While the main story coming out of the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology focused on the relatively disappointing results of the PointBreak trial, one positive trial received quite a bit of attention. Dr. David Gerber from the University of Texas-Southwestern in Dallas presented a randomized phase II trial in previously treated advanced NSCLC of Taxotere (docetaxel) alone or in combination with one of two doses of the novel immunotherapy bavituximab, which demonstrated a doubling of overall survival (OS) after a less striking but still provocative improvement in response rate (RR) and progression-free survival (PFS) for the bavituximab-containing arms compared with standard chemo alone.
Bavituximab is an immunotherapy directed against the tumor vasculature (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. The exposed PS inhibits an anti-tumor immune response, while bavituximab binds to PS and appears to improve an anti-tumor immune response and reducing 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 (it being a very standard appropriate second line treatment in this setting) with either placebo or a lower or higher dose of bavituximab administered weekly. Although there is no clear maximal duration of treatment with chemo in this setting (prior studies of single agent second line therapy have generally allowed treatment until progression or prohibitive side effects), this study capped the duration of Taxotere at 6 cycles, with patients continuing on weekly maintenance bavituximab or placebo until progression.
The results in terms of RR and PFS look favorable, though not astounding. Specifically, the RR for Taxotere alone was 8% (3 of 38) on the placebo arm, compared with 15% (6 of 40) for the lower dose and 18% (7 of 39) on the bavituximab arms. That's encouraging enough, but 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 (after all, a few patients here or there will make a very big difference). Similarly, the PFS differences also favored bavituximab, but not overwhelmingly. Here, the median PFS duration was 3.0 months for the Taxotere + placebo arm, compared with 4.2 and 4.5 months for the arms receiving Taxotere with the lower and higher doses of bavituximab, respectively; these differences were not statistically significant. The PFS curves are shown here:
But these differences are pretty modest overall. 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; moreover, 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.
Of course, the other 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. Time didn't permit a detailed presentation of side effects, but this lack of difference included the frequency of both mild and more serve side effects, as well as the frequency of clotting and bleeding complications.
What should we conclude from this work? Dr. Gerber noted that this work merits further work in a phase III study, and I certainly agree with that. The doubling of survival is very promising, though it's important to note that the dramatic difference in survival is in part of a function of the placebo arm underperforming compared with large phase III experiences such as the randomized trial of Taxotere vs. Alimta (pemetrexed), in which the median OS was 8 months in both arms. It's also interesting that the OS difference is far greater than the difference in PFS. This is definitely a pattern you can see with immunotherapies, whether Dendreon's Provenge (sipuleucel-T) or Erbitux in NSCLC, or others.
But I am personally cautious about presuming this is all but guaranteed to be the next great drug based on phase II work. We have seen irrational exuberance from phase II work ranging from Erbitux to the vascular disrupting agent ASA404 to talactoferrin and many others, all associated with far less impressive results when held to the scrutiny of more careful testing in large populations. There is only so much optimism we can draw from a trial of 40 patients in which the RR was <20% (these results aren't like those of EGFR inhibitors in EGFR mutation-positive patients, or crizotinib in ALK rearrangement-positive patients, which are wildly positive even with small numbers, showing a RR of >50%). The fact that many of the patients came from international centers that aren't known for their clinical trial reliability, also signals a reason to be wary that the results may not hold up.
At the end of the day, I think it's far too early to presume that bavituximab will be a major breakthrough in NSCLC, but I'm definitely enthusiastic that it deserves to be tested properly in a phase III randomized trial, and I think there's good reason to be hopeful that it could prove to be a significant advance.
How encouraged are you by these results?
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