title: Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations.
abstract: To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations.
  
  
  
  Chemotherapy-naïve for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2:1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-free-survival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65).
  
  
  
  PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P = .014; two-sided P = .029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+G, but toxicities were manageable.
  
  
  
  P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care.
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Ying
authors: Y
authors: Cheng
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Haruyasu
authors: H
authors: Murakami
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Pan-Chyr
authors: PC
authors: Yang
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Jianxing
authors: J
authors: He
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Kazuhiko
authors: K
authors: Nakagawa
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Jin Hyoung
authors: JH
authors: Kang
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Joo-Hang
authors: JH
authors: Kim
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Xin
authors: X
authors: Wang
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Sotaro
authors: S
authors: Enatsu
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Tarun
authors: T
authors: Puri
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina.
authors: Mauro
authors: M
authors: Orlando
authors: Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin Hyoung Kang, The Catholic University of Korea, Seoul; Joo-Hang Kim, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Korea; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; and Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina. chihyang@ntu.edu.tw.
authors: James Chih-Hsin
authors: JC
authors: Yang
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068437:Pemetrexed; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib