RE:RE:RE:RE:Had a thoughtIt must have some impact to the whole TNBC-wide area in oncology and there's just so many trials going on, that it could very well have played a part - especially since they are in those large centers loaded with trials.
On JFMs point - one thing I picked up on again in the new paper was that fact, reported before, that there was a strain of one tumor type (I believe it was a colon tumor line of cells) that was a well known tumor type that taxanes didn't work on at all. But they found TH1902 got in there and worked on it. I believe it was also done with the mice, not just the cell's in vitro. They had a number of hypothesis around resistance and their tests all came out positive. I think the other revolved around the Bxc-l gene being up or down regulated the right way when it came to resistance and that seemed to excite them immensely. But like you say, human environments still all different, but it gives me hope they will have some better results than is typical around resistance.
I guess that's the kind of anecdotes that further the science -- if they see someone with one of those taxane resistant types of tumors and they achieved stability or something like that. What seems to us to be a small "win" would actually be rather huge in the oncology field for something totally resistant.
qwerty22 wrote: I don't want to over-egg this. I do think every late stage tnbc patient who can access Trodelvy will want to try it even if it ends up failing. I guess I'm just looking for reasons why things seem to have been slower than we expected. Maybe they haven't and I just had too high expectations on how quickly things would proceed. As an 'excuse' for slow enrolment it's fairly benign, not at all indicating a failure on the part of the drug, just one of those things. As an 'excuse' for a lack of efficacy it's fairly benign too.
It's probably not a massive deal, eventually we'll see how many tnbc patients they enrolled. A clinical trial is a big complex thing and this might (only might) be a small part of that.
jfm1330 wrote: With Trodelvy having 33% response rate and 45% clinical benefit rate (those with at least stable disease for at least 6 months), there is still many TNBC patients with overexressed sortilin available for the phase Ib and also for a possible phase II.
The remaining question at this point, given the dose they are at in the phase Ia right now (likely twice the MTD of docetaxel alone), is if the linker is working as planned, so allowing selective cleavage inside sortilin expressing cells, and bypassing of MDR efflux pump. The other concern, is the number of taxane resistant patients in these advanced cancer patients with no other valid options.
If TH1902 works as planned, will it allow to overcome taxane resistance? In the Trodely trial, 98% of the patients enrolled were taxanes resistant. So resistant to taxanes injected under the free form. Animal model showed that TH1902 is more effective than docetaxel injected alone, but these tests were made on commercial TNBC cells. Will it be the same on real big heterogenous tumors? For sure it won't work on 100% of the TNBC/sortilin+ patients. We don't need that, not even close. But we need it to work on some, and obviously, the higher the percentage of responders, the better it would be.
My hope at this point lies on the dose they are at right now (likely twice MTD of docetaxel). Also the fact that Marsolais said that what they see is similar to what they saw on animals in the preclinical work, and Levesque saying that the level of free docetaxel they see in the blood of patients after injection with TH1902 is very low, similar to the preclinical data he showed in his presentation.