LUGANO, Switzerland – A randomised trial in 650 patients has confirmed the safety and efficacy of a new second line treatment for metastatic colorectal cancer, researchers report at the ESMO Asia 2017 Congress. (1)
Oral fluorinated pyrimidines have been investigated to replace intravenous 5FU in colorectal cancer (CRC). Capecitabine combined with oxaliplatin (XELOX) has demonstrated comparable efficacy and safety to FOLFOX for the management of metastatic and adjuvant CRC. However, the combined capecitabine and irinotecan (XELIRI) regimen failed to replace FOLFIRI due to concerns over safety and efficacy. (2)
A modified XELIRI (mXELIRI) regimen was subsequently developed with reduced doses of irinotecan (200 mg/m2 on day 1) and capecitabine (1600 mg/m2 on days 1–14). In combination with bevacizumab it has shown favourable tolerability and efficacy comparable to XELOX plus bevacizumab in the first and second line settings. (3,4)
Following these two trials, the Asian XELIRI ProjecT (AXEPT) was designed. This multicentre, open-label, randomised phase 3 trial assessed the efficacy and safety of mXELIRI versus FOLFIRI, with or without bevacizimab, as second line treatment for patients with metastatic CRC. It was designed to demonstrate non-inferiority of the capecitabine containing regimen in terms of overall survival, with 95% confidence interval (CI) upper limit of the hazard ratio (HR) pre-specified as less than 1.3.
The trial enrolled 650 patients aged 20 years or older with histologically confirmed unresectable colorectal adenocarcinoma. Patients had been withdrawn from first line chemotherapy for mCRC due to intolerable toxicity, disease progression or relapse fewer than 180 days after the final dose of adjuvant chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive either mXELIRI with or without bevacizumab every three weeks or FOLFIRI with or without bevacizumab every two weeks.
Patients were stratified according to the following factors: (1) country (Japan versus South Korea versus China), (2) Eastern Cooperative Oncology Group (ECOG) performance status (0–1 versus 2), (3) number of metastatic sites (one versus more than one), (4) prior oxaliplatin treatment (yes versus no), and (5) concurrent bevacizumab treatment (with versus without).
After a median follow-up of 15.8 months, the median overall survival was 16.8 and 15.4 months in the mXELIRI and FOLFIRI arms, respectively (HR 0.85, 95% CI 0.71–1.02, non-inferiority test p<0.0001). Similarly, there was no statistical difference in terms of median progression-free survival between the two arms: 8.4 months (95% CI, 7.1−9.1) for patients treated with mXELIRI compared with 7.2 months (95% CI, 6.6−8.5) for those treated with FOLFIRI (HR=0.95; 95% CI, 0.81−1.11; p=0.5078).
The incidence of grade 3/4 adverse events was significantly lower in the mXELIRI arm than the FOLFIRI arm (167 [53.9%] versus 224 [72.3%] of 310 patients; p<0.0001). The most common grade 3/4 adverse event was neutropaenia (52 [16.8%] and 133 [42.9%] patients in the mXELIRI and FOLFIRI arms, respectively; p<0.0001). The incidences of grade 3/4 diarrhoea were low in both arms (7.1% and 3.2%, respectively; p=0.0443). The efficacy and safety results were similar across all prespecified subgroups.
Lead author Tae Won Kim, Professor of the Department of Oncology, Asan Medical Centre, Seoul, Korea, said: “The AXEPT trial demonstrates that modified XELIRI with or without bevacizumab has a non-inferior efficacy to FOLFIRI with or without bevacizumab and is well tolerated. The modified XELIRI regimen could be an alternative to the standard FOLFIRI regimen as a second line backbone therapy for metastatic colorectal cancer.”
Commenting on the study, Dr Rodrigo Dienstmann, principal investigator of the Oncology Data Science (ODysSey) Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain, and research scientist at the Computational Oncology Group, Sage Bionetworks, Seattle, US, said: “Capecitabine is given orally and is more convenient for patients compared to infusional 5FU. However, at the maximum doses the combination of capecitabine and irinotecan (XELIRI) can be quite toxic.”
“The main objective of AXEPT was to assess whether a reduced dose-intensity of the chemotherapy (the modified XELIRI regimen) would not negatively impact overall survival,” he continued. “As the trial met the primary endpoint, we can say that mXELIRI is non-inferior to standard FOLFIRI (with or without bevacizumab). The toxicity profile was quite favourable for the modified regimen, with less neutropaenia. The investigators observed slightly more diarrhoea, as expected, but still acceptable. This study supports the use of mXELIRI in the second line setting, with the potential to increase patient convenience.”
Regarding the need for further research, Dienstmann said: “Quality of life data will be critical to understanding the value of this regimen. We also need biomarker analysis, such as the impact of RAS status and emerging biomarkers on response to chemotherapy with or without bevacizumab and prognosis. This would help clinicians who have to optimise the sequence of chemotherapy/targeted therapy in metastatic CRC. Pharmacogenetic studies can also be insightful. There are known genetic variations within the UGT1A1 gene across Asian and non-Asian populations, which may impact on irinotecan toxicity profile. In addition, some early studies have found a favourable safety profile with modified XELIRI given every two weeks and this deserves further study.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO Asia 2017 Congress
- LBA3_PR ‘Randomized, non-inferiority, phase III trial of second-line chemotherapy for metastatic colorectal cancer (mCRC), comparing the efficacy and safety of XELIRI + bevacizumab versus FOLFIRI + bevacizumab (AXEPT)’ will be presented by Tae Won Kim during Proffered paper session 4 on Sunday, 19 November 2017, 14:30 to 16:00 (SGT) in Hall 405. Annals of Oncology, Volume 28, 2017 Supplement 10.
- Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779–4786.
- Schmiegel W, et al. Capecitabine/irinotecan or capecitabine/oxaliplatin in combination with bevacizumab is effective and safe as first-line therapy for metastatic colorectal cancer: a randomized phase II study of the AIO colorectal study group. Ann Oncol. 2013;24(6):1580–1587.
- Hamamoto Y, et al. A phase I/II study of XELIRI plus bevacizumab as second-line chemotherapy for Japanese patients with metastatic colorectal cancer (BIX study). Oncologist. 2014;19(11):1131–1132.
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Randomized, non-inferiority, phase III trial of second-line chemotherapy for metastatic colorectal cancer (mCRC), comparing the efficacy and safety of XELIRI + bevacizumab versus FOLFIRI + bevacizumab (AXEPT)
T.W. Kim1, Y.S. Park2, K. Muro3, R. Xu4, S. Han5, K. Yamazaki6, W. Wang7, J.B. Ahn8, H. Uetake9, Y. Deng10, S. Cho11, H. Matsumoto12, Y. Ba13, K-W. Lee14, T. Nishina15, T. Zhang16, S. Iwasa17, S. Morita18, J. Sakamoto19
1Oncology, Asan Medical Center, Seoul, Republic of Korea, 2Hematology-Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 3Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan, 4State Key Laboratory of Oncology in South China, Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, 5Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea, 6Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan, 7Gastrointestinal Oncology, The First People's Hospital of Foshan, Guangdong, China, 8Internal Medicine, Severance Hospital, Yonsei University, Seoul, Republic of Korea, 9Specialized Surgeries, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan, 10Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 11Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanamdo, Republic of Korea, 12Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan, 13Digestive Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China, 14Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea, 15Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan, 16Abdominal Oncology, Union Hospital Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China, 17Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan, 18Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan, 19Tokai Central Hospital, Kakamigahara, Japan
Background: Capecitabine and irinotecan combination (XELIRI) regimen has not been recommended by major guidelines due to substantial toxicities. Recently, modified XELIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1–14 every 3 weeks: mXELIRI) has shown favorable tolerability and efficacy with or without bevacizumab (BEV). We conducted “Asian XELIRI ProjecT” (AXEPT) to demonstrate the OS non-inferiority of XELIRI6BEV versus standard FOLFIRI6BEV as second-line chemotherapy for mCRC.
Methods: Patients with histologically confirmed mCRC, ECOG performance status (PS) 0–2, and disease progression or intolerance of the first-line regimen were eligible. Patients were randomized (1:1) to receive standard FOLFIRI6BEV (5 mg/kg on day 1), repeated every 2 weeks (FOLIRI arm) or mXELIRI6BEV (7.5 mg/kg on day 1) repeated every 3 weeks (mXELIRI arm). A total of 464 events were estimated as necessary to show OS non-inferiority with a power of 80% at a one-sided a of 0.025, requiring a target sample size of 600 patients. The 95% confidence interval upper limit of the hazard ratio was pre-specified as less than 1.3. Stratification factors included country, ECOG PS, number of metastatic sites, prior oxaliplatin treatment, and concomitant BEV treatment.
Results: Between Dec 2013 and Aug 2015, 650 patients were enrolled and randomized either to receive mXELIRI6BEV (n=326) or FOLFIRI6BEV (n=324). After a median follow-up of 15.8months (IQR; 8.7–24.9), median overall survival was 16.8 months in the mXELIRI arm and 15.4 months in the FOLFIRI arm (HR 0.85, 95% CI 0.71–1.02, non-inferiority test p<0.0001). Overall, the incidence of grade 3/4 adverse events with mXELIRI was significantly lower than that with FOLFIRI (53.9% vs 72.3%; p<0.0001). The most common grade 3/4 adverse event was neutropenia 16.8% and 42.9% patients in mXELIRI and FOLFIRI arms, respectively; p<0_0001). The incidences of grade 3/4 diarrhea were low in both arms (7.1% vs 3.2%; p=0.0443).
Conclusions: mXELIRI6Bev is well-tolerated and non-inferior to FOLFIRI6Bev in terms of OS. mXELIRI could be an alternative to FOLFIRI as a standard second-line backbone treatment for mCRC.
Clinical trial identification: NCT01996306; UMIN000012263
Legal entity responsible for the study: This trial is supported by Epidemiological and Clinical Research Information Network (ECRIN: global sponsor).
Funding: This trial was funded by Chugai Pharmaceutical Co., Ltd. and F. Hoffmann-La Roche Ltd.
Disclosure: T.W. Kim: Research Fund: Roche, Merck Serono, Bayer.
K. Muro: Research grants from MSD, Daiichi Sankyo, Ono, Shionogi, Kyowa Hakko Kirin, and Gilead Sciences, and also honoraria from Chugai, Takeda, Eli Lilly, Merck Serono, Taiho, and Yakult.
K. Yamazaki: Honoraria: Takeda, Chugai, Taiho, Yakult, Merck Serono, Bristol Myers Squib, Lily, Sanofi
S. Morita: Honoraria from Chugai and Daiichi-Sankyo.
All other authors have declared no conflicts of interest.
Keyword: Metastatic colorectal cancer, XELIRI, Bevacizumab, Second-line