A randomized trial in 650 patients has confirmed the safety and efficacy of a new second-line treatment for metastatic colorectal cancer, researchers reported at the European Society for Medical Oncology (ESMO) Asia 2017 Congress (Abstract LBA3_PR).
Oral fluorinated pyrimidines have been investigated to replace intravenous fluorouracil (5-FU) in colorectal cancer. Capecitabine combined with oxaliplatin (XELOX) has demonstrated comparable efficacy and safety to leucovorin, 5-FU, and oxaliplatin (FOLFOX) for the management of metastatic and adjuvant colorectal cancer. However, the combined capecitabine and irinotecan (XELIRI) regimen failed to replace leucovorin, 5-FU, and irinotecan (FOLFIRI) due to concerns over safety and efficacy.
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 (Avastin), it has shown favorable tolerability and efficacy comparable to XELOX plus bevacizumab in the first- and second-line settings.
Following these two trials, the Asian XELIRI ProjecT (AXEPT) was designed. This multicenter, open-label, randomized phase III trial assessed the efficacy and safety of mXELIRI vs FOLFIRI, with or without bevacizimab, as second-line treatment for patients with metastatic colorectal cancer. It was designed to demonstrate noninferiority of the capecitabine-containing regimen in terms of overall survival, with 95% confidence interval (CI) upper limit of the hazard ratio (HR) prespecified 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 Patients had been withdrawn from first-line chemotherapy for metastatic colorectal cancer due to intolerable toxicity, disease progression, or relapse fewer than 180 days after the final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 3 weeks or FOLFIRI with or without bevacizumab every 2 weeks.
Patients were stratified according to the following factors: country (Japan vs South Korea vs China); Eastern Cooperative Oncology Group (ECOG) performance status (0–1 vs 2); number of metastatic sites (one vs more than one); prior oxaliplatin treatment (yes vs no); and concurrent bevacizumab treatment (with vs 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, noninferiority test P < .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 = .5078).
The incidence of grade 3/4 adverse events was significantly lower in the mXELIRI arm than the FOLFIRI arm (167 [53.9%] vs 224 [72.3%] of 310 patients; P < .0001). The most common grade 3/4 adverse event was neutropenia (52 [16.8%] and 133 [42.9%] patients in the mXELIRI and FOLFIRI arms, respectively; P < .0001). The incidences of grade 3/4 diarrhea were low in both arms (7.1% and 3.2%, respectively; P = .0443). The efficacy and safety results were similar across all prespecified subgroups.
Lead author Tae Won Kim, MD, Professor of the Department of Oncology at Asan Medical Centre in Seoul, Korea, said, “The AXEPT trial demonstrates that modified XELIRI with or without bevacizumab has a noninferior 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.”
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