The poster published in the ESMO congress is underwhelming (imo), to say the least, when it states:
Currently the ORR by the BICR is 6.3% (4/64) in the protocol defined mITT population. This rate is encouraging considering that most patients previously received ≥3 prior lines of therapy in the metastatic setting with the majority of patients having baseline liver metastases. In the SUNLIGHT study patients randomized to TAS-102+BEV achieved an ORR of 6.1% in a population of patients with mCRC, 97.4% of whom had previously received ≤2 prior lines of therapy in the metastatic setting.
Yes, I agree, we are doing the same as SOC but …
We have 64 "evaluable for response" patients at the time of analysis, I take this to mean evaluable for ORR quantification (not ctDNA clearance). But maybe I am incorrect on this.
From this point on, I will speculate as I don’t have more information available (maybe somebody can chip in)?
We know 3 heavily treated patients rendered NED and went to have surgery. These plus another one (imo) are the 4 patients with ORR and where (radiologically) evaluated by the BICR in regards to CR+PR.
Therefore, there are 60 patients that either have passed or still have not been evaluated by BICR. Of course, we know that 28 have evaluable data (again, ctDNA data), so they are alive. Also, I assume that ALL the 64 patients are evaluable as far as ORR is concerned (radiological baseline)
Of these 28, 11 have ctDNA clearance >=90%, 17 ctDNA clearance < 90%. These thresholds are important as is the definition on the INSPIRE trial for clearance. As a reminder of their study: >=90 reduction/full clearance meant almost always PR or CR, in the study all 12 patients with clearance had objective responses and 100% OS. Clearance often preceded RECIST response, all alive at median 25.4 months; long term responders across all tumor types.
So, it this were going to be our case (that is, Leronlimab effectiveness = Pembrolizumab), and ONLY 28 patients to be studied, we would have an ORR in a total of 11 patients with a total ORR of:
11/64= 17.2%
Now, let’s assume that all the 64 patients are to be studied (that is, ORR evaluable), and the proportions of ctDNA clearance are similar for the whole group:
(64*11)/28= 25 patients with total clearance for an ORR of 25/64=33%
Now, these number can get much better as in INSPIRE with ctDNA clearances of 50%-89% (meaning 5 extra patients out of 28 in CLOVER, or 11 out of 64) they obtained mostly PR or durable SD, with strong clinical benefit. Many showed tumor shrinkage (−30% or more) or long SD ≥ 6 cycles of Keytruda.
Basically, if some of the CLOVER patients with clearances below 90% show tumor shrinkage (as per RESIST) the ORR numbers above could increase substantially.
Now, I have to be clear: this comparison is only valid considering an equivalent effectiveness for Keytruda and Leronlimab as far as the longitudinal translation of ctDNA clearance to ORR, in spite that this can produce “goosebumps” in only mentioning, I don’t think this is the case (I hope I am wrong). Keytruda produced 32 Billion in global sales in 2025 (around 50% of Merck’s total revenue). But, having said that, if some of the CLOVER patients show tumor shrinkage (the primary endpoint is the ORR per RECIST v1.1 criteria) after such a stellar ctDNA clearance we will have a treatment much better than current SOC, and FDA approval.
The real point here is:
Why did we reported only 6.3% ORR in ESMO ? I think it was because BICR had evaluated few patients and there is a difference between “evaluable” patients in the ctDNA clearance cohort and in the ORR one (where I suspect all the patients must have radiological baselines).
Also, one important nuance worth noting: ORR is only one efficacy measure. For refractory metastatic colorectal cancer, we should also focus on:
• PD-L1 expression on circulating tumor cells (CTCs)
• PD-L1 expression on cancer associated macrophage-like cells (CAMLs).
• ctDNA kinetics/findings
• Disease Control Rate (DCR)
• Progression-Free Survival (PFS)
• Overall Survival (OS)
Now is time to wait for ASCO in January for more data. Our ctDNA number should clear the path for solid ORR results.
NOTE: the above does NOT constitute advise for reinforcing shock absorbers on trucks or cars.
Currently the ORR by the BICR is 6.3% (4/64) in the protocol defined mITT population. This rate is encouraging considering that most patients previously received ≥3 prior lines of therapy in the metastatic setting with the majority of patients having baseline liver metastases. In the SUNLIGHT study patients randomized to TAS-102+BEV achieved an ORR of 6.1% in a population of patients with mCRC, 97.4% of whom had previously received ≤2 prior lines of therapy in the metastatic setting.
Yes, I agree, we are doing the same as SOC but …
We have 64 "evaluable for response" patients at the time of analysis, I take this to mean evaluable for ORR quantification (not ctDNA clearance). But maybe I am incorrect on this.
From this point on, I will speculate as I don’t have more information available (maybe somebody can chip in)?
We know 3 heavily treated patients rendered NED and went to have surgery. These plus another one (imo) are the 4 patients with ORR and where (radiologically) evaluated by the BICR in regards to CR+PR.
Therefore, there are 60 patients that either have passed or still have not been evaluated by BICR. Of course, we know that 28 have evaluable data (again, ctDNA data), so they are alive. Also, I assume that ALL the 64 patients are evaluable as far as ORR is concerned (radiological baseline)
Of these 28, 11 have ctDNA clearance >=90%, 17 ctDNA clearance < 90%. These thresholds are important as is the definition on the INSPIRE trial for clearance. As a reminder of their study: >=90 reduction/full clearance meant almost always PR or CR, in the study all 12 patients with clearance had objective responses and 100% OS. Clearance often preceded RECIST response, all alive at median 25.4 months; long term responders across all tumor types.
So, it this were going to be our case (that is, Leronlimab effectiveness = Pembrolizumab), and ONLY 28 patients to be studied, we would have an ORR in a total of 11 patients with a total ORR of:
11/64= 17.2%
Now, let’s assume that all the 64 patients are to be studied (that is, ORR evaluable), and the proportions of ctDNA clearance are similar for the whole group:
(64*11)/28= 25 patients with total clearance for an ORR of 25/64=33%
Now, these number can get much better as in INSPIRE with ctDNA clearances of 50%-89% (meaning 5 extra patients out of 28 in CLOVER, or 11 out of 64) they obtained mostly PR or durable SD, with strong clinical benefit. Many showed tumor shrinkage (−30% or more) or long SD ≥ 6 cycles of Keytruda.
Basically, if some of the CLOVER patients with clearances below 90% show tumor shrinkage (as per RESIST) the ORR numbers above could increase substantially.
Now, I have to be clear: this comparison is only valid considering an equivalent effectiveness for Keytruda and Leronlimab as far as the longitudinal translation of ctDNA clearance to ORR, in spite that this can produce “goosebumps” in only mentioning, I don’t think this is the case (I hope I am wrong). Keytruda produced 32 Billion in global sales in 2025 (around 50% of Merck’s total revenue). But, having said that, if some of the CLOVER patients show tumor shrinkage (the primary endpoint is the ORR per RECIST v1.1 criteria) after such a stellar ctDNA clearance we will have a treatment much better than current SOC, and FDA approval.
The real point here is:
Why did we reported only 6.3% ORR in ESMO ? I think it was because BICR had evaluated few patients and there is a difference between “evaluable” patients in the ctDNA clearance cohort and in the ORR one (where I suspect all the patients must have radiological baselines).
Also, one important nuance worth noting: ORR is only one efficacy measure. For refractory metastatic colorectal cancer, we should also focus on:
• PD-L1 expression on circulating tumor cells (CTCs)
• PD-L1 expression on cancer associated macrophage-like cells (CAMLs).
• ctDNA kinetics/findings
• Disease Control Rate (DCR)
• Progression-Free Survival (PFS)
• Overall Survival (OS)
Now is time to wait for ASCO in January for more data. Our ctDNA number should clear the path for solid ORR results.
NOTE: the above does NOT constitute advise for reinforcing shock absorbers on trucks or cars.
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