Colorectal Cancer: A Practical Review - Episode 3

Regorafenib in Metastatic Colorectal Cancer

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The multikinase inhibitor regorafenib was approved for the treatment of patients with metastatic colorectal cancer (CRC) following prior lines of therapy in September 2012. This treatment has a unique set of adverse events that appear very early following and then begin to taper off in subsequent cycles. Given this unique toxicity profile, regorafenib can be a complicated therapy to administer, notes Howard S. Hochster, MD.

Given the unique nature of treatment with regorafenib, researchers are attempting to uncover a distinct population of patients who are most likely to respond, notes Hochster. A study utilized next-generation sequencing on available archival tissue from the pivotal CORRECT trial (n = 281). This analysis demonstrated that ‘high-risk’ patients by Marisa hierarchical molecular tumor classification (n = 26; CSC and CINnormL) had a greater progression-free survival (PFS) benefit with regorafenib versus other subgroups (HR = 0.10; P = .0009). While it is a preliminary observation, the use of molecular classifications to evaluate subsets of colon cancer biology has the potential to help direct therapy, says Hochster.

The value of a drug is enhanced if it is possible to avoid treating patients who are not likely to benefit, states Richard L. Goldberg, MD. Many of the later line therapies for patients with CRC have demonstrated similar PFS benefits, enhancing the need for a biomarker for treatment selection. With a growing number of options, a biomarker would help protect patients from treatments that are not going to help them, says Goldberg.Regorafenib’s package insert recommends a starting dose of 160 mg, but one of the major barriers to its use is toxicity, which includes fatigue and hand-foot syndrome. This is a medication that requires frequent dose adjustments and interruptions, explains Fadi Braiteh, MD, much like sorafenib, a tyrosine kinase inhibitor. It may be prudent to initiate patients at a lower dose than 160 mg, says Braiteh, explaining that the dose can always be adjusted upwards, as patients return every week.