Efficacy and Safety of mXELIRI Regimen versus Standard FOLFIRI Regimen, W or W/o Bevacizumab as a Second-line Therapy for Metastatic Colorectal Cancer

14 Oct, 20

Introduction

Modified XELIRI (mXELIRI; capecitabine plus irinotecan) regimen has shown promising efficacy and tolerability profiles in the first-line and second-line settings.

To compare the efficacy and safety of the mXELIRI regimen with that of standard FOLFIRI (leucovorin, fluorouracil, and irinotecan), with or without bevacizumab in both regimens, as second-line therapy for metastatic colorectal cancer.

Patient Profile

Patients who were aged 20 years or older with histologically confirmed and unresectable colorectal adenocarcinoma, and who had withdrawn from first-line chemotherapy for metastatic colorectal cancer

Methods

Multicentre, open-label, randomised, noninferiority, phase 3 trial in 98 hospitals from three countries: Japan (n=73), South Korea (n=8), and China (n=17)

Study Design

16 patients in the mXELIRI group and 14 in the FOLFIRI group were identified as ineligible after enrolment or did not receive any study treatment

Study Regimen

mXELIRI: Irinotecan 200 mg/m² intravenously on day 1 plus oral capecitabine 800 mg/m² twice daily on days 1−14, repeated every 21 days, with or without bevacizumab 7·5 mg/kg intravenously on day 1
FOLFIRI with or without: Irinotecan 180 mg/m² intravenously on day 1, leucovorin 200 mg/m² intravenously on day 1, fluorouracil 400 mg/m² intravenously on day 1, and a 46-h continuous intravenous infusion of fluorouracil [2400 mg/m²], repeated every 14 days, with or without the addition of bevacizumab 5 mg/kg intravenously on day 1

Study Endpoint

The primary endpoint was overall survival, defined as the time from the date of randomisation to the date of death from any cause.
Secondary endpoints were
- progression-free survival (from the date of randomisation to the date of confirmed progression or death from any cause, whichever occurred first)
- time to treatment failure (from the date of randomisation to the date of confirmed progression, death from any cause, or discontinuation of protocol treatment, whichever occurred first)
- overall response (the proportion of eligible patients with measurable lesions at baseline with a best overall response of complete response or partial response)
- disease control (proportion of eligible patients with measurable lesions with a best overall response of complete response, partial response, or stable disease)
- relative dose intensity (the ratio of delivered dose intensity of chemotherapy to dose intensity planned per protocol)
- incidence of adverse events, and the association between UGT1A1 polymorphisms (UGT1A1*28 or UGT1A1*6, or both) and the incidence of adverse events

Results

Baseline characteristics were well-balanced between the treatment groups
The median follow-up was 15.8 months
mXELIRI with or without bevacizumab was non-inferior to FOLFIRI with or without bevacizumab as second-line therapy in metastatic colorectal cancer in terms of overall survival at the predefined noninferiority upper margin of 1·30 (figure 1)

Figure 1: Primary endpoint results

No significant differences were detected in progression-free survival, time to treatment failure, overall response, or disease control between the treatment groups
The mXELIRI group showed a manageable tolerability profile that was comparable with that of the FOLFIRI group
- Neutropenia was the most common grade 3–4 adverse event affecting 52 [17%] of 310 patients in the mXELIRI group and 133 [43%] of 310 in the FOLFIRI group
- In mXELIRI group, incidences of grade 3–4 diarrhoea were higher (22 [7%]) than in the FOLFIRI group (ten [3%])
- 310 [46(15%)] patients in the mXELIRI group and 63 (20%) of 310 in the FOLFIRI group reported serious adverse events
- Two treatment-related deaths (one pneumonitis and one lung infection) were observed in the mXELIRI group, and there was one treatment-related death (lung infection) in the FOLFIRI group

Conclusion

The study demonstrated that overall survival with mXELIRI with or without bevacizumab was non-inferior to that with FOLFIRI with or without bevacizumab in the second-line treatment of patients with metastatic colorectal cancer.
The findings suggested that mXELIRI might be an effective, well-tolerated, and more convenient alternative to FOLFIRI as a standard second-line backbone therapy for patients with metastatic colorectal cancer, at least for Asian populations.

References

Lancet Oncol 2018; 19: 660–71