Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial
Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated.
Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population.
Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients ³70 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046).
Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly prolong DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy.Clinical trial information: UMIN000006252.
Author(s) and affiliation(s): Hirohito Tada, Tetsuya Mitsudomi, Takeharu Yamanaka, Kenji Sugio, Masahiro Tsuboi, Isamu Okamoto, Yasuo Iwamoto, Noriaki Sakakura, Shunichi Sugawara, Shinji Atagi, Toshiaki Takahashi, Hidetoshi Hayashi, Morihito Okada, Hiroshige Yoshioka, Hidetoshi Inokawa, Kazuhisa Takahashi, Masahiko Higashiyama, Ichiro Yoshino, Kazuhiko Nakagawa, West Japan Oncology Group; Suita Tokushukai Hospital, Suita, Japan; Department of Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan; Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan; Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan; Department of Thoracic Surgery and Oncology, National Cancer Center Hospital East, Chiba, Japan; Kyushu University Hospital, Fukuoka, Japan; Department of Medical Oncology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; Aichi cancer center, Nagoya, Japan; Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan; Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan; Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan; Kindai University Faculty of Medicine, Osaka, Japan; Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan; Kansai Medical University, Hirakata, Japan; Yamaguchi-Ube Medical Center, Ube, Japan; Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan; Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardivascular Diseases, Osaka, Japan; Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan; Kindai University Hospital, Osaka, Japan
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