Distinct Epidemiology and Clinical Consequence of Classic Versus Rare EGFR Mutations in Lung Adenocarcinoma Zoltan Lohinai, MD, Mir Alireza Hoda, MD,

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Distinct Epidemiology and Clinical Consequence of Classic Versus Rare EGFR Mutations in Lung Adenocarcinoma Zoltan Lohinai, MD, Mir Alireza Hoda, MD, Katalin Fabian, MD, Gyula Ostoros, MD, PhD, Erzsebet Raso, PhD, Tamas Barbai, MS, Jozsef Timar, MD, PhD, DSc, Ilona Kovalszky, MD, PhD, Mihaly Cserepes, MS, Anita Rozsas, MS, Viktoria Laszlo, PhD, Michael Grusch, PhD, Walter Berger, PhD, Walter Klepetko, MD, Judit Moldvay, MD, PhD, Balazs Dome, MD, PhD, Balazs Hegedus, PhD Journal of Thoracic Oncology Volume 10, Issue 5, Pages 738-746 (May 2015) DOI: 10.1097/JTO.0000000000000492 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Patient cohort and mutational analysis flow chart (n = 814 patients). Journal of Thoracic Oncology 2015 10, 738-746DOI: (10.1097/JTO.0000000000000492) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Distribution and epidemiology of KRAS and EGFR mutations in lung adenocarcinoma patients. A, Mutational status in the full cohort (n = 814). B, There was no significant association between mutational status and gender. C, Patients with KRAS mutation were significantly younger than those with classic EGFR mutations or with EGFR/KRAS double WT tumors (p = 0.0002). D, In contrast to classic EGFR mutations, rare EGFR mutations were significantly associated with smoking (p = 0.0062). EGFR, epidermal growth factor receptor; WT, wild-type. Journal of Thoracic Oncology 2015 10, 738-746DOI: (10.1097/JTO.0000000000000492) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Kaplan–Meier curves for the OS of advanced lung adenocarcinoma patients (n = 419). A, ECOG PS 1–2 (vs. ECOG PS 0; p < 0.0001), (B) stages IIIB–IV (vs. stage IIIA; p = 0.002), and (C) smoking (vs. never-smoking; p = 0.006) were significant prognostic factors for reduced OS. D, Moreover, patients with tumors harboring classic EGFR mutations had a significantly better OS than those with EGFR/KRAS double WT (p = 0.02) or with KRAS mutant tumors (p = 0.002). Importantly, EGFR classic mutation was not associated with benefit in OS if these patients were compared with the rare EGFR mutant cohort (p = 0.529). OS, overall survival; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; WT, wild-type. Journal of Thoracic Oncology 2015 10, 738-746DOI: (10.1097/JTO.0000000000000492) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Anti-EGFR tyrosine kinase inhibitor treatment in advanced lung adenocarcinoma patients with confirmed sensitizing (classic EGFR mutations pooled together with patients with sensitizing rare EGFR mutations [G719x and L861Q]) versus all other rare EGFR mutations. A, Irrespective of treatment line, patients with sensitizing EGFR mutations responded significantly better to TKI therapy (data presented as number of patients; p = 0.047). Furthermore, these patients had significantly longer PFS (B) and OS (C) than those with other rare EGFR mutations (p = 0.043 and 0.01, respectively). EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PFS, progression-free survival; OS, overall survival. Journal of Thoracic Oncology 2015 10, 738-746DOI: (10.1097/JTO.0000000000000492) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions