Modified XELIRI Noninferior to FOLFIRI for Metastatic CRC

mXELIRI could be practice-changing by providing an alternative to irinotecan-based regimens for some patients, but may not work in non-Asian populations.

Modified XELIRI-capecitabine plus irinotecan-could be an alternative second-line treatment to replace FOLFIRI in patients with metastatic colorectal cancer, according to the results of the XPERT trial, which compared the regimens in Asian patient populations.

The phase III trial showed that modified XELIRI (mXELIRI), with or without the addition of bevacizumab, is well tolerated and noninferior to FOLFIRI, the current standard of care.

“Our study results show that overall survival with mXELIRI with or without bevacizumab was noninferior to that with FOLFIRI with or without bevacizumab in the second-line treatment of patients with metastatic colorectal cancer,” Rui-Hua Xu, of the Collaborative Innovation Center for Cancer Medicine, Guangzhou, China, and colleagues wrote in Lancet Oncology. “The results of this study suggest 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.”

Two prior phase II studies of XELIRI showed excessive gastrointestinal toxicity, preventing recommendation of the regimen in first- or second-line treatment of colorectal cancer. A modified regimen of XELIRI has had better tolerability in two phase II trials.

In the current phase III trial, Xu and colleagues tested whether this modified XELIRI regimen was noninferior to FOLFIRI with or without bevacizumab as second-line treatment. The study included 650 patients with metastatic colorectal cancer who were randomly assigned to mXELIRI with or without bevacizumab (n = 326) or FOLFIRI with or without bevacizumab (n = 324).

With a median follow-up of 15.8 months, 490 patients had died. The median overall survival was 16.8 months for mXELIRI and 15.4 months for FOLFIRI (HR, 0.85; 95% CI, 0.71–1.02; noninferiority P value < .0001).

“The prespecified noninferiority test using an upper margin HR of 1.25 remained positive, whereas the prespecified test for superiority at an upper margin HR of 1.0 was not significant,” the researchers wrote.

Median progression-free survival did not differ between the two groups. The median was 8.4 months for mXELIRI compared with 7.2 moths for FOLFIRI. The median time to treatment failure was 5.8 months for mXELIRI compared with 4.8 months for FOLFIRI.

“Of note, the incidence of gastrointestinal toxicities in the mXELIRI group in our trial-especially grade 3–4 diarrhea (7%)-was lower than that in most of the previous trials with full-dose XELIRI,” the researchers wrote. “Grade 3–4 neutropenia was more common with FOLFIRI than with mXELIRI in our study, but the incidences of febrile neutropenia and treatment discontinuation due to toxicity were low and similar in both treatment groups.”

The most common grade 3/4 adverse events were neutropenia, which affected 17% of patients in the mXELIRI group and 43% of patients in the FOLFIRI group. In the mXELIRI group, the incidence of grade 3/4 diarrhea was 7%, compared with a 3% incidence in the FOLFIRI group. Serious adverse events occurred in 15% of patients in the mXELIRI groups and 20% of patients in the FOLFIRI group. Three treatment-related deaths occurred: one from pneumonitis and one from lung infection in patients treated with mXELIRI, and one from lung infection in the FOLFIRI group.

In an editorial published with the study, Timothy J. Price, of The Queen Elizabeth University of Adelaide, Australia, wrote that the results of this study have to potential to change practice by providing an alternative option to irinotecan-based schedules in selected patients.

However, a key question moving forward will be whether or not these results, found in an Asian population, will translate to non-Asian patients.

“Debate is ongoing as to difference in pharmacogenomics between white and Asian patients for capecitabine, and a recent extensive review of irinotecan did not conclusively answer this same question, with the authors of the review highlighting the wide variability between analyses published so far,” Price wrote.