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Nexavar versus a Placebo, Final Results
Ronald Bukowski of the Cleveland Clinic made an oral presentation, describing the final results of the randomized Phase 3 trial of 451 patients taking Nexavar versus 452 patients taking a placebo. All patients had clear cell pathology and were rated as having low or intermediate prognostic risk. The dosage was 400 mg of Nexavar twice a day with endpoints of progression free survival and overall survival. The patients must have failed one prior systemic therapy no more than eight months prior to their participation in the trial. This is the trial that led to FDA approval for Nexavar in December 2005.
The trial commenced in November 2003. The progression free survival, calculated in January 2005, was 5.5 months for Nexavar versus 2.8 months for the placebo. In March 2005, the patients on the placebo arm were permitted to cross over to receive Nexavar with 48% of them receiving the drug. The 216 patients who crossed over were on the placebo for 12 weeks and on Nexavar for 40 weeks. In an analysis done in June 2005, if the patients who crossed over to Nexavar treatment are excluded, the overall survival data were: median survival of Nexavar group 17.8 months, median survival of the placebo group, not including crossover patients, 14.3 months. This was statistically significant. In their final analysis, done in September 2006 they included the crossover patients, and the results were: median survival of Nexavar group 17.8 months, median survival of placebo group including crossovers 15.2 months, a difference of 2½ months. This difference was not statistically significant.
In addition to discussing the Nexavar study, Dr. Bukowski also spoke about biomarkers. The investigators found that during treatment with Nexavar, the levels of VEGF went up while sVEGFR (soluble vascular endothelial growth factor receptor) went down. Nexavar is an inhibitor of VEGFR, which is why it is used to fight kidney cancer. He made no comment on the VEGF level, but others have hypothesized the rise in VEGF may indicate the reason for eventual resistance to targeted therapies like Nexavar. Dr. Bukowski also plotted the relationship between baseline VEGF levels and progression free survival (PFS) and found that placebo patients with low VEGF had PFS = 3.3 months, while those with high VEGF had PFS = 2.7 months. However, baseline VEGF levels were not predictive of Nexavar benefit.
Primo Lara of UC Davis was the discussant. He reminded everyone of the downside of targeted therapies, specifically that there have not been any true durable responses, complete responses are rare, there are chronic irritative toxicities, the cost of treatment is very high, and there are no predictive biomarkers for treatment. Dr.Lara said it has also been observed in lung, colon, breast, and prostate cancers that high VEGF levels are prognostic for worse survival and we don't know why VEGF levels rise during Nexavar treatment. He went on to say that what is needed are biomarkers that predict response to drug therapy, especially for early resistance. He identified VHL gene mutation status (for clear cell patients) as one possible biologic markers. Another is a marker that identifies a pro-angiogenic pathway that helps tumors escape anti-VEGF therapy such as bFGF (basic fibroblast growth factor).
Reporter's comment: with respect to increases in VEGF levels, Avastin blocks VEGF, which is why the combinations of Avastin with targeted therapies to lower both VEGF and VEGFR levels is appealing. What Dr. Lara did not discuss was the efficacy of Nexavar. These trial results are not impressive, especially considering Nexavar is being compared to a placebo.