Last month, Threshold Pharmaceuticals (THLD
) surprised the market with positive data for its lead program (TH-302) in pancreatic cancer. Although actual results were not published and despite several issues with the trial design, TH-302 generated what is possibly the best pancreatic cancer data set in over a decade.
Phase II data
Based on top line results from a large randomized phase II, adding TH-302 (two different doses) to standard chemotherapy led a statistically significant difference in progression-free survival (PFS). PFS is the time patients live without experiencing disease progression. Patients who received TH-302 with Gemzar had a median PFS of 5.6 months compared to 3.6 months in patients who received Gemzar alone (p = 0.005).
The response rate in the combination arms was also superior to that in the Gemzar arm (22% vs. 12%). Interestingly, patients who received the higher dose of TH-302 appeared to do better than those receiving the lower dose, which is an important indication of the drug's activity. According to the press release, TH-302's safety profile was consistent with a previous phase I trial for TH-302 and Gemzar, where skin and mucosal toxicities were the most significant side effects.
To put things in perspective, a statistically difference in PFS in pancreatic cancer is a very rare event. Even Amgen's (AMGN) ganitumab (AMG-479), currently in phase III in pancreatic cancer, could not demonstrate a statistically significant PFS or OS benefit in its randomized phase II. Ganitumab+Gemzar had a PFS of 5.1 vs. 2.1 months with Gemzar alone in an 80-patient trial. Unlike Amgen, Threshold evaluated TH-302 in a very large trial (214 patients), enabling the drug to reach statistical significance and making it more predictable of future phase III studies.
The most impressive results to date in pancreatic cancer were generated using the aggressive chemotherapy regimen FOLFIRINOX. In a recently published phase III trial, FOLFIRINOX was superior to Gemzar in both PFS (6.4 vs. 3.3 months) and overall survival (11.1 vs. 6.8 months), with both differences being highly statistically significant. Despite the clear benefit, FOLFIRINOX is associated with severe side effects, which preclude its use in the broad patient population. If proven effective, TH-302+ Gemzar could be widely used due to a favorable safety profile.
There are still several open questions pertaining TH-302's data. As a general comment, available information is based on a short press release, so caution is obviously needed when evaluating the data. Three main issues are physician's bias, the cross over protocol chosen for the trial and potential safety issues.