Takashi Seto1, Terufumi Kato2, Makoto Nishio3, Koichi Goto4, Shinji Atagi5, Yukio Hosomi6, Noboru Yamamoto7, Toyoaki Hida8, Makoto Maemondo9, Kazuhiko Nakagawa10, Seisuke Nagase11, Isamu Okamoto12, Takeharu Yamanaka13, Kosei Tajima14, Ryosuke Harada14, Masahiro Fukuoka15, Nobuyuki Yamamoto16. 1. National Kyushu Cancer Center, Fukuoka, Japan. 2. Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan. 3. The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan. 4. National Cancer Center Hospital East, Chiba, Japan. 5. Kinki-chuo Chest Medical Center, Osaka, Japan. 6. Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan. 7. National Cancer Center Hospital, Tokyo, Japan. 8. Aichi Cancer Center, Aichi, Japan. 9. Miyagi Cancer Center, Miyagi, Japan. 10. Kinki University Faculty of Medicine, Osaka, Japan. 11. Tokyo Medical University Hospital, Tokyo, Japan. 12. Kyushu University Hospital, Fukuoka, Japan. 13. National Cancer Center, Chiba, Japan. 14. Chugai Pharmaceutical Co Ltd, Tokyo, Japan. 15. Izumi Municipal Hospital, Osaka, Japan. 16. Wakayama Medical University, Wakayama, Japan. Electronic address: nbyamamo@wakayama-med.ac.jp.
Abstract
BACKGROUND: With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. METHODS: In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease receivederlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. FINDINGS:Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9-18·1) with erlotinib plus bevacizumab and 9·7 months (5·7-11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36-0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group). INTERPRETATION:Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted. FUNDING: Chugai Pharmaceutical Co Ltd.
RCT Entities:
BACKGROUND: With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. METHODS: In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. FINDINGS: Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9-18·1) with erlotinib plus bevacizumab and 9·7 months (5·7-11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36-0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group). INTERPRETATION:Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted. FUNDING: Chugai Pharmaceutical Co Ltd.
Authors: Daria Gaut; Myung Shin Sim; Yuguang Yue; Brian R Wolf; Phillip A Abarca; James M Carroll; Jonathan W Goldman; Edward B Garon Journal: Clin Lung Cancer Date: 2017-06-20 Impact factor: 4.785
Authors: Cathy J Bradley; K Robin Yabroff; Angela B Mariotto; Christopher Zeruto; Quyen Tran; Joan L Warren Journal: J Clin Oncol Date: 2017-01-03 Impact factor: 44.544
Authors: Suresh S Ramalingam; Suzanne E Dahlberg; Chandra P Belani; Joel N Saltzman; Nathan A Pennell; Gopakumar S Nambudiri; John C McCann; Jerome D Winegarden; Mohammed A Kassem; Mohamed K Mohamed; Jan M Rothman; Alan P Lyss; Leora Horn; Thomas E Stinchcombe; Joan H Schiller Journal: J Clin Oncol Date: 2019-07-30 Impact factor: 44.544