Jean-Charles Soria1, Yi-Long Wu2, Kazuhiko Nakagawa3, Sang-We Kim4, Jin-Ji Yang2, Myung-Ju Ahn5, Jie Wang6, James Chih-Hsin Yang7, You Lu8, Shinji Atagi9, Santiago Ponce10, Dae Ho Lee4, Yunpeng Liu11, Kiyotaka Yoh12, Jian-Ying Zhou13, Xiaojin Shi14, Alan Webster15, Haiyi Jiang14, Tony S K Mok16. 1. Department of Medicine, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif, France. 2. Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. 3. Department of Medical Oncology, The Faculty of Medicine, Kinki University, Osakasayama City, Osaka, Japan. 4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 5. Division of Hematology-Oncology, Department of Medicine, The Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 6. Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China. 7. Department of Oncology, The National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. 8. Department of Thoracic Cancer, Cancer Centre, West China Hospital, West China Medical School, Sichuan University, Sichuan, China. 9. Department of Thoracic Oncology, Kinki-chuo Chest Medical Center, Osaka, Japan. 10. Medical Oncology Service, Hospital Universitario 12 de Octubre, Madrid, Spain. 11. Department of Medical Oncology, The First Hospital of China Medical University, Shengyang City, China. 12. Division of Thoracic Oncology, National Cancer Centre Hospital East, Chiba, Japan. 13. Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Zhejiang, China. 14. AstraZeneca, Shanghai, China. 15. AstraZeneca, Macclesfield, UK. 16. State Key Laboratory of South China, Hong Kong Cancer Institute, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong, China. Electronic address: tony@clo.cuhk.edu.hk.
Abstract
BACKGROUND: Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. METHODS: The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. FINDINGS:Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to theplacebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65-1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5-5·7 in the gefitinib group and 4·6-5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. INTERPRETATION: Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting. FUNDING: AstraZeneca.
RCT Entities:
BACKGROUND: Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. METHODS: The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. FINDINGS: Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65-1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5-5·7 in the gefitinib group and 4·6-5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. INTERPRETATION: Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting. FUNDING: AstraZeneca.
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