While PFS is the agreed upon primary endpoint for the HEAT study and reinforced via the trial’s SPA (Thermodox must demonstrate a 33% PFS improvement), I have and continue to express some concern over the use of this endpoint. To clarify, while PFS is a well-accepted endpoint by the FDA and very commonly used in clinical trials (in particular because it is thought to be strongly related to overall survival and other clinically significant endpoints, but PFS allows for quicker data generation/earlier NDA submission), I believe this might not be the best endpoint to measure the effect of Thermodox.
As it relates to the HEAT study, let’s clarify exactly what a PFS "event" could consist of:
- Local tumor progression – This would be progression relating to the originally ablated tumor.
- Intrahepatic distant progression – Emergence of an entirely new tumor in the liver, which may or may not be related to the originally ablated tumor.
- Extrahepatic disease progression – Tumor spread to other parts of the body
- Death – Death from any cause
When Dr. Borys, Celsion’s Chief Medical Officer was asked about the choice of PFS as an endpoint, he expressed that the company was “comfortable” with the endpoint because “the most common first site of recurrence is local recurrence.” Unfortunately, this is not universal in every study I have looked at (you can find these under RFA in Current Practice). For example, from the filename “WJGS-Current Status of RFA for HCC 2010.pdf”, we see the following in Table #1:
Keep in mind, these are from smaller studies than the HEAT trial, and are generally looking at smaller lesion sizes, so we do not have an apples to apples comparison (this cannot be stressed enough, since local progression rises exponentially with larger lesion sizes). Nevertheless, LTP was on the low side, while “new recurrences”, which included intrahepatic and extrahepatic distant spread, was relatively high.
This is a subtle, but important point for investors to keep in mind with regard to the HEAT study. I have seen some evidence that suggests LTP is related to some intrahepatic spread, so by controlling the tumor locally, Thermodox might be precluding the onset of new lesions elsewhere in the liver.
I, for one, am extremely excited to see what the HEAT study will reveal.