1. Introduction: In recent years, the discovery of targetable gene alterations such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements has revolutionized the therapeutic approach to advanced NSCLC. The outstanding activity shown by EGFR-and ALK- tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients with EGFR mutations or ALK rearrangements, respectively, leads to the logical question of what role these agents may have if used in the adjuvant setting. 2. Rationale for adjuvant targeted therapy: At the present time there is no evidence suggesting a worse prognosis for EGFR-mutated NSCLC in early stage disease [1]. Similarly, retrospective studies exploring the impact of ALK rearrangements in early stage NSCLC suggested that ALK status lacks a prognostic role, as no significant difference in DFS was found between ALK-rearranged and ALK-negative patients [2-3]. Nevertheless, EGFR mutations and ALK rearrangements are both highly predictive of response to selected targeted therapy in advanced NSCLC. 3. Prospective trials: See table. 4. Conclusions and future directions A critical issue is how to select the patients who may need adjuvant targeted therapy. Measurement of residual disease by circulating tumor cells and/or DNA could help identify the high-risk population. However, for these patients it should be clarified whether targeted therapy should be used sequentially after platinum-based chemotherapy or as stand-alone treatment; therefore, better understanding of the biology at recurrence and novel testing strategies for residual disease are crucial in order to help select those patients who could benefit the most from adjuvant targeted therapy. 5. (1) Liang W, He Q, Wang W, et al. The impact of EGFR mutations on the prognosis of resected non-small cell lung cancer: a meta-analysis of literature. Ann Oncol 2017;28:abstr ii20-3. (2) Paik JH, Choi CM, Kim H, et al. Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma. Lung Cancer 2012;76:403-9. (3) Pan Y, Zhang Y, Li Y, et al. ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: a comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features. Lung Cancer 2014;84:121-6. (4) Goss GD, O'Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol 2013;31:3320-6. (5) Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2015;33:4007-14. (6) Pennell NA, Neal JW, Chaft JE, et al. SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. J Clin Oncol 2014;32:abstr 7514. (7) Li N, Ou W, Ye X, et al. Pemetrexed-carboplatin adjuvant chemotherapy with or without gefitinib in resected stage IIIA-N2 non-small cell lung cancer harbouring EGFR mutations: a randomized, phase II study. Ann Surg Oncol 2014;21:2091-6. (8) Feng S, Wang Y, Cai K, et al. Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy. PLoS One 2015;10:e0140794. (9) Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148. Targeted therapy, ADJUVANTTabled 1Prospective trials of an EGFR-TKI as adjuvant treatmentAuthor, phaseStage, biomarker selectionNo. of pts, designLength of exposure to EGFR-TKIPrimary end-pointResults for primary end-pointGoss et al., 3 (NCIC CTG BR.19) [4]IB–IIIA, unselected503, gefitinib vs. placebo2 yearsOSHR =1.24, P=0.14Kelly et al., 3 (RADIANT) [5]IB→IIIA, EGFR + by IHC and/or FISH973, erlotinib vs. placebo (2:1)2 yearsDFSHR =0.90, P=0.324Pennel et al., 2 (SELECT) [6]IA→IIIA100, erlotinib2 yearsDFS2-year DFS rate =90%Li et al., 2, randomized [7]IIIA (N2), EGFR mutation60, CBDCA/PEM → gefitinib vs. carboplatin/pemetrexed6 monthsDFSHR =0.37, P=0.014Feng et al., 2, randomized [8]IB (high risk)*→IIIA, EGFR mutation41, platinum-based chemotherapy → icotinib vs. platinum-based chemotherapy4–8 monthsDFS2-year DFS 90.5% vs. 66.7%, P=0.066Wu et al., 3 (CTONG 1104) [9]II–IIIA (N1,N2), EGFR mutation222, gefitinib ×2 years vs. cisplatin/vinorelbine2 yearsDFS28.7 vs. 18.0 months, HR =0.60, P=0.05EVANIIIA (N2), EGFR mutation222, erlotinib ×2 years vs. cisplatin/vinorelbine2 years2 years -DFSR81.35% vs. 44.62%, P<0.001Ongoing randomized phase 3 trials of an EGFR-TKI as adjuvant treatment for patients with EGFR mutant NSCLCClinical trialRegionStage, planned accrual, EGFR mutationStudy designPrimary end-pointNCT02125240 (ICWIP)ChinaII→IIIA, 300, ex19del and L858RRand. to icotinib ×2 years vs. placebo ×2 years (platinum-based chemotherapy ×4 cycles)DFSNCT01996098 (ICTAN)ChinaII→IIIA, 477, ex19del and L858RRand. to icotinib ×12 months vs. icotinib ×6 months vs. observation (platinum-based chemotherapy ×4 cycles)DFSNCT02193282 (ALCHEMIST)U.S.IB (≥4 cm)-IIIA, 450, ex19del and L858R without T790MRand. to erlotinib ×2 years vs. placebo ×2 years (after standard adjuvant chemotherapy)OSNCT02201992 (ALCHEMIST)U.S.IB (≥4 cm)-IIIA, 378, ALK-positiveRand. to crizotinib ×2 years vs. placebo for 2 years (after standard adjuvant chemotherapy)OSWJOG6401LJapanII→IIIA, 230, ex19del and L858R without T790MRand. to gefitinib ×2 years vs. cisplatin/vinorelbine ×4 cycles5-year DFSNCT02448797 (EVIDENCE)ChinaII→IIIA, 320, ex19del and L858RRand. to icotinib ×2 years vs. cisplatin/vinorelbine ×4 cyclesDFSNCT02518802ChinaII→IIIA (N1, N2), 220, ex19del and L858RRand. to cisplatin/pemetrexed ×4 cycles + gefitinib ×2 years vs. cisplatin/pemetrexed ×4 cyclesDFSNCT01996098 (ICTAN)ChinaII→IIIA, 477, ex19del and L858RRand. to icotinib ×12 months vs. icotinib ×6 months vs. observation (platinum-based chemotherapy ×4 cycles)DFSNCT02511106 (ADAURA)InternationalIB→IIIA, 700, ex19del and L858R ± other EGFR mutationRand. to osimertinib ×2 years vs. placebo ×2 years (standard adjuvant chemotherapy allowed)DFS Open table in a new tab