We have to be pragmatic about the SP (more so with last week’s depreciation). It is what it is, no more, no less. The “market” is pricing us at around $0.20+ per share. Fair or no fair is beyond the point, paraphrasing a little: “the numbers will set the SP free”. If our numbers are good the SP will go up, if they are not it, will go down. “Freely in both cases”.
Our CLOVER trial is testing whether adding leronlimab to the standard late line regimen TAS 102 + bevacizumab can improve outcomes in microsatellite stable mCRC.
So, what numbers are we up against?
First, a very brief background:
TAS 102 alone (trifluridine/tipiracil) RECOURSE trial, app. 2012-2014 (800 patients across different countries). Run by Taiho Oncology / Taiho Pharmaceutical (Japan). Approved by FDA as Lonsurf (2015). Main results:
Overall Survival (OS): 7.5 months
Progression Free Survival (PFS): 2.4 months
Adverse Events: >= Grade 3= 69%
Come the SUNLIGHT Trial (Nov 2020 – Feb 2022) with 492 patients with refractory mCRC, Taiho Oncology (co -developer of TAS 102) and Servier (global sponsor). Randomization: 1:1 (TAS-102): (TAS 102 + bevacizumab), the trial was run to determine whether adding bevacizumab (an anti VEGF antibody) to TAS 102 improves survival in patients with mCRC who have already received 1–2 prior lines of therapy.
Primary endpoint: Overall survival (OS)
Secondary endpoints: Progression free survival (PFS), safety, ECOG performance deterioration time. Main results:
Overall Survival (OS): 10.8 months
Progression Free Survival (PFS): 5.6 months with combination
Adverse Events: Grade ≥3 (similar between arms) ≈72% (Most common adverse events: neutropenia, nausea, anemia
How these drugs work is important for our tial: TAS 102 is a fixed dose combination of: Trifluridine (FTD), the active cytotoxic drug, and Tipiracil (TPI) a metabolism blocker that keeps trifluridine active in the body. Trifluridine is a nucleoside analog (a fake DNA building block) that “fools” the tumor cells to mistakenly incorporate it into their DNA during replication causing disfunction, replicating failure and eventually apoptosis. Tipiracil keeps trifluridine from being destroyed staying in the bloodstream longer allowing it to reach tumor cells and accumulate inside DNA. i.e, they work together in a way that allows trifluridine to reach tumor cells and damage them effectively.
Now, the addition of the anti VEGF (Vascular Endothelial Growth Factor) antibody bevacizumab (as in SUNLIGHT) improved the endpoints substantially. VEGF works mainly by driving hypoxia (low oxygen), VEGF driven tumors are extremely hypoxic making them more resistant to chemotherapy and genetically more unstable and aggressive. The anti-VEGF action of bevacizumab results in more susceptibility to DNA damaging agents making tumor cells less able to activate survival pathways and repair nucleoside analog damage. Hence the superior results obtained.
The main point is: this is the “standard of care now” and this is what our numbers have to improve on. We will likely receive some information end of October (ESMO) and January ASCO-GI potentially with ORR, PFS, DCR data.
The numbers in October are, imo, very important (have refered to PDL-1 induction via CPS measurement and ctDNA in previous posts), however what is critical here is how will BP look at them (I think I know how the FDA will).
Let me explain: Neither RECOURSE or SUNLIGHT trials reported ctDNA or PD L1 measurements (as far as I know) as mechanism-based oncology was not there at the trial design (at the time purely clinical-endpoint driven). I was surprised by this as was searching for reference points to be able to analyze the potential results from October's ESMO.
Apparently ctDNA became widely adopted in CRC trials after 2018–2020 (SUNLIGHT was designed earlier), especially for MRD (Minimal Residual Disease) studies.
Is this good or bad news ??
Bad news: Well, if one wants to back up the truck after ESMO (if not done yet) with the ctDNA/PD-L1 results one will have to “fly solo” as there is no reference point. They (the numbers) will have to stand by themselves. CLOVER targets MSS colorectal cancer, the hardest to treat subtype (the group that does not respond to immunotherapy) and has the highest unmet need, using modern biomarkers (ctDNA, PD L1 on CTCs/CAMLs, CCR5 expression) to track response. I will be probably flying solo or otherwise towards very blue skies then.
Good news: VEGF and CCR5 converge on PD L1 biology. The former produces PD-L1 upregulation (through HIF 1α and STAT3) while the latter through CSN5. So, VEGF and CCR5 together create a PD-L1 high, immune excluded tumor making PD L1 a mechanistic biomarker for CCR5 blockade. As Leronlimab (anti CCR5) reduces CCL5 driven PD-L1 stabilization and addresses other mechanisms (CD8 infiltration, macrophage re-programming, Tregs reduction) they target two halves of the same suppressive system making VEGF + CCR5 + cytotoxic backbone biologically coherent.
In other words: This is, by design, a synergistic model that will very likely produce good numbers at the end.
Our CLOVER trial is testing whether adding leronlimab to the standard late line regimen TAS 102 + bevacizumab can improve outcomes in microsatellite stable mCRC.
So, what numbers are we up against?
First, a very brief background:
TAS 102 alone (trifluridine/tipiracil) RECOURSE trial, app. 2012-2014 (800 patients across different countries). Run by Taiho Oncology / Taiho Pharmaceutical (Japan). Approved by FDA as Lonsurf (2015). Main results:
Overall Survival (OS): 7.5 months
Progression Free Survival (PFS): 2.4 months
Adverse Events: >= Grade 3= 69%
Come the SUNLIGHT Trial (Nov 2020 – Feb 2022) with 492 patients with refractory mCRC, Taiho Oncology (co -developer of TAS 102) and Servier (global sponsor). Randomization: 1:1 (TAS-102): (TAS 102 + bevacizumab), the trial was run to determine whether adding bevacizumab (an anti VEGF antibody) to TAS 102 improves survival in patients with mCRC who have already received 1–2 prior lines of therapy.
Primary endpoint: Overall survival (OS)
Secondary endpoints: Progression free survival (PFS), safety, ECOG performance deterioration time. Main results:
Overall Survival (OS): 10.8 months
Progression Free Survival (PFS): 5.6 months with combination
Adverse Events: Grade ≥3 (similar between arms) ≈72% (Most common adverse events: neutropenia, nausea, anemia
How these drugs work is important for our tial: TAS 102 is a fixed dose combination of: Trifluridine (FTD), the active cytotoxic drug, and Tipiracil (TPI) a metabolism blocker that keeps trifluridine active in the body. Trifluridine is a nucleoside analog (a fake DNA building block) that “fools” the tumor cells to mistakenly incorporate it into their DNA during replication causing disfunction, replicating failure and eventually apoptosis. Tipiracil keeps trifluridine from being destroyed staying in the bloodstream longer allowing it to reach tumor cells and accumulate inside DNA. i.e, they work together in a way that allows trifluridine to reach tumor cells and damage them effectively.
Now, the addition of the anti VEGF (Vascular Endothelial Growth Factor) antibody bevacizumab (as in SUNLIGHT) improved the endpoints substantially. VEGF works mainly by driving hypoxia (low oxygen), VEGF driven tumors are extremely hypoxic making them more resistant to chemotherapy and genetically more unstable and aggressive. The anti-VEGF action of bevacizumab results in more susceptibility to DNA damaging agents making tumor cells less able to activate survival pathways and repair nucleoside analog damage. Hence the superior results obtained.
The main point is: this is the “standard of care now” and this is what our numbers have to improve on. We will likely receive some information end of October (ESMO) and January ASCO-GI potentially with ORR, PFS, DCR data.
The numbers in October are, imo, very important (have refered to PDL-1 induction via CPS measurement and ctDNA in previous posts), however what is critical here is how will BP look at them (I think I know how the FDA will).
Let me explain: Neither RECOURSE or SUNLIGHT trials reported ctDNA or PD L1 measurements (as far as I know) as mechanism-based oncology was not there at the trial design (at the time purely clinical-endpoint driven). I was surprised by this as was searching for reference points to be able to analyze the potential results from October's ESMO.
Apparently ctDNA became widely adopted in CRC trials after 2018–2020 (SUNLIGHT was designed earlier), especially for MRD (Minimal Residual Disease) studies.
Is this good or bad news ??
Bad news: Well, if one wants to back up the truck after ESMO (if not done yet) with the ctDNA/PD-L1 results one will have to “fly solo” as there is no reference point. They (the numbers) will have to stand by themselves. CLOVER targets MSS colorectal cancer, the hardest to treat subtype (the group that does not respond to immunotherapy) and has the highest unmet need, using modern biomarkers (ctDNA, PD L1 on CTCs/CAMLs, CCR5 expression) to track response. I will be probably flying solo or otherwise towards very blue skies then.
Good news: VEGF and CCR5 converge on PD L1 biology. The former produces PD-L1 upregulation (through HIF 1α and STAT3) while the latter through CSN5. So, VEGF and CCR5 together create a PD-L1 high, immune excluded tumor making PD L1 a mechanistic biomarker for CCR5 blockade. As Leronlimab (anti CCR5) reduces CCL5 driven PD-L1 stabilization and addresses other mechanisms (CD8 infiltration, macrophage re-programming, Tregs reduction) they target two halves of the same suppressive system making VEGF + CCR5 + cytotoxic backbone biologically coherent.
In other words: This is, by design, a synergistic model that will very likely produce good numbers at the end.
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