SOUTH SAN FRANCISCO (TheStreet) -- Detailed results from Oxigene's (OXGN) phase II study of fosbretabulin plus Avastin in recurrent ovarian cancer were presented this week, and as expected, the combination of the two drugs reduced the risk of tumor progression in patients with recurrent ovarian cancer.Those results included the "hardest-to-treat" patients no longer responding to platinum-based chemotherapy. That's the good news. The bad news is the study doesn't yield enough data to make a convincing case for fosbretabulin's approval. Oxigene has more clinical work to do.
Let's dig into the study results:
This phase II study enrolled 107 patients with recurrent ovarian cancer, both platinum sensitive and resistant, and randomized them to treatment with the combination of fosbretabulin and Roche's ( RHHBY) Avastin, or Avastin alone. Patients were treated until their cancer progressed. The primary endpoint of the study was progression-free survival, defined as the time before a patient's tumor begins to grow again, or death.
The study achieved the primary endpoint with a 31% reduction in the risk of tumor progression or death favoring fosbretabulin+Avastin over Avastin alone. However, the benefit was just barely statistically significant with a p value of 0.049. [A p value greater than 0.05 denotes a failed study from a statistical perspective.]
At the median, progression-free survival for the fosbretabulin combination was 7.3 months compared to 4.8 months for the Avastin alone arm.
A further analysis was conducted based on platinum chemotherapy status. Recurrent, platinum-sensitive ovarian cancer is defined as the return of cancer greater than six months following completion of platinum-based chemotherapy. Patients with cancer recurrence less than six months after platinum-based chemo are deemed to be platinum-resistant. These latter ovarian cancer patients have more advanced disease and respond less well to future treatments.
For the 80 platinum-sensitive ovarian cancer patients, treatment with fosbretabulin+Avastin resulted in a 33% reduction in the risk of tumor progression or death. Median PFS was 7.6 months versus 6.1 months favoring the fosbretabulin arm. The difference was not statistically significant.
For the 27 platinum-resistant ovarian cancer patients, there was a 43% reduction in the relative risk of tumor progression favoring fosbretabulin+Avastin. Median PFS was 6.7 months versus 3.4 months favoring the fosbretabulin arm. The difference achieved statistically significance.
There are a lot of numbers to digest here, but to sum it up, recurrent ovarian cancer patients benefit from treatment with the combination of fosbretabulin and Avastin, and the benefit is particularly promising in the hardest-to-treat patients with platinum-resistant tumors. The principal investigator in charge of the phase II study wants Oxigene to advance fosbretabulin into a larger phase III study in recurrent ovarian cancer, based on the promising results seen in the phase II study. Oxigene has signaled plans to do just this, following meetings with the FDA to nail down a study design. The company will have to raise money to fund the study, as well.
That's the sunshine and lollipops portion of the analysis. Let's now discuss the potential risks and issues which Oxigene needs to resolve.
Avastin is not approved in the U.S. for ovarian cancer. It's hard to believe given the broad use of Roche's biggest-selling cancer drug, but those are the facts. This makes Oxigene's phase II results harder to interpret because Avastin monotherapy isn't typically used to treat recurrent ovarian cancer patients.
Roche is seeking FDA approval for Avastin in recurrent, platinum-resistant ovarian cancer and a decision is expected on Nov. 19. The submission is based on the phase III "AURELIA" study which compared the combination of Avastin plus chemotherapy compared to chemotherapy alone. Again, all 361 patients in the study were diagnosed with platinum-resistant, recurrent ovarian cancer. The results: Treatment with Avastin and chemotherapy led to a 52% reduction in the risk of tumor progression or death. The median PFS for the Avastin-chemo arm was 6.7 months versus 3.4 months for chemo alone. The results were statistically significant. Overall survival trended in Avastin's direction but was not statistically significant.
Comparing results across the respective Roche and Oxigene studies, Avastin+chemo (52% risk reduction) appears to be a more effective treatment than fosbretabulin+Avastin (43% risk reduction) for platinum-resistant ovarian cancer patients. Weirdly, the median PFS results from the two studies are exactly the same.
Roche's AURELIA study is much larger and the data more reliable. Oxigene's data are derived from a small subset of 27 platinum-resistant patients. Given the small size of the phase II, I suspect the fosbretabulin results will regress further when phase III results are eventually reported. [Yes, comparing results from two different clinical trials is problematic, but everyone does it with appriopriate caution.]
Oxigene will be challenged to design a favorable phase III study of fosbretabulin in platinum-resistant ovarian cancer. Assuming the company sticks with the fosbretabulin+Avastin combination, what's the comparator arm? There's a good chance Avastin+chemo becomes the new standard of care, assuming FDA approves the treatment regimen on Nov. 19. [I hear approval is likely, even without a survival benefit.] Based the comparative data we have, fosbretabulin will have a tough time proving superiority over Avastin. Oxigene could try to run a non-inferiority (equivalence) study but those require huge numbers of patients. Oxigene might try to demonstrate the fosbretabulin+Avastin is safer or better tolerated by patients than Avastin+chemo, but that's also a tough task. The company could also restrict enrollment of a phase III study to patients who can't be treated with chemo for a variety of reasons, but that would limit the market potential. (And would FDA agree to such a trial design?)
If FDA rejects Roche's application for Avastin in platinum-resistant ovarian cancer, Oxigene is stuck. Fosbretabulin doesn't work well on its own, but combining with Avastin becomes unfeasible because the latter isn't an approved ovarian cancer treatment. Oxigene could focus on Europe, where Avastin+chemo is already approved based on the AURELIA data. But then, again, proving fosbretabulin's superiority over standard of care is difficult.
Oxigene's outlook for advancing fosbretabulin in platinum-sensitive ovarian cancer patients might be even more risky. In Europe, Avastin+chemo is approved in this setting based on results from the phase III "OCEANS" study which demonstrated a 52% risk reduction for tumor progression. Median PFS for Avastin+chemo was 12.4 months versus 8.4 months for chemo alone. These Avastin data in platinum-sensitive ovarian cancer patients are much better than the comparable fosbretabulin data discussed above. Oxigene appears blocked here.
If Oxigene can't figure out how to move fosbretabulin+Avastin forward, the company might be best served with a different combination entirely. A phase I/II study of fosbretabulin combined with GlaxoSmithKline's ( GSK) Votrient recently began enrolling recurrent ovarian cancer patients. If results from this study are positive, Oxigene could design a larger study seeking to demonstrate the superiority of fosbretabulin+Votrient over Avastin-based therapy in recurrent ovarian cancer.