Liam Davenport

November 28, 2017

SINGAPORE — In the setting of second-line therapy for colorectal cancer (CRC), a lower-dose version of a chemotherapy regimen previously found to have an unacceptable toxicity profile has shown similar efficacy and significantly fewer adverse events. The new modified regimen could become the standard of care, the researchers suggest.

The new data were presented here at the European Society for Medical Oncology (ESMO) Asia 2017 Congress, held recently in Singapore.

They come from the Asian XELIRI ProjecT, a phase 3 randomized controlled trial conducted in 650 patients. It compared low-dose capecitabine (Xeloda, Genentech) and irinotecan (IRI), a modified XELIRI regimen, to the established FOLFIRI regimen of folinic acid (FOL), 5-fluorouracil (F), and IRI. Patients in both treatment groups were also randomly assigned to receive or not receive bevacizumab.

The results show that both overall survival and progression-free survival were similar in the two groups but that substantially fewer grade 3/4 adverse events occurred with the lower-dose regimen. These effects were consistent across country, disease, and treatment subgroups, the researchers note.

Lead author, Tae Won Kim, MD, professor in the Department of Oncology, Asan Medical Centre, Seoul, Korea, said in a release that the 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," Dr Kim suggested.

Rodrigo Dienstmann, MD, Vall d'Hebron Institute of Oncology, Barcelona, Spain, who was not involved in the study, commented: "This study supports the use of modified XELIRI in the second line setting, with the potential to increase patient convenience, due to the oral administration of capecitabine."


While the combination of capecitabine and oxaliplatin (XELOX) was previously shown to have efficacy and safety similar to those of FOLFOX (FOL, F, and oxaliplatin) in metastatic CRC, there were concerns about XELIRI because of substantial toxicities in comparison with FOLFIRI.

A modified version of XELIRI was then developed, with lower IRI (200 mg/m2 on day 1) and capecitabine (1600 mg/m2 on days 1 to 14) doses. This version has a favorable tolerability profile compared with XELOX with or without bevacizumab in the first- and second-line settings.

The current study, the Asian XELERI ProjecT, set out to determine the noninferiority of modified XELIRI vs FOLFIRI as a second-line treatment in metastatic CRC.

The study involved 650 patients with histologically confirmed metastatic CRC, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and disease progression or intolerance to first-line therapy. Patients were randomly assigned to modified XELIRI (n = 326) or FOLFIRI (n = 324) with or without bevacizumab.

After a median follow-up of 15.8 months, median overall survival was 16.8 months in the modified XELIRI group and 15.4 months in patients treated with FOLFIRI, at a hazard ratio of 0.85 (noninferiority test P < .0001).

Median progression-free survival did not significantly differ between the two groups, at 8.4 months for patients receiving the modified XELIRI regimen and 7.2 months among those treated with FOLIRI, at a hazard ratio of 0.95 (P = .5078).

Patients treated with modified XELIRI had significantly fewer grade 3/4 adverse events, at an incidence of 53.9%, compared with 72.3% for FOLFIRI (P < .0001). The most common grade 3/4 event was neutropenia, seen in 16.8% and 42.9% of patients, respectively (P < .0001).

The team notes that the incidence of grade 3/3 diarrhea was low in both treatment groups, at 7.1% in modified XELIRI patients and 3.2% in those given FOLFIRI (P = .0443).

Stratification of the patients by country, ECOG performance status, number of metastatic sites, prior oxaliplatin treatment, and concurrent bevacizumab treatment did not reveal any significant differences in efficacy and safety results.

Noting the favorable toxicity profile with modified XELIRI, Dr Dienstmann said that, in the future, "quality-of-life data will be critical to understanding the value of this regimen."

He continued: "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 optimize the sequence of chemotherapy/targeted therapy in metastatic CRC," he said.

Dr Dienstmann also pointed out that known genetic variations within the UGT1A1 gene across Asian and non-Asian populations may affect the toxicity profile of irinotecan.

"In addition, some early studies have found a favorable safety profile with modified XELIRI given every 2 weeks, and this deserves further study," he added.

The study was funded by Chugai Pharmaceutical Co Ltd and F. Hoffmann-La Roche Ltd. Dr Kim disclosed receiving research funds from Roche, Merck Serono, and Bayer. Other authors disclosed receiving research grants from MSD, Daiichi Sankyo, Ono, Shionogi, Kyowa Hakko Kirin, and Gilead Sciences and honoraria from Chugai, Takeda, Eli Lilly, Merck Serono, Taiho, Yakult, Bristol-Myers Squibb, Sanofi, and Daiichi-Sankyo. The other authors have disclosed no relevant financial relationships.

ESMO Asia 2017 Congress. Abstract LBA3_PR. Presented November 18, 2017.

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