"FDA may very likely want to see the efficacy of l
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Posted On: 11/21/2025 6:30:01 PM
"FDA may very likely want to see the efficacy of leronlimab as a stand alone."
Frankly, I'd like to see the efficacy of leronlimab mono-therapy as well. But not at the expense of lives lost. And if you use the TNBC numbers as a guide, well, then you would certainly want an ICI right after your PD-L1 numbers go up.
But mCRC isn't TNBC. So why not take the apples-to-apples example provided by the solid tumor basket trial? That would be 5 mCRC patients, 3 partial responses for a 60% Overall Response Rate, and 15.4 months median Overall Survival. You might recall that one of those patients, after developing liver mets, had surgery and is still alive, almost 5 years now, with no evidence of disease. And this is leronlimab as a mono-therapy with standard of care. Pretty darn good numbers for MSS mCRC. Approvable numbers in fact. If the rollover protocol is included in the study so that if I progressed I'd get an ICI (assuming my PD-L1 numbers are up) well shoot--I'd take that in a heartbeat! Leronlimab as a mono-therapy in mCRC is not some kind of death sentence, and no one has the right to make that assumption or state it as fact.
Sure, the numbers are small. The FDA--and of course Wall Street--might very well laugh at those kind of numbers. But we are so early in the study of leronlimab that with the exception of HIV, all the number sets are going to be small... until we get a pivotal trial together. In the meanwhile, Geoffrey Fourqurean made an interesting and pertinent point when talking about leronlimab in the Covid trials--that even in the smaller studies, leronlimab displays relatively consistent results. Here is the full quote--"Across small but consistent datasets, CCR5 antagonism was associated with reductions of IL-6, movement of lymphocyte subsets towards homeostasis, and survival trends in the sickest cohorts." We also find strong and consistent signals in the oncology data--87% reduction in metastasis in preclinical studies in mice, 88% upregulation of PD-L1 in the TNBC studies, 60% ORR in mCRC in the basket trial. Lots of CTC data from Creativ Biotech too. And of course, 5 outta 5 ain't bad, either. (Take a bow, Ladies!). Not only consistent datasets... but very strong signals of measurable anti-cancer activity. At this point in the process, as we wait for data... I'm going to entertain the idea that those numbers aren't biotech wet-dreams but at the least... ballpark figures. Close to what we are going to end up with.
Mfglola--as far as the rollover protocol may work out--how do they define "disease progression" in solid tumor trials? I'm thinking it would be visual measurement revealing tumor growth, but do they define it as, say 25% larger, or something like that? If leronlimab upregulates PD-L1 in a 90-day timeframe, would you see disease progression--or on the other hand, regression of the tumor--in such a short timeframe? Progression or regression in 90 days?
If the protocol is changed to give people an ICI as soon as their PD-L1 numbers rise we are not going to get much in the way of ORR numbers, or other information regarding leronlimab's effect on metastasis or survival as a mono-therapy. That means we will probably fail the original endpoint of the trial--ORR. (Fail the trial but save lives... that would be a Cytodyn-like thing to do, wouldn't it?). As far as ORR and data on metastasis--that can wait for a trial in first-line mCRC (first-line/not as sick/more time to respond and/or provide an ICI). So for this trial, doing the right thing is pretty clear... "Hey FDA--yeah, you! Change the goddamn protocol and save some lives! Like this year!!!" Misiu and Ken and mfglola--I hear ya! Let's hope the FDA does.
But that would be like changing horses in mid-stream... Changing endpoints after the trial started, introducing a new drug into the mix, with limited data on the combos... I get the feeling the FDA does not like to do that kind of thing. Maybe it won't be an issue; like, "your PD-L1 numbers meet the threshold? Go over there and get your ICI." Case closed. But maybe it's gonna be same old same old... This will be a real test of Dr Lazelari's attempts to make nice with the FDA... as well as his persuasive abilities. But you know, it's the FDA! And the FDA, like most of the government bureaucracy, seems to be stressed out these days. And they are sticklers for detail. I suspect their decision on whether or not to include an ICI could go either way. But any deaths would be on the FDA. Lalezari has been trying hard to do the right thing. He's the poster-child for patient-centric care... Or should I say Host-Directed Therapy? (Both Fourqurean and Lalezari are great communicators; I'd like to see them on the same panel someday, somewhere... talkin' leronlimab).
One final comment on a practical issue... The trial is open label. So anyone in the trial that sees their PD-L1 numbers go up is going to want an ICI, even if it means dropping out of the trial to get it. Which could mean delays and dropouts and lots of consternation amongst the patient population--which we do not want to see. I'll go out on a limb here and say I think Lalezari has the FDA right where he wants them--save lives, or look foolish and botch or delay the trial of a life-saving cancer drug with virtually no side effects. But it's not easy to pressure an organization that holds absolute power over your aspirations... So at the upcoming FDA meeting, Dr J, be strong! But play nice!
Frankly, I'd like to see the efficacy of leronlimab mono-therapy as well. But not at the expense of lives lost. And if you use the TNBC numbers as a guide, well, then you would certainly want an ICI right after your PD-L1 numbers go up.
But mCRC isn't TNBC. So why not take the apples-to-apples example provided by the solid tumor basket trial? That would be 5 mCRC patients, 3 partial responses for a 60% Overall Response Rate, and 15.4 months median Overall Survival. You might recall that one of those patients, after developing liver mets, had surgery and is still alive, almost 5 years now, with no evidence of disease. And this is leronlimab as a mono-therapy with standard of care. Pretty darn good numbers for MSS mCRC. Approvable numbers in fact. If the rollover protocol is included in the study so that if I progressed I'd get an ICI (assuming my PD-L1 numbers are up) well shoot--I'd take that in a heartbeat! Leronlimab as a mono-therapy in mCRC is not some kind of death sentence, and no one has the right to make that assumption or state it as fact.
Sure, the numbers are small. The FDA--and of course Wall Street--might very well laugh at those kind of numbers. But we are so early in the study of leronlimab that with the exception of HIV, all the number sets are going to be small... until we get a pivotal trial together. In the meanwhile, Geoffrey Fourqurean made an interesting and pertinent point when talking about leronlimab in the Covid trials--that even in the smaller studies, leronlimab displays relatively consistent results. Here is the full quote--"Across small but consistent datasets, CCR5 antagonism was associated with reductions of IL-6, movement of lymphocyte subsets towards homeostasis, and survival trends in the sickest cohorts." We also find strong and consistent signals in the oncology data--87% reduction in metastasis in preclinical studies in mice, 88% upregulation of PD-L1 in the TNBC studies, 60% ORR in mCRC in the basket trial. Lots of CTC data from Creativ Biotech too. And of course, 5 outta 5 ain't bad, either. (Take a bow, Ladies!). Not only consistent datasets... but very strong signals of measurable anti-cancer activity. At this point in the process, as we wait for data... I'm going to entertain the idea that those numbers aren't biotech wet-dreams but at the least... ballpark figures. Close to what we are going to end up with.
Mfglola--as far as the rollover protocol may work out--how do they define "disease progression" in solid tumor trials? I'm thinking it would be visual measurement revealing tumor growth, but do they define it as, say 25% larger, or something like that? If leronlimab upregulates PD-L1 in a 90-day timeframe, would you see disease progression--or on the other hand, regression of the tumor--in such a short timeframe? Progression or regression in 90 days?
If the protocol is changed to give people an ICI as soon as their PD-L1 numbers rise we are not going to get much in the way of ORR numbers, or other information regarding leronlimab's effect on metastasis or survival as a mono-therapy. That means we will probably fail the original endpoint of the trial--ORR. (Fail the trial but save lives... that would be a Cytodyn-like thing to do, wouldn't it?). As far as ORR and data on metastasis--that can wait for a trial in first-line mCRC (first-line/not as sick/more time to respond and/or provide an ICI). So for this trial, doing the right thing is pretty clear... "Hey FDA--yeah, you! Change the goddamn protocol and save some lives! Like this year!!!" Misiu and Ken and mfglola--I hear ya! Let's hope the FDA does.
But that would be like changing horses in mid-stream... Changing endpoints after the trial started, introducing a new drug into the mix, with limited data on the combos... I get the feeling the FDA does not like to do that kind of thing. Maybe it won't be an issue; like, "your PD-L1 numbers meet the threshold? Go over there and get your ICI." Case closed. But maybe it's gonna be same old same old... This will be a real test of Dr Lazelari's attempts to make nice with the FDA... as well as his persuasive abilities. But you know, it's the FDA! And the FDA, like most of the government bureaucracy, seems to be stressed out these days. And they are sticklers for detail. I suspect their decision on whether or not to include an ICI could go either way. But any deaths would be on the FDA. Lalezari has been trying hard to do the right thing. He's the poster-child for patient-centric care... Or should I say Host-Directed Therapy? (Both Fourqurean and Lalezari are great communicators; I'd like to see them on the same panel someday, somewhere... talkin' leronlimab).
One final comment on a practical issue... The trial is open label. So anyone in the trial that sees their PD-L1 numbers go up is going to want an ICI, even if it means dropping out of the trial to get it. Which could mean delays and dropouts and lots of consternation amongst the patient population--which we do not want to see. I'll go out on a limb here and say I think Lalezari has the FDA right where he wants them--save lives, or look foolish and botch or delay the trial of a life-saving cancer drug with virtually no side effects. But it's not easy to pressure an organization that holds absolute power over your aspirations... So at the upcoming FDA meeting, Dr J, be strong! But play nice!
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