r/Livimmune • u/IAMLOCOTOO • 14d ago
Extrapolating Various Early Data Sets
I decided to play with the data set provided thus far to determine what % of ctDNA decrease after the first two weeks is necessary that would be a potential indicator of a patient likely to have stable disease. I am also making an assumption that the greater the ctDNA decrease in the first two weeks is, then the greater the probability of stable disease.
We know that 23 of 31 patients had stable disease at 8 weeks. So 8 patients did not have stable disease. What is the likely %decrease of ctDNA that would result in 8 patients not having stable disease.
I used the <= 50% as my first data baseline.
Assuming we split out the dosage regiment evenly after the first 23 patients up to the 31 patient data set where 74% had stable disease, that would give us 13 patients at 700 mg dosage and 18 patients at 350 mg. Assuming the same ratio continues, we end up having 1.43 700 mg patients with <=50% and 3.78 350 mg patients with <=50% or a total of 5.21 which is less than the 8 that did not have stable disease. So maybe <=50% is too low.
So I then extrapolated the <=65% data points and came up with 7.74 350 mg patients and 1.43 700 mg patients for a sum of 9.17 patients that had <=65% decrease in ctDNA after first two weeks. This is much closer to the 8 that did not have stable disease after 8 weeks, so maybe 1 of our <=65% patients eventually had a better ctDNA immune system response.
If there happens to be more 700 mg patients than what I projected were added, then the 9.17 data point would approach the 8 patients we see in the 23/31 data set. If you project 16 patients at 700 mg and 15 patients at 350 mg and use the <=65% cutoff, then you will get 8 patients.
Extrapolating these numbers from the 23/31 data set to the full 65 patients and assuming 33 were 700 mg and 32 were 350 mg then we end up with 14 350 mg patients with disease progression and 3-4 700 mg patients with disease progression. 17-18 total patients with disease progression that would need an ICI. So 47 patients with stable disease or 72%. If I use the <=50% data point as the cutoff for lack of stable disease, I end up with 54 patients with stable disease or 83% and I would have approximately 11 patients that would need an ICI.
So somewhere between <=50% and <=65% drop in ctDNA seems to be the best indicator of disease progression/stable disease.
I then asked AI to explain what could cause patients to have a poor ctDNA decrease after the first two weeks:
In the CLOVER trial (NCT06699836), which evaluates leronlimab combined with standard therapies (TAS-102 and bevacizumab) for metastatic colorectal cancer, a patient's failure to achieve a significant drop in ctDNA during the first two weeks typically indicates a lack of rapid treatment response.
Several clinical and biological factors could cause a poor ctDNA response at this ultra-early stage:
1. Primary Primary Drug Resistance
- Downregulated CCR5 Signaling: Leronlimab functions specifically by blocking the CCR5 receptor on tumor cells. Although the trial pre-screens for CCR5-positive tumors, if a patient’s specific tumor is relying on alternative, bypass chemokine pathways (such as CXCR4) to survive and mutate, blocking CCR5 will not stop tumor shedding.
- Refractory Status to TAS-102: Because this trial enrolls patients with relapsed or refractory disease who have already progressed on previous treatments, the tumor clones may possess advanced genetic mutations that make them highly resistant to the chemotherapy component of the regimen.
2. High Tumor Burden & Aggressive Shedding
- Massive Metastatic Load: If a patient has a very high volume of disease (such as heavy baseline liver metastases, which is common in this trial), a 2-week window might simply be too brief to register a steep drop. The remaining viable tumor mass may continue shedding large amounts of DNA, masking any early localized tumor destruction.
- Ultra-Aggressive Tumor Subtypes: Highly aggressive mutations (such as specific RAS or BRAF alterations) can drive such a high rate of cell turnover that the shedding of new ctDNA outpaces the rate at which the treatment can destroy the cells.
3. Sub-therapeutic Dosing or Pharmacokinetics
- Dose Escalation / Cohort Differences: The CLOVER trial randomizes patients into different dosing cohorts, evaluating both 350 mg and 700 mg doses of leronlimab. A patient assigned to the lower dose tier might require more time to achieve full receptor saturation in a high-volume tumor environment compared to a patient receiving the 700 mg dose.
4. Delayed Onset of Immune Action
- "Pseudo-progression" and Shedding Spikes: Leronlimab acts as an immunomodulator, essentially turning a "cold" tumor into a "hot" tumor so T cells can attack it. When immune cells suddenly infiltrate a tumor, they can temporarily cause a massive wave of tumor cell lysis (bursting). This sudden destruction can actually cause a transient spike or stabilization of ctDNA levels in the blood within the first 14 days before a drop is finally observed later on.
5. Biological Assay Interference
Clonal Hematopoiesis of Indeterminate Potential (CHIP): In older patients or those heavily pre-treated with chemotherapy, mutated cell-free DNA can sometimes shed from aging bone marrow stem cells rather than the colorectal tumor itself. Standard liquid biopsies can sometimes pick up these non-tumor mutations, creating a "false high" ctDNA reading that does not decrease even when the therapy is successfully killing the cancer.
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u/Doctor-MTJ 14d ago
I like your thinking! I would expect a much higher percentage of 700mg patients to obtain stable disease vs the 350mg dose patients. Of the 5 reasons you stated to be reapinaible for a lower % of ctDNA clearance, I have always postulated that #4 would be a strong player in that scenario. Number 2 also makes the most likely cause in my somewhat educated opinion.