR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; ROS proto-oncogene 1; MCBS: magnitude of clinical benefit scale; TKI: tyrosine kinase inhibitor; EMA: European Medicines Agency; CNS: central nervous system. ^#: ECMO-MCBS v1.1 for new therapy/indication approved by the EMA since 1 January 2016. The score has been calculated by the ESMO-MCBS working group and validated by the ESMO guidelines committee. Levels of evidence (I to V) and grades of recommendation (A to E) for the ESMO guidelines are adapted from the Infectious Diseases Society of America–United States Public Health Service Grading System [175]; ^¶: NCCN categories of evidence and consensus include category 1 (based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate), category 2A (based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate), category 2B (based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate) and category 3 (based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate).