I'll get back to the storyline of our growing understanding of the differences of individuals based on pharmacogenomics very soon. But I wanted to give people some breaking news that just came out. The first line ESCAPE trial of chemo with the anti-angiogenic and multi-kinase inhibitor nexavar or placebo is apparently negative according to a press release, and it even shows a harmful effect of the study drug in patients with squamous cancers, who were included in the trial.

The trial was designed very similar to the ECOG trial with avastin that led to its subsequent FDA approval. Over 900 first line, previously untreated patients with advanced NSCLC were randomized to receive standard carbo/taxol chemotherapy IV every three weeks for up to six cycles, with either nexavar (introductory post here) by mouth twice daily or a placebo on the same schedule. As in the avastin trial, patients who did not progress after six cycles of chemo continued on "maintenance" nexavar or placebo until progression or prohibitive side effects. The trial design is summarized here:

(Click on image to enlarge)

Importantly, the ECOG 4599 trial that tested avastin excluded patients with squamous NSCLC subtype because it appeared from early work with avastin that patients with squamous tumors who received this agent experienced an unacceptably high risk of fatal or near-fatal episodes of pulmonary hemorrhage, coughing up blood (nearly 30% of patients with squamous NSCLC in the phase II study of avastin in NSCLC (abstract here). In the ESCAPE trial, all NSCLC subtypes were included. This way, if the trial was positive, it would be applicable to a broader range of patients than would be recommended for avastin: squamous cell NSCLC patients account for approximately 25-35% of NSCLC in the US.

The trial was conducted worldwide and enrolled very readily, I believe completing accrual mid-year in 2007, primarily drawing from countries where avastin wasn't readily available (since some patients and oncologists would have misgivings about giving chemo with placebo, and no anti-angiogenic agent, to patients who would be eligible for avastin with chemo). It was looking for a signficant improvement in overall survival with nexavar as the primary endpoint.

What we learned from the press release is that an independent Data Monitoring Committee reviewed the currently available information from the trial and noted that information should now be publicly disclosed because there is apparently no way for the nexavar arm to do significantly better vs. placebo. Moreover, the patients with squamous cancers apparently had higher mortality if they received nexavar compared with placebo.

These results suggest that multikinase inhibitors, or at least nexavar, isn't a step forward compared with avastin, either in terms of its activity in avastin-eligible patients or in terms of ability to treat a broader range of patients. Importantly, while some might feel that not offering avastin or other anti-angiogenic agents to patients with squamous cancers is overly cautious, the very preliminary information we now have from the ESCAPE trial demonstrates that it may be hard to thread the needle of offering anti-angiogenic agents to broader populations that include squamous cell carcinoma patients without excessive risk.

Back to pharmacogenomics next.