NOTCH1 and CREBBP co‐mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR‐mutated NSCLC: translational research of phase III IMPACT study

• Published in: Molecular oncology Vol. 18; no. 2; pp. 305 - 316
• Main Authors: Ikeda, Satoshi, Tsuboi, Masahiro, Sakai, Kazuko, Misumi, Toshihiro, Akamatsu, Hiroaki, Shoda, Hiroyasu, Sakakura, Noriaki, Nakamura, Atsushi, Ohde, Yasuhisa, Hayashi, Hidetoshi, Okishio, Kyoichi, Okada, Morihito, Yoshino, Ichiro, Okami, Jiro, Takahashi, Kazuhisa, Ikeda, Norihiko, Tanahashi, Masayuki, Tambo, Yuichi, Saito, Haruhiro, Toyooka, Shinichi, Inokawa, Hidetoshi, Chen‐Yoshikawa, Toyofumi, Yokoyama, Toshihide, Okamoto, Tatsuro, Yanagitani, Noriko, Oki, Masahide, Takahama, Makoto, Sawa, Kenji, Tada, Hirohito, Nakagawa, Kazuhiko, Mitsudomi, Tetsuya, Nishio, Kazuto
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2024; John Wiley and Sons Inc; Wiley
• Subjects: adjuvant therapy; Biomarkers; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - surgery; Chemotherapy; Cisplatin; Comparative analysis; CREB-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein; early‐stage; Epidermal growth factor; epidermal growth factor receptor; Epidermal growth factor receptors; ErbB Receptors - genetics; Ethics; Gefitinib; Gene mutations; Genetic aspects; Humans; Kinases; Lung Cancer; Lung cancer, Non-small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - surgery; Multivariate analysis; Mutation; Mutation - genetics; Non-small cell lung carcinoma; non‐small cell lung cancer; Notch1 protein; Oncology, Experimental; p53 Protein; Patients; Pharmaceutical industry; Protein binding; Protein Kinase Inhibitors - adverse effects; Proteins; Receptor, Notch1 - genetics; Review boards; Small cell lung carcinoma; Statistical analysis; Translational Research, Biomedical; Tumor proteins; Tumors; tyrosine kinase inhibitor; Vinorelbine; Vinorelbine - therapeutic use; United Kingdom; France; United States; Japan; Germany; United States > US; non-small cell lung cancer; adjuvant therapy; early-stage; tyrosine kinase inhibitor; epidermal growth factor receptor
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13542

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC). Although the primary endpoint of disease‐free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer‐related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co‐mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co‐mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co‐mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07–28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co‐mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR‐mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively. This study explored biomarkers of adjuvant therapy for resected epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer using tumor specimens from the phase III IMPACT study. NOTCH1 co‐mutation can serve as a poor prognostic factor for overall survival in the gefitinib group while probably predicting a poor response to adjuvant EGFR‐TKI. Meanwhile, CREBBP co‐mutation may be a biomarker for predicting a poor response to adjuvant platinum‐based chemotherapy.