First-Line Sequential Chemotherapy Not Equal To Combination Strategy For Metastatic CRC

When added to fluoropyrimidine plus bevacizumab, the use of irinotecan on first progression did not meet noninferiority criteria compared with upfront combination treatment

medwireNews: The XELAVIRI trial has failed to meet noninferiority criteria for treatment with irinotecan at the time of first progression versus upfront use in patients with metastatic colorectal cancer (CRC) who receive first-line therapy with fluoropyrimidine and bevacizumab.

Median time to failure of the strategy (TFS) was 9.6 months for the 212 patients who were initially treated with capecitabine or fluorouracil chemotherapy plus bevacizumab and offered irinotecan only on first progression 

This compared with 9.9 months for the 209 patients who were given all three agents in combination, with de-escalation of irinotecan for patients with stable disease for more than 6 months.

The hazard ratio (HR) for TFS of 0.86 exceeded the noninferiority margin of 0.80 and thus the noninferiority of the sequential strategy “could not be demonstrated nor ruled out”, the investigators write in the Journal of Clinical Oncology.

However, further analysis indicated that the optimal regimen in this patient population may depend on RAS/BRAF mutation status, say Dominik Paul Modest, from the University of Munich in Germany, and co-authors.

Patients with RAS/BRAF wild-type tumours derived significantly better TFS from the combination treatment versus the sequential strategy, with a median TFS of 12.6 versus 9.1 months and a HR of 0.61.

There was also improved TFS among patients with RAS wild-type disease with combination therapy (HR=0.65).

But for patients with a RAS mutation, median TFS was a comparable 9.4 and 10.0 months with the combination and sequential arms, respectively.

“Whereas initial combination chemotherapy plus [bevacizumab] was clearly superior in patients with RAS/BRAF wild-type tumors, initial treatment with [fluoropyrimide plus bevacizumab] could be an acceptable approach in patients with RAS mutant tumors”, the researchers write.

They add: “These data suggest that RAS/BRAF mutation status may also be an important parameter in the optimal selection of [bevacizumab]-based therapy.”

Nevertheless, the team found no significant difference in overall survival between the treatment arms in the full study population or the study subgroups by mutation status.

 

Reference

Modest DP, Fischer von Weikersthal L, Decker T, et al. Sequential versus combination therapy of metastatic colorectal cancer using fluoropyrimidines, irinotecan, and bevacizumab: A randomized, controlled study – XELAVIRI (AIO KRK0110) . J Clin Oncol; Advance online publication 2 November 2018.
DOI: 10.1200/JCO.18.00052

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