Jake--MGK2 answered your questions pretty thoughtfully from a science-based perspective, with lots of great footnotes that are worth looking into (and if you don't want to get bogged down for the entire afternoon, just read the abstract and the discussion/conclusions parts of the paper!). I'll try to keep it simple and focus on outcomes...
Why do I think the ORR in the Clover trial will be less than the 75% noted in the basket trial? The simple answer is that half the patients in the Clover trial got a 350mg dose, and we do not know if that dose will shrink the tumors 30% or more (the standard RECIST criteria for a Partial Response). Furthermore, the trial is short--a year long plus any follow up or rollovers--so will 350mg be sufficient to reduce the tumor 30% in that abbreviated timeframe? By the October ESMO conference, or January? I'm going to say--just a guess here--prolly not. Will the 700mg dose hit that 75% ORR? That would be more likely in my opinion. Again--that is just a guess. But that is based on the synergism of the Clover combo; Tas-102, as MGK2 details, works better alongside leronlimab than the FOLFOX backbone, and bev helps the drugs get inside the tumor and limits metastasis. But the 350mg dose will bring down the
Three caveats here. The first is pretty obvious, the small sample size we are talking about in the basket trial. 33 patients is much better in the Clover trial, but still relatively small in the eyes of the FDAs. The second has to do with the durability of the response--are the early ctDNA reductions going to translate into tumor size/volume reductions? Dr Kasi seems to think so, and I will take his word on this... until we have actual data. But do remember, Dr Kasi has been championing this line of thought for a while now. So he is going to talk up the significance of ctDNA reductions even though he's going out on a limb... I take it as a positive that he has some skin in this game, and is quite positive about early results. And the third caveat is--we don't know if the DSMB has moved anybody whose tumors might be growing but haven't reached the 20% threshold that defines "progression." So there is that also. Will they be pulled or included in the final trial results? The DSMB is apparently a black box that we don't have any access to... So count that as a "known unknown." Along with the durability of response. What I do anticipate--a Disease Control Rate that is outta this world!
Your question about politely asking the doc to bump you up to 700mg of leronlimab gets to a very human question in all this, which, I think, is a public relations issue rather than a scientific one. I probably would be banging the table about bumping up the dose, frankly! Not to mention getting an ICI into me ASAP. And I'm sure many more would join me (think concerned family members, banging on the doctor's door!). But consider a patient who is responding favorably to the 350mg dose, from an oncologist's point of view.
The ctDNA counts are going down significantly, and the tumor is shrinking, say 10 or 20%. And the patient is feeling better, less pain and fatigue. Why not continue with the 350mg dose? As the tumor shrinks, the margins also become more defined, and the tumor might very well become amenable to surgical resection. With a little more time. (That was the case for the Complete Response in the basket trial--the tumor shrunk by 43%, the margins tightened up, and the surgeon took over from there). That makes a strong case for continuing treatment as is.
So, for an oncologist, the most compelling reason for sticking to the 350mg dose--if it ain't broke, don't fix it! If leronlimab is showing biological activity as measured by ctDNA reductions and small but medically-relevant tumor shrinkage, with no new visible metastasis and improving quality of life, most doctors would say "Proceed." If they are smart and have been paying attention, they also know they have the 700mg dose--and an ICI--in their back pocket. In their toolkit. If and when they need it. Which, for 3rd and 4th line mCRC patients, they probably will, eventually... But not right now, not this moment. If a very patient oncologist sat down with me, explained all of the above, and assured me they would be watching me like a hawk and at the first sign of disease progression I would be bumped up to 700mg and an ICI, I would think it over, and likely go with the flow, knowing the options in my back pocket. And given the trial is only a year long, if I'm I'm alive and feeling better at 10 months or so, by definition I would already be alive longer than the historical SOC would suggest (or close to it anyway). Are ya feeling lucky, brother? On death's doorstep a year ago, I'm feeling better, and playing with house money now...
Will the general public listen to those kind of arguments? If and when more cures come out of the EAP program, or the stories of the Ladies of Leronlimab circulate, and especially if we get some complete responses in the 700mg cohort--with or without an ICI and surgery--that's when the shit will hit the fan. As I said, at that point it becomes a public relations issue, a management-of-expectations issue. I think Dr Lalezari and the Cytodyn are preparing for that. But the FDA? Not so sure there...
Why do I think the ORR in the Clover trial will be less than the 75% noted in the basket trial? The simple answer is that half the patients in the Clover trial got a 350mg dose, and we do not know if that dose will shrink the tumors 30% or more (the standard RECIST criteria for a Partial Response). Furthermore, the trial is short--a year long plus any follow up or rollovers--so will 350mg be sufficient to reduce the tumor 30% in that abbreviated timeframe? By the October ESMO conference, or January? I'm going to say--just a guess here--prolly not. Will the 700mg dose hit that 75% ORR? That would be more likely in my opinion. Again--that is just a guess. But that is based on the synergism of the Clover combo; Tas-102, as MGK2 details, works better alongside leronlimab than the FOLFOX backbone, and bev helps the drugs get inside the tumor and limits metastasis. But the 350mg dose will bring down the
Three caveats here. The first is pretty obvious, the small sample size we are talking about in the basket trial. 33 patients is much better in the Clover trial, but still relatively small in the eyes of the FDAs. The second has to do with the durability of the response--are the early ctDNA reductions going to translate into tumor size/volume reductions? Dr Kasi seems to think so, and I will take his word on this... until we have actual data. But do remember, Dr Kasi has been championing this line of thought for a while now. So he is going to talk up the significance of ctDNA reductions even though he's going out on a limb... I take it as a positive that he has some skin in this game, and is quite positive about early results. And the third caveat is--we don't know if the DSMB has moved anybody whose tumors might be growing but haven't reached the 20% threshold that defines "progression." So there is that also. Will they be pulled or included in the final trial results? The DSMB is apparently a black box that we don't have any access to... So count that as a "known unknown." Along with the durability of response. What I do anticipate--a Disease Control Rate that is outta this world!
Your question about politely asking the doc to bump you up to 700mg of leronlimab gets to a very human question in all this, which, I think, is a public relations issue rather than a scientific one. I probably would be banging the table about bumping up the dose, frankly! Not to mention getting an ICI into me ASAP. And I'm sure many more would join me (think concerned family members, banging on the doctor's door!). But consider a patient who is responding favorably to the 350mg dose, from an oncologist's point of view.
The ctDNA counts are going down significantly, and the tumor is shrinking, say 10 or 20%. And the patient is feeling better, less pain and fatigue. Why not continue with the 350mg dose? As the tumor shrinks, the margins also become more defined, and the tumor might very well become amenable to surgical resection. With a little more time. (That was the case for the Complete Response in the basket trial--the tumor shrunk by 43%, the margins tightened up, and the surgeon took over from there). That makes a strong case for continuing treatment as is.
So, for an oncologist, the most compelling reason for sticking to the 350mg dose--if it ain't broke, don't fix it! If leronlimab is showing biological activity as measured by ctDNA reductions and small but medically-relevant tumor shrinkage, with no new visible metastasis and improving quality of life, most doctors would say "Proceed." If they are smart and have been paying attention, they also know they have the 700mg dose--and an ICI--in their back pocket. In their toolkit. If and when they need it. Which, for 3rd and 4th line mCRC patients, they probably will, eventually... But not right now, not this moment. If a very patient oncologist sat down with me, explained all of the above, and assured me they would be watching me like a hawk and at the first sign of disease progression I would be bumped up to 700mg and an ICI, I would think it over, and likely go with the flow, knowing the options in my back pocket. And given the trial is only a year long, if I'm I'm alive and feeling better at 10 months or so, by definition I would already be alive longer than the historical SOC would suggest (or close to it anyway). Are ya feeling lucky, brother? On death's doorstep a year ago, I'm feeling better, and playing with house money now...
Will the general public listen to those kind of arguments? If and when more cures come out of the EAP program, or the stories of the Ladies of Leronlimab circulate, and especially if we get some complete responses in the 700mg cohort--with or without an ICI and surgery--that's when the shit will hit the fan. As I said, at that point it becomes a public relations issue, a management-of-expectations issue. I think Dr Lalezari and the Cytodyn are preparing for that. But the FDA? Not so sure there...
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