"Perhaps Leronlimab... actually enhances the efficacy of whichever ICI drug is used once the tumor becomes hot or even if the tumor was hot in the first place."
Jake, I think the short answer to your question is yes. But there are two different questions there that deserve a little elaboration, so let me separate them out. And add a little information on accelerated approvals.
The first deals with "whichever ICI is used." I do not really know if there is a single, best-in-class ICI that has separated itself from the rest. Results vary depending on indication, line, and PD-1/PDL-1 status. Frankly, there isn't a lot of head-to-head comparisons as companies seem to be testing their drugs in specific subsets of cancers to try and establish SOCs in various settings. I took a look at dMMR positive CRC and found different drugs are approved in different lines. For example:
• Dostarlimab: Currently approved for dMMR recurrent/advanced solid tumors (US) without treatment options. Its primary differentiator is its rapid adoption into Phase III studies for perioperative (before/after surgery) treatment (e.g., AZUR-2). (45% ORR in dMMR/MSI-H solid tumors in the GARNET trial)
• Pembrolizumab: FDA-approved 1st-line for MSI-H metastatic CRC. (ORR 43.5%; Keynote 177 trial)
• Nivolumab/Ipilimumab: FDA-approved for MSI-H CRC (second-line and metastatic). (71% ORR; CheckMate 8HW trial)
The second part of the question about using whichever ICI "once the tumor becomes hot or even if the tumor was hot in the first place." I think leronlimab will work very well in "hot" tumors because it adds the ability to limit or eliminate metastasis, as well as the recent news that it inhibits CTLA4, LAG3, and TIM3, which are other immune checkpoints that are involved in T cell exhaustion.
When looking into dostarlimab, I was surprised to see that it was approved for "any dMMR/MSI-H positive solid tumor." I'd always thought that it typically takes Phase 3 trials in specific indications to approve a cancer therapeutic. I was wrong! In other words, it looks like there might be a pathway towards some kind of accelerated approval for Leronlimab based on one trial, for all solid tumors with the same bio-marker characteristics. (Like, perhaps, solid tumors that are negative/low PD-1/PDL-1 expression?) Check out this Google AI discussion of the GARNET trial, which formed the basis of approval for any dMMR/MSI-H solid tumors:
"The GARNET trial (NCT02715284) was designed as a pivotal, registrational trial, despite being a phase 1, nonrandomized, single-arm study of dostarlimab (Jemperli). It was used to support regulatory approval for patients with advanced or recurrent mismatch repair-deficient (dMMR) solid tumors.
Key details regarding the design of the GARNET trial include:
• Study Type: It was a Phase 1, open-label, single-group, multicenter study designed to evaluate antitumor activity (ORR, DOR) and safety.
• Registrational Purpose: The trial served as a pivotal study to support the accelerated approval of dostarlimab in dMMR/MSI-H endometrial cancer and solid tumors.
• Design Specifics: While the overall trial was phase 1, it included specific, large expansion cohorts (e.g., A1 for dMMR endometrial cancer) intended for efficacy evaluation."
This is the first time I've seen it was possible to approve a drug for many indications (i.e., solid tumors) from a single trial. Phase 1 and open-label, no less! (Of course we'll need confirmation in larger, post-approval trials). I guess great data and addressing un-met needs writes the ticket. And I suspect we'll have both...
I don't know who we are going to select as our partner... But out of the top four, GSK has direct experience with the accelerated pathway that will take us to where we want to go. It's gotta count for something...
Jake, I think the short answer to your question is yes. But there are two different questions there that deserve a little elaboration, so let me separate them out. And add a little information on accelerated approvals.
The first deals with "whichever ICI is used." I do not really know if there is a single, best-in-class ICI that has separated itself from the rest. Results vary depending on indication, line, and PD-1/PDL-1 status. Frankly, there isn't a lot of head-to-head comparisons as companies seem to be testing their drugs in specific subsets of cancers to try and establish SOCs in various settings. I took a look at dMMR positive CRC and found different drugs are approved in different lines. For example:
• Dostarlimab: Currently approved for dMMR recurrent/advanced solid tumors (US) without treatment options. Its primary differentiator is its rapid adoption into Phase III studies for perioperative (before/after surgery) treatment (e.g., AZUR-2). (45% ORR in dMMR/MSI-H solid tumors in the GARNET trial)
• Pembrolizumab: FDA-approved 1st-line for MSI-H metastatic CRC. (ORR 43.5%; Keynote 177 trial)
• Nivolumab/Ipilimumab: FDA-approved for MSI-H CRC (second-line and metastatic). (71% ORR; CheckMate 8HW trial)
The second part of the question about using whichever ICI "once the tumor becomes hot or even if the tumor was hot in the first place." I think leronlimab will work very well in "hot" tumors because it adds the ability to limit or eliminate metastasis, as well as the recent news that it inhibits CTLA4, LAG3, and TIM3, which are other immune checkpoints that are involved in T cell exhaustion.
When looking into dostarlimab, I was surprised to see that it was approved for "any dMMR/MSI-H positive solid tumor." I'd always thought that it typically takes Phase 3 trials in specific indications to approve a cancer therapeutic. I was wrong! In other words, it looks like there might be a pathway towards some kind of accelerated approval for Leronlimab based on one trial, for all solid tumors with the same bio-marker characteristics. (Like, perhaps, solid tumors that are negative/low PD-1/PDL-1 expression?) Check out this Google AI discussion of the GARNET trial, which formed the basis of approval for any dMMR/MSI-H solid tumors:
"The GARNET trial (NCT02715284) was designed as a pivotal, registrational trial, despite being a phase 1, nonrandomized, single-arm study of dostarlimab (Jemperli). It was used to support regulatory approval for patients with advanced or recurrent mismatch repair-deficient (dMMR) solid tumors.
Key details regarding the design of the GARNET trial include:
• Study Type: It was a Phase 1, open-label, single-group, multicenter study designed to evaluate antitumor activity (ORR, DOR) and safety.
• Registrational Purpose: The trial served as a pivotal study to support the accelerated approval of dostarlimab in dMMR/MSI-H endometrial cancer and solid tumors.
• Design Specifics: While the overall trial was phase 1, it included specific, large expansion cohorts (e.g., A1 for dMMR endometrial cancer) intended for efficacy evaluation."
This is the first time I've seen it was possible to approve a drug for many indications (i.e., solid tumors) from a single trial. Phase 1 and open-label, no less! (Of course we'll need confirmation in larger, post-approval trials). I guess great data and addressing un-met needs writes the ticket. And I suspect we'll have both...
I don't know who we are going to select as our partner... But out of the top four, GSK has direct experience with the accelerated pathway that will take us to where we want to go. It's gotta count for something...
27
