Jin Li1, Shukui Qin2, Ruihua Xu3, Thomas C C Yau4, Brigette Ma5, Hongming Pan6, Jianming Xu7, Yuxian Bai8, Yihebali Chi9, Liwei Wang10, Kun-Huei Yeh11, Feng Bi12, Ying Cheng13, Anh Tuan Le14, Jen-Kou Lin15, Tianshu Liu16, Dong Ma17, Christian Kappeler18, Joachim Kalmus18, Tae Won Kim19. 1. Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. 2. Department of Medical Oncology, Chinese People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing, China. 3. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 4. Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. 5. Department of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China. 6. Medical Oncology, Sir Run Run Shaw Hospital Medical School, Zhejiang University, Hangzhou, China. 7. Beijing 307 People's Liberation Army Hospital Cancer Centre, Beijing, China. 8. Third Affiliated Hospital of Harbin Medical University, Harbin, China. 9. Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China. 10. Comprehensive Cancer Center, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China. 11. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 12. Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China. 13. Jilin Provincial Tumor Hospital, Changchun, China. 14. Department of Oncology, Cho Ray Hospital, Ho Chi Minh City, Vietnam. 15. Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan. 16. Department of Medical Oncology, Zhong Shan Hospital, Fudan University, Shanghai, China. 17. Department of Medical Oncology, Guangdong General Hospital, Guangzhou, Guangdong, China. 18. Bayer Pharma AG, Berlin, Germany. 19. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, South Korea. Electronic address: twkimmd@amc.seoul.kr.
Abstract
BACKGROUND: In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. METHODS: In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. FINDINGS:Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive eitherregorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40-0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3-9·8] in the regorafenib group vs 6·3 months [4·8-7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group. INTERPRETATION: This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting. FUNDING: Bayer HealthCare Pharmaceuticals.
RCT Entities:
BACKGROUND: In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. METHODS: In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. FINDINGS: Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40-0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3-9·8] in the regorafenib group vs 6·3 months [4·8-7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group. INTERPRETATION: This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting. FUNDING: Bayer HealthCare Pharmaceuticals.
Authors: Janneke F Linnekamp; Sander R van Hooff; Pramudita R Prasetyanti; Raju Kandimalla; Joyce Y Buikhuisen; Evelyn Fessler; Prashanthi Ramesh; Kelly A S T Lee; Grehor G W Bochove; Johan H de Jong; Kate Cameron; Ronald van Leersum; Hans M Rodermond; Marek Franitza; Peter Nürnberg; Laura R Mangiapane; Xin Wang; Hans Clevers; Louis Vermeulen; Giorgio Stassi; Jan Paul Medema Journal: Cell Death Differ Date: 2018-01-05 Impact factor: 15.828
Authors: Rachel P Riechelmann; Luiz S Leite; Giovanni M Bariani; Joao Glasberg; Thomas G Rivelli; Leonardo Gomes da Fonseca; Daniela R Nebuloni; Maria I Braghiroli; Marcelo A Queiroz; Alice M Isejima; Christian Kappeler; Luciana Kikuchi; Paulo M Hoff Journal: Oncologist Date: 2019-06-07