Prognostic impact of targetable driver alterations in resected early-stage lung cancer

Background: Apart from ALK fusions and the common EGFR mutations, targetable molecular alterations are irrelevant for adjuvant treatment decision making in early-stage non-small cell lung cancer (NSCLC). This retrospective analysis aimed to investigate if there is a difference in recurrence-free survival in stage I-III NSCLC harboring druggable molecular alterations compared to subtypes without targetable molecular alterations. Methods: All consecutive patients who underwent surgery with curative intent for NSCLC (stage I-III) with targetable mutations between January 2015 and December 2020 at three Austrian institutions were identified and compared with tumors without targetable molecular alterations. Tumors with the EGFR- mutated subtype were excluded due to already existing results from prospective trials. Results: One hundred and sixty subjects had tumors with molecular alterations and 355 subjects served as control cohort. There was a higher prevalence of female sex (P<0.001) and never-smokers (P=0.01) among patients with tumors harboring oncogenic driver mutations. The three most common alterations were the KRAS G12C mutation (n=92), ALK fusions (n=21), and the BRAF V600E mutation (n=15). The 1-, 3- and 5-year cumulative incidence of recurrence estimates were 16%, 38% and 46% in patients without molecular alterations and 16%, 38% and 48% in patients with the KRAS G12C mutation and 12%, 33% and 55% in patients with other molecular alterations, respectively (P=0.89). Univariable predictors of an increased recurrence risk were higher tumor stage (P<0.001), receipt of neoadjuvant treatment (P<0.001) and receipt of adjuvant treatment (P=0.03). The lack of association between molecular alteration status and recurrence risk prevailed after multivariable adjustment for tumor stage and perioperative treatment (P=0.82 for KRAS G12C mutation and P=0.43 for any other molecular alteration). Conclusions: NSCLC patients with resected tumors that harbor molecular alterations have the same recurrence risk as patients with tumors without molecular alterations if treated with surgery plus chemotherapy when indicated.