I'd like to add my appreciation for the dialogue between twinter and MGK2... Lots of great science there. Answering some fundamental questions with authority... and footnotes. ScoreCarder chips in with his business-as-usual perspective... and knowledge of the FDA process and timelines. Adding in the the perspectives of Plotinus and Misiu just rounds it out all out, with real-world consequences--and patients lives--in the balance. Truly meaningful back-and-forth--which is why I love this board.
Getting back to Cycl2R's original questions about the eventual outcomes of the Clover trial, I'd like to add a few observations from the basket trial that evaluated leronlimab in mCRC. First things first--the dose used for every patient in the 5 patient cohort was 525mg of leronlimab. So not an optimum dose, but not sub-standard. Things like the weight of the individual patient may come into play here... small patients may very well have gotten an optimal dose, while heavier patients could have gotten something less. And if there was liver involvement--liver metastasis--that would mean more CCR5 cells active in the liver, which means more leronlimab would be needed to occupy those receptors. Lung metastasis don't involve as many CCR5 receptors, so the kind of organs that get metastasized have bearing on receptor occupancy. Which is just to say there are a lot of variables at play here... AI tells me: "The site of a patient's colorectal cancer metastasis alters the pharmacokinetics of leronlimab, fundamentally impacting whether a 350mg or a 700mg dose is required."
Out of the five patients in the basket trial, one was given leronlimab as a monotherapy. No chemo. That patient lived 4.2 months. (Rest-in-peace, good soul). Here is an AI-generated response concerning the other four patients:
"Summary Analysis of the 5-Patient Cohort
The collective outcomes show that when Leronlimab was paired with a functional chemotherapy partner (Patients 1, 2, 3, and 4), it achieved a 100% Disease Control Rate (DCR) consisting of 1 CR, 2 PRs, and 1 SD. The only therapeutic failure occurred when the drug was stripped of a chemotherapy partner (Patient 5). This critical insight directly led to the design of the CLOVER trial, ensuring that no patient receives Leronlimab alone and that all participants are paired with an active, resistance-breaking oral partner (TAS-102)".
The median Overall Survival was 15.8 months for the entire cohort... and stayed that way if you subtract the 4.2 months of life at the low end, as well as the 57 months (NED) on the high end. But if you exclude the monotherapy failure, the average--not the median--overall survival was between 23 and 36 months (according to AI). The historical baseline OS of Tas-102 and Avastin is 7.5 months. So, leronlimab and the Folfox chemo backbone basically tripled the average OS. Or better.
I had initially speculated that the inclusion of Avastin may have led to the excellent early ctDNA declines... but that didn't really make sense, upon reflection. Anti-angiogenesis effects--whether from Avastin, or leronlimab, or the combination--would result in loss of blood supply to the tumor, and most likely lead to stable disease/no progression, but not tumor death (ctDNA declines) and shrinkage. MGK2 caught this, and his comments reflected what I gathered from AI--that Tas-102 preferentially interferes with the tumor's DNA replication, killing the tumor more effectively than the Folfox chemo backbone. And leronlimab clearly makes Tas-102 work better, synergistically, and leads to much more ctDNA declines than happened in the basket trial, as evidenced in the early results of the Clover trial (70% declines early, even better later).
It's not like Avastin didn't have any impact. AI tells me the following: "The addition of Avastin to the fluropyrimidine doublet paired synergystically with leronlimab to control tumor volume. This clinical signal served as the primary proof-of-concept that adding a VEGF inhibitor to a CCR5 blocker enhances treatment efficacy--directly inspiring the triplet-drug architecture of the contemporary Clover trial." Additionally, Bev "physically normalizes the tumor's existing blood vessels so that chemo and immune cells can penetrate the tumor more effectively." (AI).
Cycl2R--Four patients cleared their ctDNA entirely during recent follow-up monitoring in the Clover trial. And 3 out of 4 patients that cleared their ctDNA were from the 350mg group! I'm gonna go out on a limb here... But I'm gonna say that the the 350mg dose of leronlimab, combined with Bev and Taz--is going to beat the SOC and be approvable by the FDA. Like, double or triple or quadruple the SOC. I mean, excluding the one non-chemo patient from the basket trial, you get a 75% ORR. With no ICI. The FDA will start drooling over themselves if we show an ORR of, say, 50% in this MSS mCRC patient population. Leronlimab has proved pretty consistent results in cancer trials. So why not just say it--I expect a 60%+ ORR in the Clover trial (including the 700mg cohort, just to be clear). Consistent/better than the basket trial. I'd lean to even better results, because of the Tas-102 instead of the Folfox/oxaliplatin chemo... but I'm going to be conservative here.
Twinter, MGK2, Scorecarder--Ohm, if you are around--whaddaya think? It's an early call... but a sound call I think, extrapolating from some very significant early results. I think the FDA will confuse things, approve the 350mg dose for mCRC, with Tas-102 and bev, and get in the way of what we all want to see--the LL/ICI combo, and radical Complete Response numbers. What does the FDA do best--slow things down? What I really hope for is the 700mg dose will separate itself in terms of efficacy rather quickly, and increase the PD-L1 numbers as well as achieve some Complete Responses without an ICI... and the FDA will just say "Fuck it, this is a radical breakthrough, even if there is stable disease, just give 'em an ICI and we'll call them cured." But can the FDA go there? Probably... Not!!!
A boy can dream... can't he? But tell me, anyone out there, y'all see an approval for the 350mg dose with Tas and bev? Those are the tea leaves I am reading... Can't predict a timeline, though. But I think the FDA is going to be blown away by the Clover results. And the public--when it gets wind of the EAP TNBC results--is going to go mad. Mad happy! And anyone with cancer, or their loved ones, will demand access. That could get crazy... and quickly. Cytodyn, and especially the FDA--as the gate-keeper--will have some dancing to do. They best be nimble on their feet. It makes me a little queasy that RFKjr will probably bring news of leronlimab to the world... But I don't really care anymore. Great news is great news. Can't wait.
Getting back to Cycl2R's original questions about the eventual outcomes of the Clover trial, I'd like to add a few observations from the basket trial that evaluated leronlimab in mCRC. First things first--the dose used for every patient in the 5 patient cohort was 525mg of leronlimab. So not an optimum dose, but not sub-standard. Things like the weight of the individual patient may come into play here... small patients may very well have gotten an optimal dose, while heavier patients could have gotten something less. And if there was liver involvement--liver metastasis--that would mean more CCR5 cells active in the liver, which means more leronlimab would be needed to occupy those receptors. Lung metastasis don't involve as many CCR5 receptors, so the kind of organs that get metastasized have bearing on receptor occupancy. Which is just to say there are a lot of variables at play here... AI tells me: "The site of a patient's colorectal cancer metastasis alters the pharmacokinetics of leronlimab, fundamentally impacting whether a 350mg or a 700mg dose is required."
Out of the five patients in the basket trial, one was given leronlimab as a monotherapy. No chemo. That patient lived 4.2 months. (Rest-in-peace, good soul). Here is an AI-generated response concerning the other four patients:
"Summary Analysis of the 5-Patient Cohort
The collective outcomes show that when Leronlimab was paired with a functional chemotherapy partner (Patients 1, 2, 3, and 4), it achieved a 100% Disease Control Rate (DCR) consisting of 1 CR, 2 PRs, and 1 SD. The only therapeutic failure occurred when the drug was stripped of a chemotherapy partner (Patient 5). This critical insight directly led to the design of the CLOVER trial, ensuring that no patient receives Leronlimab alone and that all participants are paired with an active, resistance-breaking oral partner (TAS-102)".
The median Overall Survival was 15.8 months for the entire cohort... and stayed that way if you subtract the 4.2 months of life at the low end, as well as the 57 months (NED) on the high end. But if you exclude the monotherapy failure, the average--not the median--overall survival was between 23 and 36 months (according to AI). The historical baseline OS of Tas-102 and Avastin is 7.5 months. So, leronlimab and the Folfox chemo backbone basically tripled the average OS. Or better.
I had initially speculated that the inclusion of Avastin may have led to the excellent early ctDNA declines... but that didn't really make sense, upon reflection. Anti-angiogenesis effects--whether from Avastin, or leronlimab, or the combination--would result in loss of blood supply to the tumor, and most likely lead to stable disease/no progression, but not tumor death (ctDNA declines) and shrinkage. MGK2 caught this, and his comments reflected what I gathered from AI--that Tas-102 preferentially interferes with the tumor's DNA replication, killing the tumor more effectively than the Folfox chemo backbone. And leronlimab clearly makes Tas-102 work better, synergistically, and leads to much more ctDNA declines than happened in the basket trial, as evidenced in the early results of the Clover trial (70% declines early, even better later).
It's not like Avastin didn't have any impact. AI tells me the following: "The addition of Avastin to the fluropyrimidine doublet paired synergystically with leronlimab to control tumor volume. This clinical signal served as the primary proof-of-concept that adding a VEGF inhibitor to a CCR5 blocker enhances treatment efficacy--directly inspiring the triplet-drug architecture of the contemporary Clover trial." Additionally, Bev "physically normalizes the tumor's existing blood vessels so that chemo and immune cells can penetrate the tumor more effectively." (AI).
Cycl2R--Four patients cleared their ctDNA entirely during recent follow-up monitoring in the Clover trial. And 3 out of 4 patients that cleared their ctDNA were from the 350mg group! I'm gonna go out on a limb here... But I'm gonna say that the the 350mg dose of leronlimab, combined with Bev and Taz--is going to beat the SOC and be approvable by the FDA. Like, double or triple or quadruple the SOC. I mean, excluding the one non-chemo patient from the basket trial, you get a 75% ORR. With no ICI. The FDA will start drooling over themselves if we show an ORR of, say, 50% in this MSS mCRC patient population. Leronlimab has proved pretty consistent results in cancer trials. So why not just say it--I expect a 60%+ ORR in the Clover trial (including the 700mg cohort, just to be clear). Consistent/better than the basket trial. I'd lean to even better results, because of the Tas-102 instead of the Folfox/oxaliplatin chemo... but I'm going to be conservative here.
Twinter, MGK2, Scorecarder--Ohm, if you are around--whaddaya think? It's an early call... but a sound call I think, extrapolating from some very significant early results. I think the FDA will confuse things, approve the 350mg dose for mCRC, with Tas-102 and bev, and get in the way of what we all want to see--the LL/ICI combo, and radical Complete Response numbers. What does the FDA do best--slow things down? What I really hope for is the 700mg dose will separate itself in terms of efficacy rather quickly, and increase the PD-L1 numbers as well as achieve some Complete Responses without an ICI... and the FDA will just say "Fuck it, this is a radical breakthrough, even if there is stable disease, just give 'em an ICI and we'll call them cured." But can the FDA go there? Probably... Not!!!
A boy can dream... can't he? But tell me, anyone out there, y'all see an approval for the 350mg dose with Tas and bev? Those are the tea leaves I am reading... Can't predict a timeline, though. But I think the FDA is going to be blown away by the Clover results. And the public--when it gets wind of the EAP TNBC results--is going to go mad. Mad happy! And anyone with cancer, or their loved ones, will demand access. That could get crazy... and quickly. Cytodyn, and especially the FDA--as the gate-keeper--will have some dancing to do. They best be nimble on their feet. It makes me a little queasy that RFKjr will probably bring news of leronlimab to the world... But I don't really care anymore. Great news is great news. Can't wait.
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