The so-called TML (Treatment across Multiple Lines) study reported by Bennouna and colleagues investigated the efficacy of bevacizumab (Avastin) beyond progression from first- to second-line therapy in advanced colorectal cancer, a strategy that was supported by data from observational cohort studies and that about one-third of U.S. oncologists had already used in clinical practice. The results of the study confirm that prolonged inhibition of the vascular endothelial growth factor (VEGF) system is beneficial for patients in terms of improved overall survival with relatively mild toxicity.

The efficacy of prolonged VEGF inhibition was confirmed by the results of the VELOUR trial, which demonstrated a survival benefit for the use of ziv-aflibercept (Zaltrap), another VEGF inhibitor, even in patients who had been pretreated with bevacizumab. The magnitude of benefit, an approximately 20% reduction of death events on the study (expressed by a hazard ratio of 0.81) and a median gain in overall survival of 1.4 months might not satisfy everyone, but it is a proof of concept that also challenges our traditional understanding of resistance mechanisms and will impact the design of future trials in colorectal cancer.

Insight into Subpopulations

The publication of detailed study results now also allows us further insight into subpopulations in the trial. At first glance, it appears that patients with KRAS wild-type cancers derive more benefit from the use of bevacizumab beyond progression than patients with KRAS mutant tumors. Although the definitive statistical analysis, the test of interaction, did not demonstrate any difference between these groups, it needs to be noted that KRAS wild-type tumors have commonly been reported to show a trend toward better response to treatment interventions, including in the most recent phase III regorafenib (Stivarga) last-line trial. This observation makes the upcoming results of trials that compare bevacizumab and cetuximab (Erbitux) head to head in front-line therapy even more interesting. ■

Disclosure: Dr. Grothey reported no potential conflicts of interest.