RE:Investigators, very helpful - lots to digest Having the KOLs was highly beneficial --realistic, reminder of clinical benefit equation, placing actual results into the context of their practices and what they see. [I thought FMB was ready to give warts-and-all answers which is always re-assuring]Fascinating that someone who has discontinued is still seeing stability --that is worth trying to understand and I can only think it has something to do with disrupting the CSC and VM part[That is super intriguing, my mind went to think the drug had targeted the most aggressive aspects of the tumour (like you) and left behind a relatively inactive mass. Has to be speculative atm]. There's a lot to unpack, but I don't think these KOLs thing the program is dead [ my main take home]it stumbled and they think there are answers given they saw PRs and lots of SDs. They seemed to also point that SDs of 3-6 months is a winner for these last stage patients where there appears to be no real solutions on offer from the ADC side.[I was surprised at the short PFS time but they are the experts]
Qwerty's right that the main issue for them is the neuropathy. They seemed to say that, while more data would be needed, they don't think it's because of the sort1 expression around the nervous system, but the accumulated amount of "free docetaxol" that is at issue. [I'd say there is a correlation with free-docetaxel but that ain't causation. The joy of having FMB there, Christian provided the correlation point, she chimed in with that isn't causation. I think we wait to see on that point]Yet they were very clear they think dosing and timing has worked in the past at "controling" this (Winer said it). I don't know enough, but are they saying the one huge dose may leave more "free" taxol buzzing around doing bad things and that if they do smaller doses it always be a lower dose, not accumulate in the body as much, allow the receptors to get occupied and then recycled to cell surface, and they hope that will lower it to a tolerable level? Clearly will be there, they just want to get it tolerable for what they see as the novel benefit -- allowing people to take this for a long, long time. Marsolais pointed to at least one patient where the neuropathy was likely because the surface area vs weight dosing gave the patient that 420+ type dose which caused the known problems they saw previously. [ There's clearly been a lot of thought and analysis gone into this, more than was presented. I think we should see this as far from a Hail Mary, a rationally design response to the data but bearing in mind the limited data set can't provide all the answers]
All in -- loads of information to digest, actually very good questions from the analysts and attendees, candid responses from KOLs. Need to rewatch and get the finer points. Look forward to other's views here, but I can see why they think this is a "way forward", but as the KOLs kept repeating, it must show that clinical benefit --the simple equation of confirmed benefits outweighing adverse events. I think they also dispelled the need to do Sort1 testing pre-treatment and pointed out no ADC did that, they all just picked cancers known to have a lot of the target. They did seem to place the overexpression of Sort1 as being high (Dr Winer) and it seemed he meant more prevalent than what he's seen in other targeted therapies. [Many thing in life and trials are a compromise. That's the case here. There are benefits and drawbacks to prescreening, they provided a logical explanation why they think not pre-screening is the way forward. At 74% SORT+ in Ovarian the assumption is if there is a signal to be found it will emerge even without pre-screening and allcomers adds some extras in the event of positive results. I'm still comfortable with this]
Wino115 wrote: Having the KOLs was highly beneficial --realistic, reminder of clinical benefit equation, placing actual results into the context of their practices and what they see. Fascinating that someone who has discontinued is still seeing stability --that is worth trying to understand and I can only think it has something to do with disrupting the CSC and VM part. There's a lot to unpack, but I don't think these KOLs thing the program is dead, it stumbled and they think there are answers given they saw PRs and lots of SDs. They seemed to also point that SDs of 3-6 months is a winner for these last stage patients where there appears to be no real solutions on offer from the ADC side.
Qwerty's right that the main issue for them is the neuropathy. They seemed to say that, while more data would be needed, they don't think it's because of the sort1 expression around the nervous system, but the accumulated amount of "free docetaxol" that is at issue. Yet they were very clear they think dosing and timing has worked in the past at "controling" this (Winer said it). I don't know enough, but are they saying the one huge dose may leave more "free" taxol buzzing around doing bad things and that if they do smaller doses it always be a lower dose, not accumulate in the body as much, allow the receptors to get occupied and then recycled to cell surface, and they hope that will lower it to a tolerable level? Clearly will be there, they just want to get it tolerable for what they see as the novel benefit -- allowing people to take this for a long, long time. Marsolais pointed to at least one patient where the neuropathy was likely because the surface area vs weight dosing gave the patient that 420+ type dose which caused the known problems they saw previously.
All in -- loads of information to digest, actually very good questions from the analysts and attendees, candid responses from KOLs. Need to rewatch and get the finer points. Look forward to other's views here, but I can see why they think this is a "way forward", but as the KOLs kept repeating, it must show that clinical benefit --the simple equation of confirmed benefits outweighing adverse events. I think they also dispelled the need to do Sort1 testing pre-treatment and pointed out no ADC did that, they all just picked cancers known to have a lot of the target. They did seem to place the overexpression of Sort1 as being high (Dr Winer) and it seemed he meant more prevalent than what he's seen in other targeted therapies.