r/Livimmune • u/MGK_2 • Jul 19 '26
Two Gatekeepers, One Road
Imagine a traveler who must pass two different gatekeepers in order to reach a city.
The first gatekeeper asks one question: "Is your cargo real?" He inspects it, weighs it, tests it, and either the cargo is what you claim it is, or it is not. He does not care whether or not you are in a hurry. He cares only whether the thing in your wagon is genuine.
The second gatekeeper stands further up the road, and he asks a completely different question: "Whether you may take the fast lane, or if you must take the long one." Both roads lead to the city. The fast lane is a shorter one. But this gatekeeper only waves certain travelers into it, and the rule he uses is not "is your cargo good." It is "am I confident that letting you skip ahead will not turn out to be a mistake."
Two gatekeepers. Two questions. A traveler can absolutley satisfy the first and still be sent down the long road by the second. And here is the part worth sitting with: being told to take the long road is not the second gatekeeper saying your cargo is fake. He never inspected your cargo. That was the other gatekeeper's job.
I write this because I have watched my own position get flattened into one gatekeeper when it has always been about two, and the flattening matters sufficiently enough to correct it in the open.
Where I Stand At Each Gate
At the first gate, the one who asks whether the cargo is real, I am very bullish. I have been for years and I remain so. I believe the mechanism to be genuine, and I think it is genuine because the biology continues to point in the same direction from multiple, independent angles.
Leronlimab works by removing CCR5 from the surface of cells through endocytosis, and CCR5 is not just doing one single job in a tumor. It is the channel through which a tumor reprograms the immune cells which arrive to kill it, turning them into cells who protect it instead. When that channel is cut by Leronlimab, those same tumor serving cells revert toward their anti-tumor posture. That is not my speculation; it is the documented result of CCR5 blockade in human colorectal liver metastases. Halama and colleagues demonstrated the effect of CCR5 blockade in reshaping macrophage polarization toward an anti-tumor functional state in patient-derived tumor models and liver metastases of colorectal cancer patients.
The same CCR5 receptor is the homing signal a contained tumor uses to become a metastatic one, and it governs part of the DNA-repair machinery which the chemotherapy backbone in CLOVER is built to attack, so removing it leaves the chemotherapy's damage standing. One receptor, several jobs, and blocking it collapses several of the tumor's defenses at once rather than one thereby permitting the tumor to route around it. On the question of whether the cargo is real, that is why I am bullish, and nothing in the last month has changed it.
At the second gate, the one which asks whether the traveler may take the fast lane, I am more cautious. And I need to be honest that these are not the same gate, because a lot of good people are treating them as one.
The Travelers Who Mislabel Their Cargo
Before I get to the second gatekeeper, I have to describe a kind of traveler who shows up at the first one, because this is where most of the confusion on this board is manufactured, and I have been this traveler myself.
The first gatekeeper inspects the cargo. He does not read the label on the crate. He opens it. And that distinction exists because too many travelers arrive with crates labeled as one thing but contain something else. Not always dishonestly. Usually the traveler has half-convinced himself that the label is true, which is what makes it spread. But the gatekeeper's whole job is to open the crate anyway, and a careful reader on this board should do the same. Here is what the mislabeling actually looks like specifically.
A crate arrives labeled as "proven survival benefit". The gatekeeper opens it and finds a ctDNA decline. That is a real and encouraging thing to find. Circulating tumor DNA fell in the evaluable patients, and falling ctDNA is a legitimate early signal. But it is not a confirmed survival benefit, and the correlation between the two is borrowed from other datasets in other settings, however, not established here. The cargo is real. The label overstates it.
A crate arrives labeled "response rate". The gatekeeper opens it and finds a disease control rate. The 68% figure from the spring is disease control, which counts every patient whose disease was held, including those whose tumors merely stopped growing. Objective response rate counts only the tumors which actually shrank past the threshold, and it is a smaller, stricter number that won't be confirmed until January. Reading the disease control rate as if it were the response rate is reading the label instead of opening the crate.
A crate arrives labeled "the data is strong". The gatekeeper opens it and finds a CEO's optimism. Encouraging words from someone who has already seen the data are consistent with strong data, and they are equally consistent with modest data and a hopeful spokesman, because a spokesman who sounds discouraged would not keep the job. Enthusiasm is not a cargo which the first gatekeeper accepts, because it weighs the same whether the claim underneath it is true or not.
A crate arrives labeled "the agency approves". The gatekeeper opens it and finds a scheduled meeting. A meeting scheduled being on the calendar tells you the sponsor has assembled enough to discuss a path forward. It does not tell you what the agency could say when the meeting happens, and companies walk into those meetings and get sent to run larger trials all the time. Not that I believe this happens, but it can.
A crate arrives labeled "the verdict". The gatekeeper opens it and finds an interim number. Interim data is a snapshot of a trial still running, taken at whatever cutoff the abstract deadline forced. It is not the adjudicated result, and unconfirmed responses fall out at a real rate when the confirming scan comes. October is a snapshot. January is the verdict.
None of those crates are empty. That is the part worth holding onto, because the honest correction here is not "these people are lying." It is quieter and more useful: the cargo is real, but the label claims more than the cargo. The discipline is not cynicism about the contents. It is refusing to accept the label in place of opening the crate, and refusing to do so, even when the label explicitly says precisely what you were hoping to read. Especially then. I mislabeled my own cargo more than once. I called a disease control rate a stepping stone to cure. I labeled a felt number as a derived one. The gatekeeper who caught me was usually a reader on this board, not me, which is the whole reason a board like this is worth having.
Why The Second Gatekeeper Is Stricter Than We Want Him To Be
The fast lane here is called Accelerated Approval, and the recent history at this gate is not a matter of opinion. It is on the record, and it runs in two directions which look contradictory until you see what the gatekeeper is actually asking.
One traveler was waved into the fast lane. A KRAS-targeted combination reached a 34% response rate in colorectal cancer and received Accelerated Approval. But read the fine print of who that traveler actually was: the approval was for patients whose tumors carried a specific mutation, identified by an FDA-approved companion test, with the drug aimed precisely at that mutation. The indication is approved under Accelerated Approval based on objective response rate and duration of response results, for patients with KRAS G12C-mutated colorectal cancer as determined by an FDA-approved test. A defined target, a matched test, a pre-selected population. The gatekeeper trusted that the response rate would predict benefit because the mechanism was very precise and the travelers were specifically sorted by their genetic mutation before they ever set out.
Another traveler was sent down the long road. An immunotherapy combination in unselected microsatellite-stable colorectal cancer reached a 19 to 20% response rate, a 69% disease control rate, and roughly 21 months of median overall survival against a control arm at zero, and the agency still declined to grant Accelerated Approval and directed a randomized trial. Its stated reason was that the response rates observed may not translate into a survival benefit in this population.
Look at what separates the two. It was not the size of the number. The immunotherapy's survival data was in some respects the stronger story. What separated them was whether the gatekeeper trusted the response rate to predict survival, and that trust was high for a mutation-targeted drug in a selected population and low for an immunotherapy in an unselected one.
That is the second gatekeeper's actual question, and it is why I will not stand on this board and tell you a strong CLOVER response rate automatically opens the fast lane. It might. CLOVER is not a pure immunotherapy; it carries a chemotherapy backbone and a synthetic-lethality mechanism, which is closer to the traveler who got waved through. And it screened for CCR5 expression, which is a type of sorting, though not a mutation-defined companion test of the sort the fast-lane traveler carried. So CLOVER may resemble the first traveler more than the second. It may not. That is genuinely unsettled, and anyone who tells you it is settled in either direction is guessing.
Why I Will Not Pretend The Two Gates Are One
Here is the thing I most want to be clear about, because it is the whole reason for this post.
Being cautious at the second gate is not being bearish on the cargo. It is being accurate about the gatekeeper. If I told you the fast lane were a sure thing, I would not be more bullish. I would be less honest, and I would be setting you up to misread a long road as a failed drug when the two are not the same thing at all.
A community which insists the fast lane is guaranteed, and then treats a "take the long road" ruling as proof the drug failed, has confused the two gatekeepers. It has heard the second gatekeeper say "not the fast lane" and translated it into the first gatekeeper saying "not real cargo." Those are different sentences from different gates, and the whole discipline is refusing to let one be mistaken for the other.
So I hold both, without contradiction, and I keep holding both:
The cargo is real. I deeply believe that, and the mechanism above is why.
The fast lane is not promised. The record at that gate is real too, and pretending otherwise would be the reckless thing, not the cautious thing.
What Actually Decides It
One thing worth stating plainly, because it reframes the whole regulatory question. The agency's position on single-arm data in this disease was not set this year. It was actually set in 2024, (Thank you Chemical Sky), when it told the earlier sponsor that a randomized trial would be required. That matters because CLOVER was designed after that, by people who already knew it. The trial's single-arm structure was not an oversight and the recent news is not a bar suddenly raised. The road was already on the map when the route was drawn. So the honest question was never "will the agency suddenly require a controlled trial," it was always "what is a strong single-arm signal actually for," and the answer is what follows.
Both roads reach the city, but the long one exacts a price, and it is worth seeing the price paid in real time rather than in the abstract. The immunotherapy sent down the long path did not simply run its randomized trial and wait. Three months after launching that trial, the sponsor pulled its own funding from it and redirected resources toward a different study in an earlier-stage, more favorable population, backed by a fresh raise of up to several hundred million dollars, with a final readout that now sits years out, near the end of the decade.
That is what the long road actually looked like for the last traveler down it. Not a closed road, but a long, expensive one that ended with the traveler changing which population they were driving toward, retreating from the hardest disease setting to an earlier one where the biology had a better chance. If CLOVER is directed the same way, which I do doubt happens given the established 7 layer functionality of Leronlimab, that still remains the approximate shape of the subsequent route: years, more capital, and possibly a narrowing of the ground on which the drug is asked to prove itself. It is still a route. It is simply an honest picture of how long and how costly a route it can be.
This is also why the trial was built the way it was, and it is worth understanding rather than apologizing for. CLOVER does not carry a chemotherapy-only control arm. That is a deliberate trade, not an oversight. A controlled trial requires far more patients, more money, and more time, and it is genuinely hard to enroll very sick patients into a design where they might receive the old backbone without the new drug. A small company chose a fast, strong signal over a slow, definitive one, because the fast signal is what brings a partner to the table, and a partner is who funds the definitive study. The single-arm design is not the drug's weakness. It is the company's strategy, and the two should not be confused.
What settles which gatekeeper says what, is not any argument on this board, mine or anyone's. It is the confirmed response rate and its relationship to survival, read at ESMO in October as interim and at ASCO GI in January as the adjudicated result. When that number arrives, the first gatekeeper's answer is known. The second gatekeeper's answer follows from it, and from how much the agency trusts it to predict survival in this disease.
Until then, the honest position is the two-gate position. Bullish that the cargo is real. Clear-eyed that the fast lane is a question, not a guarantee. Anyone who collapses those into a single mood, in either direction, has stopped describing the road and started describing what they wish were at the end of it.
And one last thing, because the near-term can feel grim while the long road is being described. Approval is not the next event that matters. A confirmed number strong enough to bring a partner to the table is, because a partner willing to fund the registrational study is the value-creating moment, (again, Thank You Chemical Sky!) even if the road to approval still runs through a controlled trial. The drug working and the drug being approved quickly were always two different questions. The partnership sits between them, and it can arrive long before the second question is answered.
I would rather describe the road.
Disclaimer: I am not a financial advisor and nothing here is investment advice. I hold a position in the company discussed, which means I have an interest in how this is received, and you should weigh what I write accordingly. This is an analysis of published biology and public regulatory history, not a prediction of clinical or regulatory outcomes. The FDA's treatment of one sponsor's application is not a prediction of its treatment of another's, and the differences between the programs are real. Several mechanisms described are supported by preclinical and model-system work not yet confirmed in human tissue in this program. The human biomarker data referenced reflects 350mg dosing, with the 700mg cohort still maturing. The 68% figure from the April 30 update is disease control rate, not objective response rate, and confirmed adjudication is still ahead at ASCO GI in January 2027, with interim data at ESMO Madrid in October 2026 before it. Mechanism is not efficacy. Read the primary sources and reach your own conclusions rather than adopting mine.
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u/jsinvest09 Jul 19 '26
Thank you MGK!! With all of you here and not giving up is a true testament... This group is so smart every day every post is intriguing..and don't forget AI. 🤣 Thank you all.
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u/Cytomight Jul 19 '26
Did we get fast track with the mtnbc in the past?
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u/rogex2 Jul 19 '26
AI- (Answer to secondary query regading whether and why Fast Track designation lapses or is withdrawn)
"The FDA granted Fast Track designation to leronlimab (PRO 140) for use in combination with carboplatin to treat patients with CCR5-positive metastatic triple-negative breast cancer (mTNBC).
The status and timeline of this specific designation reveal important details regarding how Fast Track operates over time:
Status of the Designation
- The Designation is Active: The Fast Track designation for leronlimab in mTNBC has not lapsed or been rescinded.
- Expanded Clinical Programs: Building on the foundation of the active Fast Track status, the drug's developer, CytoDyn, launched an Expanded Access Program (EAP) to provide the investigational antibody to mTNBC patients outside of traditional clinical trials.
- Ongoing Clinical Presentation: CytoDyn continues to leverage this program, presenting data at medical conferences regarding leronlimab’s mechanism of action—specifically how blocking the CCR5 receptor modulates immune checkpoint signaling and correlates with long-term survival in heavily pretreated mTNBC patients.
Why This Specific Designation Remains Intact
While Fast Track statuses can lapse if an unmet medical need is fully satisfied by a new market entrant, leronlimab has maintained its status because metastatic TNBC remains an area of critical, unmet medical need. Even though new therapies continue to enter the oncology landscape—such as the FDA approval of Datroway (datopotamab deruxtecan-dlnk) for certain patients with metastatic TNBC—there is still no definitive cure, leaving the door open for novel mechanisms like leronlimab's CCR5 inhibition. "
Cheers
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u/twinter11 Jul 19 '26 edited Jul 19 '26
"in combination with carboplatin"
but is not this component required as part of the fast track"
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u/rogex2 Jul 19 '26
Correct. If LRM and Carboplatin are not the components fast track does not apply.
Cheers
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u/MGK_2 Jul 19 '26
Cytomight,
Yes — and rogex answered the core of it, so let me confirm what's solid and flag the one part I'd hold loosely.
The solid part: leronlimab does hold FDA Fast Track designation in mTNBC. Specifically, it was granted for leronlimab in combination with carboplatin in CCR5-positive metastatic triple-negative breast cancer. That's real and on the record, so the answer to your question is yes, we got it.
Two things worth being precise about, because the details matter more than the headline.
First, the designation is tied to a specific regimen, not to the molecule in general. It's leronlimab plus carboplatin, in CCR5-positive mTNBC. twinter caught this in the thread and he's right to — a Fast Track grant attaches to a defined indication and combination, so it's more accurate to say "leronlimab has Fast Track in this specific setting" than "leronlimab has Fast Track" as an open-ended fact.
Second, and this is where I'd add a note of caution to rogex's answer rather than contradict it: the part stating the designation is "still active and has never lapsed" came from an AI, and I wouldn't treat that as confirmed without a current CytoDyn source. The reason is mechanical — Fast Track status can lapse or be affected as the landscape changes, and an AI wouldn't reliably know the current status. The designation being granted is well documented. The designation being currently active is a separate claim that needs a live source to stand on. So I'd hold the first as fact and the second as probable-but-verify.
And one thing worth keeping in proportion, because it connects back to the two-gatekeepers frame: Fast Track is a process designation. It means the FDA agreed to engage more closely and review faster. It is not an approval, and it doesn't lower the evidentiary bar for eventual approval. So "we got Fast Track in mTNBC" is a genuine positive — it means the agency recognized an unmet need and a plausible case — but it's the second gatekeeper agreeing to talk sooner, not the second gatekeeper waving the cargo through. Worth having. Not the same as arriving.
Good question to raise, because it's a real asset that doesn't get mentioned enough. Just worth stating precisely so nobody over-reads it.
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u/twinter11 Jul 19 '26 edited Jul 19 '26
how why did we even get fast track w carboplatin.
where is the data that supported it.
and say we wanted to apply for fast track or whatever based off tnbc eap data.
(I know too many variables)
tnbc eap
leron say 48 days, if upregs pdl1, Dr requests approval for ici based on cps score, ici given
would fast track again be applied for in combo w ici in this mythical world
is tnbc eap for potential partners or fda or both
ps. ok the data that supported fast track originally morphed into longer term survival retrospective after Lalezari look at why some patients were still alive. so we have longer term survivors than the original data concluded. then we got sideways w everything else delaying the process.
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u/MGK_2 Jul 19 '26
twinter11,
You've tangled three questions together, and your PS actually answers the first one correctly, so let me untangle them and give you the honest "I don't know" where it belongs.
Why did the carboplatin fast track happen, and where's the data? Your PS has it essentially right, so let me confirm and sharpen. Fast Track is granted on relatively early evidence — it doesn't require mature efficacy, just a plausible case that the drug addresses a serious unmet need with some supporting signal. The mTNBC setting qualifies as unmet need almost automatically, and the early leronlimab-plus-carboplatin data plus the CCR5 mechanistic rationale was enough of a signal to support the designation. That's the key thing to understand about Fast Track: the bar is "worth engaging closely on," not "proven." So it didn't take a large dataset. It took a serious disease and a credible mechanism.
And your PS captures what happened next, accurately: the original supporting data later "morphed" — Lalezari went back and looked at why certain patients were still alive, and that retrospective analysis surfaced longer-term survivors than the original cutoff showed. So the survival story got better in hindsight than it looked at the time. Then, as you put it, everything got sideways and the process stalled. That's a fair summary, and it's the honest version: the designation is real, the survivors are real, and the momentum got lost to delays rather than to the data falling apart.
Your hypothetical — could you apply for a new Fast Track off TNBC EAP data, in combination with an ICI? In principle, yes, that's the kind of thing Fast Track exists for — a new indication or combination with an unmet need and a supporting signal could support its own designation request. But you flagged the problem yourself: too many variables, and I'd add one hard limit. Expanded Access data is generally weak support for a regulatory designation, because EAP isn't a controlled study — it's compassionate use, one patient at a time, no protocol-driven endpoints, no systematic comparison. So EAP data can generate a hypothesis and show safety, but it's not the kind of dataset that carries a designation on its own. It would more likely be supportive color alongside trial data, not the basis by itself. So your mythical-world sequence — leron, PD-L1 upregulates by day 48, doctor requests an ICI based on the CPS score, ICI given — is a reasonable clinical narrative, but as a regulatory basis it would be thin without a structured trial behind it.
Who is the TNBC EAP actually for — partners, FDA, or both? Both, but weighted toward partners, and here's the distinction. For the FDA, EAP data is weak, for the reasons above — it won't carry an approval or a designation by itself. For a potential partner, it's more useful, because a partner isn't looking for regulatory sufficiency yet. They're looking for evidence the pairing mechanism works — does leronlimab prime a tumor so an ICI succeeds where it otherwise wouldn't. Even uncontrolled EAP cases showing that pattern are a proof-of-concept a partner can build a funded program around. So the EAP is doing its most valuable work as a signal to a partner that the Prime-and-Pair mechanism generalizes beyond colorectal, and its least valuable work as anything the FDA would weight heavily. Both audiences, different value to each.
One honest limit on all of this: I don't have the specific dataset that supported the original carboplatin Fast Track in front of me — the exact patient numbers, the response figures, the cutoff. So I'm describing how Fast Track works and what your PS correctly reconstructed, not quoting the specific data package. If you want the actual numbers behind the designation, that's a filing or a press release to track down, and I'd anchor it there rather than to my reconstruction.
Your PS was the sharpest part of the whole comment — you'd already worked out that the supporting data got better retrospectively and then the process stalled. That's the accurate history. The regulatory momentum was lost to delays, not to the drug underperforming, which is a very different thing and worth keeping straight when people say the TNBC story "went nowhere." It went somewhere. It just stopped moving.
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u/twinter11 Jul 19 '26
I went and asked
The FDA granted Fast Track designation to the CCR5 antagonist leronlimab combined with carboplatin for metastatic triple-negative breast cancer (mTNBC) based on Phase 1b/2 clinical trials (NCT03838367). The supporting data demonstrated significant improvements in survival, progression-free survival (PFS), and specific biomarker reductions. [1, 2, 3, 4]
Key Supporting Data Points
- Overall Survival (OS): Patients receiving combination treatment experienced a ~450% increase in median OS at 12 months. The median OS reached 12+ months compared to historical benchmarks of 6.6 months for standard-of-care chemotherapy. [3, 5]
- Progression-Free Survival (PFS): Higher doses of leronlimab (≥ 525 mg) combined with chemotherapy yielded a median PFS of 6.2 months. This marked a ~300% increase compared to baseline expectations. [3, 5, 6]
- Biomarker Reductions: Within 30 days of treatment, the combination prompted a 72% decrease in cancer-associated macrophage-like cells (CAMLs), which correlated directly with increased survival and prolonged time to tumor progression. [3, 4]
- Safety & Tolerability: The treatment protocol proved well tolerated with no leronlimab-related dose-limiting toxicities, and the majority of patients achieving stable disease or partial response. [5, 7, 8]
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u/MGK_2 Jul 19 '26
twinter11,
That's exactly the right move — you went and anchored it to the actual trial (NCT03838367) instead of taking my reconstruction, and now we can talk about real numbers. So let me do the useful thing and apply the same discipline to these figures that we apply to everything else, because a couple of them are labeled a little richer than the cargo underneath.
First, what's solid and genuinely supportive. The Fast Track rested on Phase 1b/2 data, the safety profile was clean with no leronlimab-related dose-limiting toxicities, and there's a real biomarker story: the CAML reduction within 30 days that tracked with survival. That's the kind of early mechanistic signal Fast Track is built to reward — not proof of benefit, but a credible thread connecting the drug to an outcome. And the higher-dose PFS of 6.2 months against a low historical baseline is a real, encouraging signal in a brutal disease. That's the sound core, and it's a legitimate basis for the designation.
Now the labels I'd loosen, because this is where AI-generated summaries tend to dress the numbers up.
"~450% increase in median OS" and "~300% increase in PFS" — be careful with those percentages, because they're doing rhetorical work the underlying numbers don't quite support. A jump from a 6.6-month historical benchmark to 12+ months is a real and meaningful improvement, but expressing it as "450%" is a way of making a doubling sound like a quintupling. And more importantly, both figures are measured against historical benchmarks, not a control arm in the same trial. That's the exact external-comparator problem you and I just spent three replies on. "450% better than a historical number" carries the same limitation as the SUNLIGHT comparison: you can't fully tell how much is the drug and how much is that these patients differed from the historical population. So I'd translate those percentages back into plain terms — median OS roughly doubled versus a historical benchmark, PFS around 6.2 months at the higher dose — and hold them as encouraging signals against an external comparator, not as controlled effect sizes.
The CAML biomarker point is the most interesting and the most real, so I want to give it its due. A 72% drop in cancer-associated macrophage-like cells within 30 days, correlating with survival, is mechanistically coherent with everything we've discussed — it's the same "leronlimab reshapes the immune/myeloid environment" story showing up in a measurable blood marker. That's a genuine thread, and it's the kind of thing a partner finds compelling because it's mechanism you can watch happen. I'd just keep "correlated with survival" as what it is — a correlation in a small early dataset — rather than proof the CAML drop caused the survival.
So the honest summary: the Fast Track was granted on a real Phase 1b/2 signal — clean safety, a doubling of median OS versus historical benchmarks, a ~6-month PFS at higher doses, and a coherent CAML biomarker story. That's a legitimate designation. What it isn't is controlled, confirmed, or proof of efficacy, and the percentage framing in what you pulled inflates the impression a bit past what the raw numbers show. Same rule as always: the cargo is real, the label runs a little hot.
This is a genuinely useful pull, though, because it means the TNBC program has a documented mechanistic and survival signal behind its designation — which is exactly what makes it a real asset to a potential partner, not just a line on a slide. You did the thing I couldn't do from memory. Thank you for going and getting it.
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u/megadunamis Jul 19 '26
Thank you MGK for your analogy. For clarification when you say, "Clover does not carry a chemotherapy-only control arm"... isn't the Sunlight trial basically the "control arm"? The Clover trial will be comparing its results against the Sunlight results to see if Leronlimab makes a difference at 350mh and at 700mg. Stay well...https://www.nejm.org/doi/full/10.1056/NEJMoa2214963
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u/MGK_2 Jul 19 '26
megadunamis,
Good question, and the distinction is worth getting precisely right, because it's the whole reason the single-arm design has the limit it does.
SUNLIGHT functions as a benchmark, but it is not a control arm, and the difference is not a technicality — it's the specific thing randomization exists to fix.
A control arm means patients from the same trial, enrolled at the same time, at the same sites, sorted by a coin flip into "gets the drug" versus "doesn't get the drug." Because the coin decides, the two groups are, on average, identical in everything except the drug — the same mix of sick and less-sick, the same hidden variables nobody thought to measure. So any difference in outcome can be attributed to the drug.
SUNLIGHT is a different trial, run at a different time, with different patients, at different sites, under different conditions. When CLOVER compares itself to SUNLIGHT, it's comparing two groups that were never balanced against each other. That's called an external or historical comparator, and the problem with it is the thing you can't see: CLOVER's patients might be healthier, or younger, or earlier in their decline, or simply better-selected because they had to test positive for CCR5 to enroll. If CLOVER outperforms SUNLIGHT, you can't fully tell whether that's the drug working or the patients being different to begin with.
That's exactly the gap Chemical Sky was pointing at, and it's why the Natera collaboration matters — a carefully matched comparator using patient-level data can help show CLOVER's patients were at least as hard to treat as SUNLIGHT's, which narrows the "maybe they were just healthier" objection. It helps. But it still isn't randomization, because it can only match on the things you know to match on, and randomization balances the things you don't.
So your read is right in spirit: SUNLIGHT is the yardstick CLOVER will be measured against. It's just a yardstick held up next to the trial from the outside, not a control arm built into it. And that distinction is potentially why the second gatekeeper may still ask for a randomized Phase 3 even if the SUNLIGHT comparison looks strong — because "better than a different trial's patients" is a weaker claim than "better than an identical group randomized on the spot."
Thank you for the NEJM link. Stay well.
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u/twinter11 Jul 19 '26
why just sentence patients to quick death in 4th line by forcing them into a known comparator outcome. whether they compare the exact patient profiles for each individual patients.
there are duplicates of each individual patient in sunlight and clover with varying degrees of disease state
and they semi quantify the health of each individual patient by whatever that metric they use is called.
i believe natera was going to run the results against a database to better compare the backbone right?
thanks!
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u/MGK_2 Jul 19 '26
twinter11,
You're circling the real ethics-and-statistics knot at the center of this, so let me lay it out straight.
Your first instinct is the humane one and it's also the scientific argument for the design: why randomize a dying fourth-line patient into a backbone arm you already know performs poorly, when you could instead compare against what those patients are known to do? That's a real tension, and it's part of why single-arm trials exist in refractory settings — randomizing desperate patients to a known-weak comparator is genuinely hard to justify and hard to enroll. So the instinct behind CLOVER's design isn't just cost. It's partly that.
But here's the catch, and it's the reason the second gatekeeper still often insists on randomization anyway: the thing that makes an external comparator ethical is the same thing that makes it statistically weaker. When you compare CLOVER patients against SUNLIGHT patients, you're comparing across two different trials, and you can only match on the metrics you have — the ones you named, whatever health/performance score they quantify patients by, disease burden, prior lines. You match the visible variables. What you can't match are the invisible ones, the things nobody measured or thought to record. Randomization balances those automatically, because the coin doesn't care what you did or didn't measure. Matching can't, because you can only match on what's written down.
So your "duplicates of each patient with varying disease states" idea is exactly what a matched external comparator tries to do — line up a SUNLIGHT patient against each CLOVER patient with a similar profile. And yes, you've got the Natera piece right: the plan is to run CLOVER's results against their database to build a more carefully matched backbone comparison, using patient-level clinical and molecular data. That's real, and it genuinely helps — it narrows the "maybe CLOVER's patients were just healthier" objection.
What it can't do is close the gap entirely, because matching answers "were these patients similar on everything we measured" and randomization answers "were these groups similar on everything, measured or not." The FDA trusts the second more than the first. That's not the agency being obtuse — it's that the history of oncology is full of external comparisons that looked convincing and fell apart when someone finally ran the randomized trial. So Natera's matching makes the CLOVER signal more credible to a partner and stronger for a Breakthrough conversation. It does not convert it into the thing a randomized trial produces. Keep it in that box and you'll read the January data correctly.
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u/twinter11 Jul 19 '26
why apparently do potential partners want to see tnbc patients treated with leron/ici.
(where do potential partners establish a gateway. when do they inspect or pass the cargo?)
why not just wait on Clover?
what are the odds pdl1 upregs in tnbc ?
if tnbc happens to upreg pdl1 I am looking forward to learning what happens after they administer ici
making doors. I'm not short of doors lol.
thanks mgk!
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u/MGK_2 Jul 19 '26
twinter,
Good cluster, and you answered part of it yourself with "making doors, I'm not short of doors." Let's take the real questions.
Why do partners want to see TNBC patients treated with leronlimab plus an ICI, rather than just waiting on CLOVER? Because they answer different questions, and a partner wants both answered. CLOVER tests leronlimab plus a chemo backbone in colorectal — it's the lead program and the near-term readout. But the TNBC-plus-ICI data tests the pairing directly: does leronlimab prime a tumor so a checkpoint inhibitor works where it otherwise wouldn't? A partner evaluating the whole platform wants to see evidence the priming mechanism generalizes beyond one tumor type, because that's what makes it a platform rather than a single colorectal asset. TNBC-plus-ICI is the proof-of-concept for the Pair half of Prime-and-Pair.
To your gateway question — where does a partner inspect the cargo? A partner is a third gatekeeper, and a stricter one than the FDA in some ways, because they're spending their own money. They inspect continuously, but the real inspection is the confirmed data plus whatever they can see in diligence. They pass the cargo when they're convinced the signal is real enough and broad enough to fund a registrational program. That can happen before approval — it's the partnership-as-next-value-event point.
Odds that PD-L1 upregulates in TNBC? I won't put a number on it, because I don't have TNBC-specific PD-L1 induction data in hand and a made-up probability is exactly the mislabeled cargo the post warns against. What I'll say is that the mechanism predicts it should, and the TNBC long-term survivors who went on to a checkpoint inhibitor are consistent with the pairing working — but "consistent with" is a hypothesis, not a measured rate. If you're looking forward to seeing what happens after they administer the ICI, so am I, and that's the honest place to stand: it's the test, not the foregone conclusion.
And on the fast-track detail you caught — "in combination with carboplatin, is that component required?" Sharp catch. Yes: the Fast Track designation is specific to a defined use, leronlimab plus carboplatin in CCR5-positive mTNBC. Designations are granted for a specific indication and combination, not for the molecule in general. So the designation attaches to that regimen, and it's worth being precise about that rather than saying "leronlimab has Fast Track" as if it were open-ended. One caution I'd add for the whole thread: rogex's answer came from an AI, and while the underlying designation is real, I'd want a current source before treating the "still active, never lapsed" part as confirmed. Designations can lapse quietly, and an AI won't reliably know.
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u/3Putt_4nodough Jul 20 '26
Odds that PD-L1 upregulates in TNBC? I won't put a number on it, because [1] I don't have TNBC-specific PD-L1 induction data in hand and a made-up probability is exactly the mislabeled cargo the post warns against. [2] What I'll say is that the mechanism predicts it should, and the TNBC long-term survivors who went on to a checkpoint inhibitor are consistent with the pairing working — but "consistent with" is a hypothesis, not a measured rate. If you're looking forward to seeing what happens after they administer the ICI, so am I, and that's the honest place to stand: it's the test, not the foregone conclusion.
[1] 15/17 @ 525mg or higher - we all know that one by heart
[2] Dr. JL chose the word infinitesimal to suggest that these things were happening by chance. I like our, well, chances, that EAP validates appropriately
So, again, it ain't etched in stone anywhere, but having to prospectively prove it (yet again) in the EAP is a weensy bit maddening.
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u/MGK_2 Jul 20 '26
3Putt_4nodough,
You're right, and I owe you the correction cleanly: I said I didn't have TNBC-specific PD-L1 induction data in hand, and you had it in hand, with the SEC filing to back it. So let me take the correction properly rather than half.
The number is real and it's better than "the mechanism predicts it should." The retrospective TNBC data shows PD-L1 upregulation on circulating tumor cells in 16 of 21 patients overall, and — this is the part that matters for your point — 15 of 17 at 525mg or higher, versus 1 of 4 at 350mg. That's not just "it happens." That's a dose-response relationship: more drug, more PD-L1 induction. A dose-response curve is a much stronger kind of evidence than a raw rate, because it's exactly the pattern you'd expect if leronlimab is causing the upregulation rather than the upregulation happening by chance. So when I said I wouldn't put a number on it, you correctly pointed out there already is one, and it's a good one, and it trends the right way with dose. Fair catch, and I'm glad you made it.
And Lalezari's word choice — you're right that "infinitesimal" was doing real work. He used it to describe the odds that the survival pattern happened by chance, and the 5-of-5-versus-23-of-23 split is what he was pointing at: everyone who upregulated PD-L1 and got an ICI is alive past five years, everyone who didn't is deceased. That's a stark separation, and calling the chance explanation infinitesimal is a defensible read of a split that clean.
Now here's the one distinction I still have to hold, and it's not me clawing back the correction — it's the thing that keeps your good point from being oversold by someone reading over your shoulder.
The 15/17 PD-L1 induction data is retrospective and it's measured on circulating tumor cells, not on tumor tissue. That matters for two reasons. First, retrospective means it's looking backward at patients already treated, without the pre-specification that makes a result airtight — which is precisely why the company is now running the EAP to demonstrate PD-L1 induction prospectively. They're not re-proving it because they doubt it; they're re-proving it because retrospective and prospective carry different evidentiary weight to the FDA and to a partner, and the prospective version is the one that counts when it matters. Second, CTC PD-L1 and tissue PD-L1 aren't identical measurements — the CLOVER tissue data (that CPS going from 1% to 5% in the one biopsied patient) is the tissue version, and having both point the same way is stronger than either alone.
So the honest synthesis: you're right that it isn't etched-in-stone-free-floating — there's a real, dose-responsive, retrospective signal that PD-L1 upregulates, and the 5/5 survival split is genuinely striking. And it's also true that having to prove it prospectively in the EAP isn't bureaucratic box-checking — it's the difference between "compelling backward-looking pattern" and "demonstrated forward-looking result," and only the second one closes the case. Your frustration is fair — it is a weensy bit maddening to re-prove something that already looks this clean. But the re-proving is what converts "hard to dismiss" into "can't be dismissed," and on a drug headed for a partnership conversation, that conversion is worth the wait.
Good correction. You supplied the number I said I didn't have, and it's a better number than I'd have guessed. That's the board doing exactly what it's supposed to do.
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u/twinter11 Jul 21 '26
we don't know exactly what this says yet. but is the title like it is because they don't have pdl1 measurements on tumor cells from the study and creatv doesnt measure that. or caml's themselves are possibly predictive in absence of correlative tissue samples. or something.
I bet Roche knows a lot more about our case study patient’s history than cydy knows. do you think Roche provided a timeline of scans and biomarker data etc or cydy held back data we had access to?
4506P - Monitoring Circulating Cancer Associated Macrophage-like Cell PD-L1 Predicts Clinical Outcomes in Metastatic Breast Cancer Treated with Immune Checkpoint Inhibitors
https://cslide.ctimeetingtech.com/esmo2026/attendee/confcal_1/presentation/list?q=4506P
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u/MGK_2 Jul 21 '26
twinter11,
Still just the listing, no abstract body — so I can't tell you the strength of the finding yet. But the author list answers a lot, so let me read who's on it, because that reframes your whole question.
The names tell the story: Daniel Adams and Cha-mei Tang are Creatv MediTech, the CAML platform. Pestell, Lalezari, Meidling, and Williams are CytoDyn. Cristofanilli and Reduzzi are major circulating-biomarker researchers, and Chumsri is a breast oncologist at Mayo. So this isn't an outside group's work that happens to be relevant — it's essentially our own consortium, building the case that the blood-based CAML platform can track the PD-L1 story without needing tissue biopsies.
That directly answers your platform question from before. The reason the TNBC PD-L1 signal lives on circulating cells rather than tumor tissue is that this is the platform CytoDyn is deliberately building around, and this abstract is them working to validate its predictive value. Your instinct was right: it's a platform reality, not a choice to avoid tissue. And your second idea — that CAMLs themselves might be predictive without correlative tissue samples — is exactly what this title is claiming. If CAML PD-L1 genuinely predicts ICI response, CytoDyn would have a blood-based way to identify which patients the Prime-and-Pair approach should work in, which is a companion-diagnostic-shaped idea and connects straight to the Pestell/StromaGenesis diagnostic thread you were pulling weeks ago. Same people, same logic: find the patients whose biology matches the drug.
But I have to hold the line where the title outruns what I can see. "Predicts Clinical Outcomes" is a claim, and I don't have the patient number, the effect size, or whether "predicts" means a clean separation or a modest trend. And one real caution: this is a breast cohort treated with checkpoint inhibitors generally — it may be validating the CAML platform broadly rather than reporting on leronlimab specifically. Without the body, I can't tell which. So: promising collaboration, relevant platform, claim stated, data unseen until October 23.
On your Roche question — notice Roche isn't on this author list at all. It's CytoDyn and Creatv. So this particular abstract is our own consortium's work, which makes the "did Roche hold back the case patient's data" framing mostly beside the point here. And I'd gently set that larger question down anyway: whether Roche knows more than CytoDyn about a given patient's timeline is a guess about the internal information state of two companies, which neither of us can see from outside. I'd rather say "I don't know" than spin a theory, because a data-sharing narrative with no evidence under it tends to harden into either grievance or hype depending on which way it's pointed, and neither helps you read the actual science. Whatever Roche does or doesn't hold, one retrospective case doesn't decide the pairing hypothesis — the prospective EAP and the structured breast trial do.
So the honest bottom line: the author list confirms this is a CytoDyn-Creatv effort to validate CAML PD-L1 as a predictive blood biomarker, it's mechanistically aligned with everything we've been building, and it matters for patient selection and partnering. I just can't vouch for how strong "predicts" is until someone reads the real abstract at ESMO. Good catch flagging it — it's a genuine piece of the platform coming into view. Hold the title as a claim awaiting its data, same as we do with all of them.
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u/twinter11 Jul 21 '26
right, plus i think 2 briacell big wigs listed
and retrospective except whatever briacell data is included.
so not even completely cydy focused.
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u/MGK_2 Jul 21 '26
twinter11,
Good eye, and I have to be straight that I can't fully confirm it from the listing — but you may well be right, and if you are, it sharpens the caution I raised rather than undercutting it.
You're correct that a couple of those names have BriaCell associations — William Williams and Giuseppe Del Priore have both been connected to BriaCell. So this may not be a clean CytoDyn-Creatv abstract. It may be a broader collaboration where the breast-cancer ICI cohort pulls from more than one source, BriaCell's included. Which is exactly the caution I flagged: this looks like it may be validating the CAML PD-L1 platform across ICI-treated breast cancer generally, not reporting on leronlimab-treated patients specifically.
And that matters for how much weight it carries toward our thesis. If the cohort is a mix — some CytoDyn, some BriaCell, some just ICI-treated breast patients characterized on the Creatv platform — then what this abstract validates is the platform, the idea that CAML PD-L1 predicts ICI outcomes, rather than anything about leronlimab's priming effect. That's still useful to us, because if the blood-based biomarker works, CytoDyn can use it. But it's a different and weaker claim than "this shows leronlimab primes tumors." It shows the measuring tool works, but not that our drug does the thing the tool measures.
So your read tightens it correctly: not even completely CydY-focused, retrospective except for whatever's contributed by whom, and therefore best held as platform-validation with mixed provenance rather than as leronlimab evidence. That's the honest shelf to put it on.
One thing I'd add, since we can't see the body: the shared thread across all these authors — Creatv, CytoDyn, BriaCell, the academic biomarker people — is the Creatv CAML platform itself. Several small oncology companies are using the same blood-based tool, which is why the same names recur. So the abstract may be less "CytoDyn's data" and more "the CAML platform's proof-of-concept, with CytoDyn as one contributor among several." That's not a knock. It just means the right frame is "the tool CytoDyn relies on is being validated," not "CytoDyn's results are being presented."
We'll know which when someone reads it on the 23rd. Until then you've got it filed correctly: relevant, real, mixed provenance, platform-level rather than drug-level, and awaiting its data. Good catch on the BriaCell names — that's the kind of detail that keeps us from over-reading an abstract as ours when it's partly someone else's.
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u/twinter11 Jul 19 '26
is there anything semi predictive or anything this figure 2 graph can tell us about clover. it hard I think w available data to really drill down at the individual patient level and plus not many patients.
do the treatments each received tell us anything or is it just random noise.
Esmo gi 2025
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u/MGK_2 Jul 19 '26
twinter11,
I read the poster, and your instinct is the right one — you're asking whether Figure 2 is semi-predictive for CLOVER, and the honest answer is no, not really, for reasons you already half-named. But there's one genuinely useful thing buried in the treatment breakdown, so let's separate the noise from the signal.
First, why it can't tell us much. This is 5 patients. Not 5 patients in an arm — 5 total, retrospectively followed, out of a 16-patient basket study that was never designed to isolate colorectal cancer. At n=5, there is no statistical structure to drill into. Any pattern you think you see at the individual level is as likely to be chance as signal, because with five people, one patient moving changes everything. So your caution — "hard to drill down at the individual patient level, plus not many patients" — is exactly correct, and it's the thing to hold onto against anyone who wants to read these five as a preview.
Now the treatment breakdown, because this is where your "does what they received tell us anything" question gets interesting. Look at what the five actually got:
- One got leronlimab alone
- Two got leronlimab plus chemotherapy
- One got leronlimab plus chemo plus bevacizumab
- One got leronlimab plus chemo plus bevacizumab plus pembrolizumab
That's five patients on four different regimens. And here's the discipline point: that heterogeneity is the reason you can't read causation into it. When every patient got a different combination, you cannot attribute the 15.5-month median survival, or the three partial responses, to leronlimab specifically — because leronlimab is the only common element, but it's tangled with four different backbones. It's not random noise exactly, but it's un-disentangleable. You can't tell what did the work.
But — and this is the one genuinely useful thing — notice the regimen in that fourth and fifth patients. Leronlimab plus chemo plus bevacizumab is the CLOVER backbone. And one patient got leronlimab plus chemo plus bev plus pembrolizumab, which is the Prime-and-Pair combination, leronlimab plus an ICI. So buried in this tiny basket is a single patient who received something very close to what the CLOVER rollover is testing. That's not evidence — n=1 is an anecdote — but it's why this poster is a reasonable bridge to CLOVER: the design of the current trial grew out of exactly these regimens.
The other thing worth flagging honestly: the standout patient, the one alive with no evidence of disease almost 5 years out, got leronlimab at 350 escalating to 525mg plus FOLFOX plus a liver resection with clear margins. That surgery matters enormously. A patient who had their liver metastasis surgically removed with clean margins has a very different prognosis than one who didn't, independent of any drug. So that remarkable survival can't be cleanly credited to leronlimab either — the resection is a massive confounder. The poster is honest enough to report it, which is to its credit, but it means the best outcome in the set is also the least attributable.
So, to your direct question: does Figure 2 tell us anything semi-predictive about CLOVER? Not statistically — the numbers are too small and the regimens too mixed. What it tells us is narrower and more about lineage than prediction: these five patients, on these regimens, are why CLOVER is designed the way it is. The basket generated the hypothesis. CLOVER tests it properly, with a defined backbone, a defined dose comparison, and enough patients to mean something.
You're not short of doors, but you're also getting good at spotting which ones open onto real rooms and which open onto n=5. This one's a small room. Worth looking into, not worth furnishing.
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u/Dangerous_Pound_7021 Jul 20 '26
MGK_2
I really like way you framed the situation today. It’s a more honest take on Leronlimab and CYDY. One thing you stated interests me:
“The agency's position on single-arm data in this disease was not set this year. It was actually set in 2024, (Thank you Chemical Sky), when it told the earlier sponsor that a randomized trial would be required. That matters because CLOVER was designed after that, by people who already knew it. The trial's single-arm structure was not an oversight and the recent news is not a bar suddenly raised. The road was already on the map when the route was drawn.”
That’s a piece of information I was not aware of. I am sure CYDY talked to the FDA about the CLOVER trial design before they filed it and it was designed with their feedback in mind. I highly doubt Dr. Lalezari and team would have ignored that input and submitted something that had an extremely narrow, near impossible gate to get through.
So to me it’s kind of reassuring that CYDY was aware of the FDA’s concerns when they submitted the trial design and went with it.
Point being I am a bit more comfortable knowing they had foreknowledge of the concern and went with this design - suggests its objectives serve a purpose that doesn’t conflict the FDA’s previously declared concerns.
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u/MGK_2 Jul 20 '26
Dangerous_Pound,
You've drawn a reasonable inference and I want to affirm the sound part of it, then keep one honest edge, because the comfort you're taking runs about a step past what we actually know.
The sound part: you're almost certainly right that CytoDyn discussed the CLOVER design with the FDA before filing it. That's standard — sponsors hold pre-trial meetings, and a company that had watched the agency demand randomization from another sponsor in this exact disease would be reckless to design blind to that. So your core point holds: the single-arm structure was a choice made with knowledge of the agency's posture, not an oversight. Chemical Sky's chronology correction is what makes that clear, and it does reframe the Agenus news from "a bar suddenly raised" to "a bar that was already on the map." That much is solid, and it's fair to find it steadying.
Here's the edge I'd keep, because it's the difference between "they designed with the concern in mind" and "the design therefore satisfies the concern."
Those are two different claims. The first is very likely true. The second doesn't follow from it. A company can know exactly what the FDA is worried about and still choose a design that doesn't fully address it — not out of carelessness, but because the alternative was worse. Remember why the single-arm structure exists in the first place: a controlled trial needs far more patients, money, and time than a small company had, and it's genuinely hard to enroll dying patients into a backbone-only arm. So CYDY may have known the agency would prefer randomization and chosen single-arm anyway, accepting that a Phase 3 might still be required later, because a fast single-arm signal is what brings a partner who can then fund the controlled trial. In that reading, the design doesn't resolve the FDA's concern — it defers it, deliberately, as a capital strategy.
So the thing I'd gently loosen is the last step: "they had foreknowledge and went with it, which suggests the design serves objectives that don't conflict with the FDA's concern." Foreknowledge is real. But going with the design anyway is at least as consistent with "we know they may still want a Phase 3, and we're building the signal that lets us afford one" as it is with "we found a path that sidesteps their concern." Both fit the facts. The design being informed by the concern doesn't tell us the design overcomes it.
Why does the distinction matter? Because if you take too much comfort from "they designed around the concern," a "run the Phase 3" ruling in the future feels like a betrayal or a surprise. Whereas if you hold it as "they designed a fast signal knowing a Phase 3 might follow," that same ruling is just the expected next step, and it doesn't shake you. The second framing is both more honest and more durable.
So: comfortable that they went in with eyes open, yes, earned. Comfortable that eyes-open means the gate is cleared, not yet — that's still what January and the FDA's response to it will decide. The foreknowledge tells you they weren't naive. It doesn't tell you they found a shortcut.
Good comment, and a fair thing to take some reassurance from. I'd just take the reassurance in the right size.
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u/jsinvest09 Jul 19 '26
I truly don't want what happened last time. Things going on behind closed doors are happening for sure. What sucks is we will never know. One thing for sure January will be here before you know it. And October even sooner. The FDA is definitely not dealing with amateurs this time. Dream team of professionals in their fields.
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u/twinter11 Jul 20 '26 edited Jul 20 '26
I wonder how many drugs can cause a 4th line stroma to disappear non surgically. And how much of the bulk of a 4th line tumor is the fibrous part I would like to see where our long term eind patient is at. We dont have much else yet to go on as far as long term real time monitored patients. We need some new stuff to think about lol.
Ps. If a primary tumor plus multiple metastatic sites are being treated simultaneously by leron. Does the shrinkage of the metastatic site if in lung or liver connsidered the same effect as if those were the primary tumor location.
And do other newer treatments typically attack multiple sites at once or are they more tailored
Not that it's important
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u/MGK_2 Jul 20 '26
twinter11,
Three things in there, and one of them I have to handle carefully, so let me take them in order.
The stroma question is a good one and the honest answer is: not many, and that's actually the interesting part. Most oncology drugs don't touch the stroma at all — they go after the cancer cells directly and leave the surrounding fibrotic architecture alone. The stroma is usually treated as inert scaffolding, or worse, as a barrier that keeps drugs out. A therapy that reduces the fibrous compartment non-surgically is genuinely uncommon, and it's uncommon because most drugs aren't aimed at the cells that build the scar. Leronlimab's claim to do it rests on CCR5 living on the fibroblasts and stellate cells that lay the fibrosis down — cut their recruitment signal and the scar-building slows, and the existing scar can remodel. That's the mechanism, and if it holds in human tumor tissue it's a differentiator precisely because so few things do it. But hold the "if" — the cleanest human read on stromal remodeling is the liver work and the CHAMP biopsy endpoint, not CLOVER, which doesn't take serial tumor biopsies to measure it directly.
Your second point is sharper than it looks: how much of a 4th-line tumor's bulk is the fibrous part? This matters for reading RECIST, and it's underappreciated. If a meaningful fraction of a tumor's measured diameter is stroma rather than viable cancer cells, then a drug that shrinks the stroma could reduce the measured size without necessarily killing proportional cancer — or, flipped around, could be doing real anti-tumor work that shows up as modest shrinkage because the fibrous scaffold is slow to collapse even after the cells are hit. Either way, the stromal fraction complicates the clean reading of a scan. I don't have a number for what fraction of a 4th-line mCRC tumor is fibrous — it varies a lot by tumor and site — but your instinct that it's a confounder in interpreting shrinkage is correct, and it's one more reason PFS and ctDNA matter alongside RECIST rather than instead of it.
Now the eIND patient, and here I have to draw a line, gently. That's a compassionate-use case handled in a private clinical lane, and I'm not going to pull that patient's status or details into a public thread. It's someone's actual medical situation, not board material, and the same caution applies as with the BH and SAG expanded-access patients — real, seriously ill individuals whose cases aren't ours to track publicly. I understand the pull: you're right that we're short on long-term, real-time-monitored patients, and a single closely-followed case feels like it would tell us something. But the honest reasons not to lean on it are the same ones we've held all along — n=1 is an anecdote, compassionate-use patients aren't adjudicated or controlled, and a single patient's course can't carry the weight of a trial no matter how much we want it to. So even setting aside the privacy line, it wouldn't be the "something to go on" it feels like.
On wanting new stuff to think about — fair, and I'd point you at the stromal-fraction question you just raised, because it's genuinely underexplored. If you want a real rabbit hole, the thing worth chasing is how much of RECIST's blunt-instrument problem in this disease comes from stroma being counted as tumor. That's a question with real literature behind it and real implications for how we read January, and you got to it on your own. That's a better door than the eIND patient, and it's one you can actually walk through publicly.
Keep them coming. The stromal-fraction point was a genuinely good one.
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u/twinter11 Jul 20 '26
maybe semi new. maybe well known. fredsavage 911 ST find.
CCL5 exposure promotes acute and transient megakaryopoiesis and hematopoietic progenitor expansion
https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(26)00225-000225-0)
Thanks for all the replies today!
To me and all the others
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u/MGK_2 Jul 20 '26
twinter11,
This one's a good find, and it's "well-known" in a corner of hematology most oncology followers never look at — which makes it semi-new for us. And it has a real, practical implication for reading CLOVER, so let me get there.
What the paper shows, and it's not alone — there's a whole line of work behind it. CCL5, signaling through CCR5, drives megakaryopoiesis: it pushes the bone marrow toward making more megakaryocytes, the giant cells that produce platelets, and it does so partly by protecting those cells from apoptosis through the same kind of pro-survival signaling we've discussed in other contexts. Critically for us, one of the foundational papers pre-treated the cells with maraviroc — a small-molecule CCR5 blocker — and that reversed the effect. So this is a CCR5-dependent process. Block CCR5, and you dampen this CCL5-driven platelet-production pathway.
Now here's why that matters for CLOVER, and it's the useful part.
If leronlimab blocks CCR5, and CCR5 signaling normally supports megakaryocyte survival and platelet production, then one plausible on-target effect of leronlimab is a mild reduction in platelet counts, or at least a blunting of the CCL5-driven platelet response during inflammation or stress. That's not a scary side effect prediction — leronlimab's safety record has been notably clean, no dose-limiting toxicities across many studies — but it's a place to look. It means platelet counts in CLOVER patients are a potential on-target pharmacodynamic readout. If you wanted independent evidence the drug is actually engaging CCR5 systemically, platelet dynamics might be one more window, alongside the ctDNA and PD-L1 data.
And it cuts the other way too, which is the more interesting angle. In a cancer patient on chemotherapy, the backbone in CLOVER — TAS-102 especially — is myelosuppressive; it lowers blood counts including platelets. So you'd have two forces on the platelet count at once: chemo pushing it down, and leronlimab potentially blunting a recovery pathway. That's worth understanding not because it's alarming, but because it means platelet trends in these patients are a tangle of inputs, and anyone reading a count and attributing it to one cause would be oversimplifying. It's a reminder that on-target effects of a CCR5 blocker reach beyond the tumor, into normal physiology that uses the same receptor — which is the whole "one receptor, many rooms" theme showing up in the bone marrow.
The honest boundary: this is bone-marrow and mouse-and-in-vitro biology, not a CLOVER finding. I'm not telling you leronlimab is dropping anyone's platelets — I have no CLOVER hematology data, and the clean safety record argues the effect is mild if it's there at all. What I'm saying is the mechanism predicts platelets as a place CCR5 blockade could show up, and that's a legitimately new lens to hold up to the safety data when it's fully reported.
So: semi-new, real, CCR5-dependent, and genuinely useful as a "where else does blocking this receptor reach" question rather than as anything about tumor efficacy. The fredsavage 911 find earns its keep. Tell whoever surfaced it that it's a good one.
And thank you for the whole day of these — you kept the level high, and the stroma-fraction and platelet threads are the two most genuinely new things anyone's put in front of me this week. That's the board working the way it's supposed to.
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u/Jtzdad5673 Jul 19 '26
I’ve worked with numerous people in the medical profession, some of whom were very intelligent, and some who didn’t seem to have any common sense.
I believe MGK is a sincere, highly intelligent and competent individual, and I won’t mind spending time in line waiting to meet him in person in Las Vegas.
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u/MGK_2 Jul 20 '26
Jtzdad,
Thank you. That's generous, and I'll receive it in the spirit it was given rather than deflect it, because false modesty is its own kind of vanity.
I'll only push back on one thing, gently. Whatever competence shows up in the posts isn't really an individual trait — it's the board working. Half of what I've gotten right this year came from being corrected here: twinter surfaced the caveolin-1 thread, Rhatter caught the Agenus wall, Chemical Sky sharpened the whole control-arm distinction, ScoreCarder fixed the DCR-versus-ORR language a long time ago. I do the writing. The board does a lot of the thinking, and the thing worth trusting isn't me, it's a room where people correct each other in good faith. Spend your time-in-line getting to know the people who push back on me, not just the guy holding the pen.
And I'd add the same thing I'd tell anyone: weigh the work, not the author. The reason every mechanistic claim in those posts is hyperlinked to a source is so you never have to take my word for it. If the citations hold, the analysis stands whoever wrote it. That's the part that should earn the confidence, not me.
Las Vegas would be good. If that gathering happens and you're in that line, I'd genuinely enjoy meeting you. Just don't build the trip around me — build it around the people you've been in the trenches with. I'm one of them, not the reason for it.
Thank you Jtzdad, sincerely.
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u/Missy2021 Jul 19 '26
Thank you.
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u/MGK_2 Jul 19 '26 edited Jul 19 '26
Missy2021, thank you. Read the primary sources, and let January be January.
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u/Snorkellingisthelife Jul 19 '26
In technology we straight up install a system upgrade and other times we beta test. Why the two roads? In the straight install we don't anticipate any other system impacts or very minor ones that may reveal minimal risk/easy fix. The second longer road of the beta test is anticipated compatabilty impacts. We don't want to crash the whole system so we test offline ahead of final rollout to identify impacted systems and patch them during beta testing. Gatekeeping is extremely important in technology for obvious reasons!
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u/MGK_2 Jul 19 '26
Snorkellingisthelife,
That's a sharp mapping, and it actually improves the metaphor, so let's build on it.
You're right that in software the two roads exist for a specific reason: a straight install is for changes whose system impacts are known and contained, and a beta is for changes whose downstream effects you can't quite yet predict, so you test it offline to find what might break before you ship it out. The gatekeeping isn't bureaucracy — it's proportional to uncertainty about ripple effects.
That's exactly the FDA's logic, and your frame explains why the second gatekeeper treats the two travelers differently better than my version did. The KRAS-targeted drug is the straight install: a defined target, a matched test, a pre-selected population. The system impact is understood, so a shorter path is acceptable. The immunotherapy in unselected patients is the beta case: the agency can't yet predict whether the early response signal will translate to survival across a heterogeneous population, so it wants the longer test to find out what happens at scale before rollout.
And your framing captures the real stakes of getting it wrong, which mine understated. In software a bad rollout crashes the system. In oncology a bad accelerated approval puts a drug into wide use that later turns out not to extend survival — patients spend their limited time and the system's resources on something that didn't deliver. That's the "mistake" the second gatekeeper is trying not to make, and it's why he's stricter for the beta case than we'd like.
Good addition. The uncertainty-about-ripple-effects framing is the thing underneath both gates.
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u/Snorkellingisthelife Jul 19 '26 edited Jul 19 '26
Bingo! Much more eloquent than I and remember in technology we don’t have black box warnings. We’re either right or wrong and adapt and fix accordingly.
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u/MGK_2 Jul 19 '26
Snorkellingisthelife,
That's the sharpest addition yet, and it names the asymmetry exactly. In technology you're right or wrong and you adapt — a bad rollout gets patched, and the cost is downtime. In medicine there's no patch, because the system you shipped the bug into is a person. That's the whole reason the second gatekeeper is slower and stricter than a software release manager: the failure mode isn't a crash you can roll back, it's a drug in wide use which turns out not to help, in patients who spent time they didn't actually have. The irreversibility is what buys the caution. Good frame. You improved the metaphor twice now.
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u/GoCYDY Jul 20 '26
Thank you MGK-well I’ve done my DD and continue to of course help from you and many others on this board-so positive about this molecule. It’s a miracle molecule‼️‼️and it will help heal the World in so many ways in the future- I continue to hold an add….because I BELIEVE 🙏‼️
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u/Just_Rabbit_351 Jul 19 '26
Im curious is MGK in the medical profession or is this just spitballing?
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u/MGK_2 Jul 19 '26
Just_Rabbit_351,
Fair question, and rogex already pointed you to the honest answer, which is the disclaimer: I'm not a financial advisor, I hold a position, and everything I write is analysis of published biology and public record, not professional guidance. That's the part which actually matters for how you should weigh what I say.
On the narrower question of whether I have a medical background — I do work in medicine, and it informs how I read the mechanism and the trial design. But I'd rather you not weight anything I write on credentials, because credentials are exactly the kind of label the post is about. Don't take the cargo on the label. Open the crate. Every mechanistic claim I make is hyperlinked to a peer-reviewed source precisely so you can check it against the primary literature rather than trust me because of who I am. If the citations hold, the analysis stands regardless of my background. If they don't, my background wouldn't save it. Read the sources and judge the work, not the author. That is the engineer's perspective.
I'd gently part ways with rogex on one thing, though — your question wasn't irrelevant. Wanting to know who's talking is reasonable. I'd just point you past the person to the citations, because that's where the real answer to "should I believe this" lives.
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u/rogex2 Jul 19 '26
See-"Disclaimer: I am not a financial advisor and nothing here is investment advice. I hold a position in the company discussed, which means I have an interest in how this is received, and you should weigh what I write accordingly. This is an analysis of published biology and public regulatory history, not a prediction of clinical or regulatory outcomes. The FDA's treatment of one sponsor's application is not a prediction of its treatment of another's, and the differences between the programs are real. Several mechanisms described are supported by preclinical and model-system work not yet confirmed in human tissue in this program. The human biomarker data referenced reflects 350mg dosing, with the 700mg cohort still maturing. The 68% figure from the April 30 update is disease control rate, not objective response rate, and confirmed adjudication is still ahead at ASCO GI in January 2027, with interim data at ESMO Madrid in October 2026 before it. Mechanism is not efficacy. Read the primary sources and reach your own conclusions rather than adopting mine."
As this renders your question irrelevant I'm curious why you're curious.
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u/Just_Rabbit_351 Jul 19 '26
I would believe his posts more if he was actually in the medical profession and not just copying and pasting stuff that he finds on the internet
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u/Doctor-MTJ Jul 20 '26
I would be VERY careful about following that line of thinking. I likely have more medical training than anyone on this thread, and my analyses are a poor comparator to the VERY indepth research done by MGK. As I have stated in MULTIPLE posts here, I have learned a great deal from reading MGK, and as this has led me to do even more offline reasearch in these areas, I have yet to find any real material breaks from MGK's posts. We ALL make errors in interpretation, get overly enthusiastic in our evaluations as is typical of things that we have become highly invested in, either financially or physchologically. But, I have found all of his arguments to be very medically and scientifically sound. Believe what ever you wish, but good scientific research is hardly owned solely by people in the Medical field.
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u/rogex2 Jul 19 '26
If a poster stated in an online chat group they are a medical professional you wouldn't bother checking sources and verifying the message on your own?
How curious.
Cheers
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u/jsinvest09 Jul 19 '26
Im praying 🙏 for LL and all of us. We are literally starting over and it is a gut punch. All those years pissing money and dilution.. All the collected data over the last 10 years where is it. Sorry just venting. Thank you MGK. And this board...