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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Trial Closes with Another Anti-Angiogenic Drug in Advanced NSCLC
Thu, 02/28/2008 - 23:15
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Just last week I described in a prior post the news that a large trial of Nexavar (sorafenib) had been reported as negative in first line advanced NSCLC, and with some evidence of an increased risk of death on the novel agent in combination with chemo in the subset of patients with squamous cell NSCLC. AstraZeneca just put out its own press release that reports (amidst more positive news about trials in colon cancer) that an important NSCLC trial being done in Canada, known as BR.24 and studying an anti-angiogenic pill, has been closed due to toxicity issues.

The drug in question is known as AZD2171, or recentin, and it's an oral inhibitor of the vascular endothelial growth factor (VEGF) receptor. This receptor is similar to EGFR, and Recentin blocks the tyrosine kinase portion of the receptor on the inside of the cell (making it a tyrosine kinase inhibitor, or TKI), the back end that sets off a cascade of activities that ultimately lead to angiogenesis, or new blood vessel formation that aids in the growth and spread of many cancers. Recentin binds to the VEGF receptor extremely well, so it has the potential to be a remarkably potent antiangiogenic agent.

The trial was known as BR.24 (BR for bronchus) and was being conducted by the National Cancer Institute of Canada, and it was designed to test recentin along with chemo, specifically the same combination of carboplatin/taxol that is so commonly used and studied for patients with previously untreated advanced NSCLC. The trial was designed to directly compare chemo with Recentin to chemo and a placebo, and unlike the experience with avastin, this trial included patients with squamous cancers, treated brain metastases, and patients on therapeutic doses of blood thinners like coumadin. It was designed to stop after about 100 patients had progressed or died (the randomized phase II trial portion), then look at the data to see i it looked promising enough and safe enough to proceed with a larger enrollment to really test whether recentin adds to chemotherapy (the phase III component of the trial).

Early on, there were problems with the trial. It started by using recentin at a dose of 45 mg per day, which was the doe that seemed to be the most that was tolerable with this chemo combinations in early studies in patients. However, as this trial was getting off the ground, it became increasingly clear that this dose was too hard on patients. My understanding is that the leading side effects have been things like bad fatigue and muscle aches -- perhaps a exaggeration of the common side effects of the carbo/taxol chemo combination -- along with more diarrhea than expected, and high blood pressure. Although we don't have details, the dat safety monitoring committee reviewed early results and recommended that the trial be continued but with a lower dose of recentin as the trial moved forward.

Now, the preliminary results have been reviewed again, and the conclusion of the data safety monitoring committee was that the trial was not looking favorable enough, or was showing too much evidence of excessive toxicity, to proceed with the larger phase III portion of the study. The press release doesn't offer much information, but it sounds like the concern was more with side effects and tolerability than any evidence that the drug wasn't helpful.

In the wake of the negative results from the ESCAPE trial with nexavar and now the BR.24 trial with recentin, I've heard a few people ask why the VEGF TKIs are failing but an antibody approach like avastin is successful. While it may be that there are meaningful differences, and perhaps the monoclonal antibodies are somehow more effective at inhibiting a target from outside the cell than the oral TKIs are at inhibiting the same target molecule from inside the cell, I would point out that it's wrong to conclude that these drugs can't be beneficial for lung cancer. It's important to remember that the most important trial for avastin in advanced NSCLC, ECOG 4599, excluded high risk patients and only included a subset of perhaps 30-40% of the general advanced NSCLC population who would most readily be considered as eligible. These newer trials have been more inclusive, trying to assimilate into the lung cancer market by being less picky about who gets treated. However, it may well be that the patients with squamous cell NSCLC, for instance, who account for about 30% of patients in the US, are really at too high a risk of suffering fatal or near fatal bleeding complications. If these new studies include high-risk patients and they experience high rates of serious complications, that could bring down a trial even if these other agents are just as good or better than avastin in the avastin-eligible patients. Even a good swimmer will drown if you force them to swim with a bowling ball, and this may be the same situation. These companies may be throwing out the baby with the bathwater, discarding (or at least tainting with failure) potentially useful drugs because they were studied in too broad a population, due to market concerns rather than scientific ones.

At this point, we don't have details on what happened on BR.24. I also don't know if there will still be a clinical development program for recentin in NSCLC.

I've mentioned in many places on this site in the last year that we are moving toward a more individualized approach toward selecting the right drugs for the right tumor/right patient. Not only is it important for us to identify the BEST agents for people to receive, we also need to identify the WORST candidates for some drugs in order to protect them from having their valuable benefits being diluted away by including too many of the exact wrong patients for that approach. The problem is that if a drug company prunes down its target group, their potential market shrinks -- still, it beats having no market if you kill your drug by being overly aggressive in designing clinical trials.

But bringing it back to human terms, we're talking about the safety of patients, which needs to always be a leading consideration when we run clinical trials. It's very important that we be as careful as we can be about pushing the field forward without taking excessive risks.

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