Bavituximab: A Great Story that Turns Out Too Good to be Tru

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Bavituximab: A Great Story that Turns Out Too Good to be True

October 5th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/10/05/ba ... o-be-true/

A few weeks ago was the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology, where there doesn’t tend to be many breakthrough results presented, but often a few nuggets of exciting new work are presented. The main story was the relatively disappointing results of the PointBreak trial, one positive trial became a quick darling of the media. Dr. David Gerber from the University of Texas-Southwestern in Dallas presented results from a randomized phase II trial in previously treated advanced NSCLC, in which patients received either Taxotere (docetaxel) alone or in combination with one of two doses of the novel immunotherapy bavituximab. The excitement came from the fact that a doubling of overall survival (OS) was reported, alongside a less striking but still provocative improvement in response rate (RR) and progression-free survival (PFS) for the bavituximab-containing arms vs. chemo alone. Unfortunately, there’s more to the story.

Bavituximab is an immunotherapy directed against the tumor’s blood supply. Administered IV once every week, it is an antibody to phosphatidylserine (PS), a phospholipid that is normally expressed internally on endothelial cells (the cells lining blood vessels) and not exposed externally, but which flips over in the cell membrane and becomes exposed to the blood supply within a tumor’s microenvironment and also by chemotherapy. Exposed PS is thought to inhibit an anti-tumor immune response; bavituximab binds to PS and is hoped to improve an anti-tumor immune response and reduce the tumor’s blood supply.

The phase II trial was designed to enroll 120 patients with previously treated advanced NSCLC, who would be randomized to Taxotere every three weeks with either placebo or a lower or higher dose of bavituximab administered weekly. This study capped the duration of Taxotere at 6 cycles (though there is no clear standard of capping the number of treatments in previously treated patients), with patients continuing on weekly maintenance bavituximab or placebo until progression.

Previously reported RR and PFS results appear favorable if not amazing astounding. In the Taxotere alone arm, the RR was 8% (3 of 38) on the placebo arm, vs. 15% (6 of 40) for the lower dose and 18% (7 of 39) on the bavituximab arms. While certainly favorable, we often tend to see RR numbers in phase II trials that are higher than you see in large phase III trials, with results in the 20% or higher range not that uncommon in the smaller studies (remember that in a small study, the difference in outcome for a few patients here or there will make a very big difference). PFS outcomes also favored bavituximab, though relatively modestly. Here, the median PFS duration was 3.0 months for Taxotere/placebo, vs. 4.2 and 4.5 months for the arms receiving Taxotere with the lower and higher doses of bavituximab, respectively (differences not statistically significant). Here are the PFS curves: (Click on link above to view graph)

What really generated interest at the Chicago lung cancer meeting was the difference in OS, which was double for the bavituximab arms, at 5.6 months in the Taxotere + placebo arm vs. 11.1 and 13.1 months for the lower and higher doses of bavituximab, respectively. A similar trend of benefit was seen across all subgroups, whether based on histology, patient sex, race, or performance status. The survival curves are as shown below. (Click on link above to view graph)

Another important factor with regard to the performance of the combination is the side effect profile, but there was really NO discernible pattern of increased side effects with the Taxotere/bavituximab combination compared with Taxotere/placebo, though there wasn’t a detailed presentation of the side effect data in Dr. Gerber’s presentation.

Unfortunately, there was a follow up statement from the sponsor company, Peregrine Pharmaceuticals, about two weeks later that acknowledged irregularities in the integrity of the survival data and suggested that people shouldn’t trust the data. The stock market responded with a swift crushing of the company, and at this point, it’s unclear whether there is really enough truth of potential value in bavituximab to justify it continuing in a larger, phase III study. At the same time, even if it actually is an effective drug, the reputation of the drug and Peregrine may be irreparably damaged.

Time will tell, but in the meantime, it’s a humbling example of not being able to trust something that seems too good to be true. We can only hope this doesn’t taint the trust of the clinical research process for other drugs and trials too much.