Battle Royale: Avastin versus Zaltrap in Avastin-pretreated CRC
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| Jun 3, 2012
Avastin® (bevacizumab, Genentech/Roche) is currently a first-line standard of care in combination with chemotherapy in both the United States and Europe; however, it is used less often in the first-line by European physicians. Avastin is also labeled for use in the second-line, based on three Phase III trials comparing second-line chemotherapy with or without Avastin in patients who did not receive first-line Avastin. The BRiTE Registry (Grothy, JCO, 2008), which was an observational study that among other treatment patterns evaluated the use of Avastin after progression in metastatic colorectal cancer patients treated in the first-line with Avastin, suggested a benefit for continued Avastin. These results are manifested in Kantar Health’s CancerMPact Treatment Architecture physician survey data, which suggest a large percentage of patients are treated with both first- and second-line Avastin (46% in the US, 38% in Europe). This environment highlighted the need for clinical data asking whether continued VEGF inhibition would provide survival benefit to patients, and are addressed by two trials at ASCO 2012: TML (Treatment across Multiple Lines; ML18147) which examined the efficacy of Avastin and chemotherapy following first-line Avastin and chemotherapy. This trial was initiated by the German AIO study group, but was soon taken over by Roche given the demand of physicians to enroll patients in this trial. The second trial is a subset analysis of the VELOUR trial, which compared the use of Zaltrap™ (aflibercept, Sanofi) in patients pre-treated with Avastin. It should be noted that the primary analysis of VELOUR had already shown a survival benefit in all patients, either previously-treated or not previously-treated with Avastin, in a presentation at the European Multidisciplinary Cancer Conference (Tabernero, Abstract 6 LBA, EMCC 2011). These trials, presented in the same oral session, set up a competition between the two. If Avastin wins out for second-line, where will Zaltrap be used?
Both trials met their primary endpoints of overall survival, but both were underwhelming. The addition of Avastin to chemotherapy improved median overall survival in the intent-to-treat population by 1.4 months (11.2 months versus 9.8 months, HR=0.81, p=0.0211), and improved median progression-free survival by 1.6 months (5.7 months versus 4.1 months, HR=0.67, p<0.0001). In patients stratified by prior Avastin treatment, Zaltrap improved overall survival by 0.8 months (12.5 months versus 11.7 months, HR=0.862) and improved progression-free survival by 2.8 months (6.7 months versus 3.9 months, HR=0.661). Both Avastin and Zaltrap presented comparable toxicities, with hypertension predominating. Avastin use was associated with slightly higher rates of venous thromboembolic events, but the nature of this type of cross-trial comparison should not influence utilization. VELOUR had one deficiency – the majority of patients from the U.S. were pretreated with Avastin in first-line. This may have influenced the trial’s inability to truly detect an interaction effect for Avastin pre-treatment, forcing statisticians to use a lesser threshold (10%) to detect significance rather than the traditional 5%.
In essence, these data might be construed as a tie, but as such represents a possible victory for Avastin and may relegate Zaltrap to the third-line setting. Physicians already are comfortable with administering Avastin, so these data may not influence their choice of therapy. The discussant (Dr. Alan Venook) indicated that Zaltrap would gain approval based on VELOUR (filed in Europe in December 2011 and with U.S. FDA, action expected in August 2012), and Avastin will earn a label addition for these Avastin-pretreated CRC patients. However, he posed an interesting question. If TML (and by extension, VELOUR) predicts that continuing VEGF inhibition beyond progression following first-line Avastin, should VEGF inhibition be continued for all lines of therapy including a third or fourth line? That would have to wait for another trial.