Expert Point of View: Alan Venook, MD

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Invited discussant Alan Venook, MD, of the University of California, San Francisco, pointed out that the hazard ratio of 0.81 and the 1.4-month improvement in overall survival in the TML trial did not reach the target hazard ratio of 0.77 in the statistical design of the study. However, “it is still a positive trial,” he noted, and one that has implications for conversations with patients.

“Once anti-VEGF therapy is initiated, discontinuing it may lead to a small survival disadvantage,” he might tell patients with metastatic colorectal cancer. “It may be a mistake to discontinue treatment at any time, and that affects all the decisions we will make over the course of your disease.”

Dr. Venook also suggested that “it may make more sense to use bevacizumab in second and subsequent lines of treatment, rather than upfront,” though he acknowledged that research is needed, with an emphasis on predictive biomarkers.

Limited Utility of Registry Studies

The TML study also underscored the risk inherent in basing clinical decisions on registry data. In the BRiTE registry of almost 2,000 patients with metastatic colorectal cancer, administration of bevacizumab beyond progression improved median overall survival from 19.9 to 31.8 months.1 These findings precipitated the closure of SWOG 0600, which, much like the TML trial, was also evaluating continued bevacizumab, “leaving questions unanswered until today,” he said.

“Though they were in the same direction, the BRiTE findings were not replicated in the TML study,” he noted, and the striking difference in outcomes “affirms the limited utility of registry studies.” He concluded that the role of bevacizumab beyond progression is still being established, but current data suggest the second-line setting is an appropriate place to use the drug.

Remaining questions may be informed by the ongoing CALGB/SWOG 80405 trial, which Dr. Venook is leading. The study is randomly assigning 2,334 untreated patients with metastatic colorectal cancer and wild-type KRAS to FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin) or FOLFIRI (leucovorin, 5-FU, irinotecan) plus either bevacizumab or cetuximab (Erbitux) every 2 weeks. “We will have biomarker information to inform us,” he added. “Predictive biomarkers should be as high a priority as finding new drugs and indications.” ■

Disclosure: Dr. Venook receives research funding from Genentech.


1. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer. Results from a large observational cohort study (BRiTE). J Clin Oncol 26:5326-5334, 2008.

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