5 ms·

It's a checkpoint inhibitor. Those have been used for ~ every cancer type for over a decade. Keytruda has been a top-selling drug for years. It looks like this

It's a checkpoint inhibitor. Those have been used for ~ every cancer type for over a decade. Keytruda has been a top-selling drug for years. It looks like this trial was neoadjuvant (before treatment/ alternative to chemo and surgery), but that's not new either. immunotherapy typically has much lower response rates though, so maybe it's the mismatch repair selection strategy that's novel at a sample size of 12... they could have gotten lucky

kjkjadksj 3y ago
Using mismatch repair has been a concept for almost a decade now, the initial pd-l1 papers were very much focused on it. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/
- deleted 3y ago
  [deleted]
- Kalanos 3y ago
  thanks. yeah i dunno then First-line nivolumab metastatic colorectal w MMR: https://pubmed.ncbi.nlm.nih.gov/34637336/ https://pubmed.ncbi.nlm.nih.gov/34637336/ first-line keytruda metastatic colorectal w MMR: https://www.nejm.org/doi/full/10.1056/NEJMoa2017699 https://www.nejm.org/doi/full/10.1056/NEJMoa2017699
tyingq 3y ago
I'm no expert, but it says it's Dostarlimab, which is billed as a monoclonal antibody. Some googling suggests that monoclonal antibodies and checkpoint inhibitors are both immunotherapy approaches, but that they aren't the same.
- mcbain 3y ago
  They are https://en.m.wikipedia.org/wiki/PD-1_and_PD-L1_inhibitors https://en.m.wikipedia.org/wiki/PD-1_and_PD-L1_inhibitors The hint is the -mab naming.
  - pfdietz 3y ago
    -ab means it's an antibody. There are many kinds of antibodies, not just to those two proteins.
    - semi-extrinsic 3y ago
      And -mab means monoclonal antibody. But your point still stands, there is a huge number of -mab drugs out there today.
      - pfdietz 3y ago
        It's a really great technology, and not just for drugs. It deservedly won the Nobel Prize in Medicine in 1984.
- Kalanos 3y ago
  checkpoint inhibitors are antibodies
- hentrep 3y ago
  For reference, dostarlimab (JEMPERLI) is essentially GSK's answer to Merck's pembrolizumab and BMS's nivolumab. Or KEYTRUDA and OPDIVO, respectively, if you're in the USA and bombarded with pharma ads. All three are monoclonal antibodies that block PD-1 on T cells, thereby stimulating the body's immune system.
  - Kalanos 3y ago
    i wouldn't refer to it an an immunostimulant. it prevents tumors from hiding.
    - tominous 3y ago
      Immunostimulant is a reasonable way to put it: it takes the brakes off one part of the immune system. (Similarly, we call caffeine a central nervous system stimulant and it works by blocking adenosine, which is one of the brakes on brain activity.) And it's not always specific to tumours. My wife's thyroid got wiped out. The endocrinologist said it was like bombing a paint factory: first a massive spike in thyroid hormones, then a crash as no more were produced. More info on the potential side effects of immune checkpoint inhibitors: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors https://www.cancer.gov/about-cancer/treatment/types/immunoth...
      - Kalanos 3y ago
        sorry about your wife. an immunostimulant is more about enraging/activating the immune system, not intervening with its capabilities
        tominous 3y ago
        If you're trying to say that immunostimulant is a term of art distinct from immune checkpoint inhibitor, then fair point. But what it seems like you're saying is checkpoint inhibitors don't "enrage/activate" the immune system, and they only target tumours, and both points are misleading if not outright wrong.
- vikramkr 3y ago
  Checkpoint inhibitors are immunotherapies. The checkpoints they're inhibiting are immune checkpoints.
adamredwoods 3y ago
The bigger question I have, if these PD-1 blockers all have the same method-of-action, why are they showing different results for different tumors?
- Kalanos 3y ago
  even within the same type of tissue, different patients are going to have different mutations/subclones in their tumors.
- vikramkr 3y ago
  Depends on if that mechanism of action works for the particular exact set of mutations that the given tumor has (every cancer is essentially unique). Part of the success of the work in that paper is identifying specific markers that indicate that the drug is going to work in that tumor
  - adamredwoods 3y ago
    Both dostarlimab and pembro are PD-1 blockers, yet they are labeled for two different cancers. If all tumors have different characteristics, why are these not labeled for all cancers, in general, that display these expressions? Is this part of the game that the FDA plays?
    - vikramkr 3y ago
      They are: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cancer-treatment-any-solid-tumor-specific-genetic-feature https://www.fda.gov/news-events/press-announcements/fda-appr... https://en.wikipedia.org/wiki/Tissue-agnostic_cancer_drug https://en.wikipedia.org/wiki/Tissue-agnostic_cancer_drug If by "game" you mean rigorous regulatory process to ensure safety and efficacy, then yeah. Different monoclonal antibodies even with the same target can behave differently. You'd have to specifically design a trial and seek approval for an indication like the one you described. Which people have done and are doing. It's an exciting field of research!
- Kalanos 2y ago
vikramkr 3y ago
The targeting here is definitely the point, its the core hypothesis in the abstract. In general this increased targeting ability has been enormously powerful in solving the response rate problem you mentioned. Fundamentally the problem isnt that the response rate is low accross the board, it's that it's incredibly high in a small subset and incredibly low in the rest. Figuring out that subset is basically wins all around - you can identify the actual subpopulation You're treating so your study is better powered (less noise from people who wouldn't be responsive), you can codevelop a diagnostic to identify chance of response, you don't treat and give side effects to patients who won't respond, also saving costs. This is a bit of a weird post and comment thread because this is an older paper about a technology that is genuinely very successful, but it's being responded to as if it's one of those random mouse trials of a brand new therapeutic strategy. This drug already had accelerated approval and was on the market when this trial was run! In case the rest of the world missed the memo - some of those mouse trials y'all read about in the early 2000s or so? Yeah they worked in humans too. This is one of them.
inglor_cz 3y ago
Just like with other tools, good selection matters. When working with screws, you don't want just any screwdriver, you want the right size. It is my impression that in this trial, the main idea was to improve the fit between patient and therapy.
xk3 3y ago
> at a sample size of 12... they could have gotten lucky right?? this seems like Simpson's Paradox https://robertheaton.com/2019/02/24/making-peace-with-simpsons-paradox/ https://robertheaton.com/2019/02/24/making-peace-with-simpso...

kjkjadksj 3y ago

Using mismatch repair has been a concept for almost a decade now, the initial pd-l1 papers were very much focused on it. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/

deleted 3y ago
[deleted]
Kalanos 3y ago
thanks. yeah i dunno then First-line nivolumab metastatic colorectal w MMR: https://pubmed.ncbi.nlm.nih.gov/34637336/ https://pubmed.ncbi.nlm.nih.gov/34637336/ first-line keytruda metastatic colorectal w MMR: https://www.nejm.org/doi/full/10.1056/NEJMoa2017699 https://www.nejm.org/doi/full/10.1056/NEJMoa2017699

tyingq 3y ago

I'm no expert, but it says it's Dostarlimab, which is billed as a monoclonal antibody. Some googling suggests that monoclonal antibodies and checkpoint inhibitors are both immunotherapy approaches, but that they aren't the same.

mcbain 3y ago
They are https://en.m.wikipedia.org/wiki/PD-1_and_PD-L1_inhibitors https://en.m.wikipedia.org/wiki/PD-1_and_PD-L1_inhibitors The hint is the -mab naming.
- pfdietz 3y ago
  -ab means it's an antibody. There are many kinds of antibodies, not just to those two proteins.
  - semi-extrinsic 3y ago
    And -mab means monoclonal antibody. But your point still stands, there is a huge number of -mab drugs out there today.
    - pfdietz 3y ago
      It's a really great technology, and not just for drugs. It deservedly won the Nobel Prize in Medicine in 1984.
Kalanos 3y ago
checkpoint inhibitors are antibodies
hentrep 3y ago
For reference, dostarlimab (JEMPERLI) is essentially GSK's answer to Merck's pembrolizumab and BMS's nivolumab. Or KEYTRUDA and OPDIVO, respectively, if you're in the USA and bombarded with pharma ads. All three are monoclonal antibodies that block PD-1 on T cells, thereby stimulating the body's immune system.
- Kalanos 3y ago
  i wouldn't refer to it an an immunostimulant. it prevents tumors from hiding.
  - tominous 3y ago
    Immunostimulant is a reasonable way to put it: it takes the brakes off one part of the immune system. (Similarly, we call caffeine a central nervous system stimulant and it works by blocking adenosine, which is one of the brakes on brain activity.) And it's not always specific to tumours. My wife's thyroid got wiped out. The endocrinologist said it was like bombing a paint factory: first a massive spike in thyroid hormones, then a crash as no more were produced. More info on the potential side effects of immune checkpoint inhibitors: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors https://www.cancer.gov/about-cancer/treatment/types/immunoth...
    - Kalanos 3y ago
      sorry about your wife. an immunostimulant is more about enraging/activating the immune system, not intervening with its capabilities
      - tominous 3y ago
        If you're trying to say that immunostimulant is a term of art distinct from immune checkpoint inhibitor, then fair point. But what it seems like you're saying is checkpoint inhibitors don't "enrage/activate" the immune system, and they only target tumours, and both points are misleading if not outright wrong.
vikramkr 3y ago
Checkpoint inhibitors are immunotherapies. The checkpoints they're inhibiting are immune checkpoints.

adamredwoods 3y ago

The bigger question I have, if these PD-1 blockers all have the same method-of-action, why are they showing different results for different tumors?

Kalanos 3y ago
even within the same type of tissue, different patients are going to have different mutations/subclones in their tumors.
vikramkr 3y ago
Depends on if that mechanism of action works for the particular exact set of mutations that the given tumor has (every cancer is essentially unique). Part of the success of the work in that paper is identifying specific markers that indicate that the drug is going to work in that tumor
- adamredwoods 3y ago
  Both dostarlimab and pembro are PD-1 blockers, yet they are labeled for two different cancers. If all tumors have different characteristics, why are these not labeled for all cancers, in general, that display these expressions? Is this part of the game that the FDA plays?
  - vikramkr 3y ago
    They are: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cancer-treatment-any-solid-tumor-specific-genetic-feature https://www.fda.gov/news-events/press-announcements/fda-appr... https://en.wikipedia.org/wiki/Tissue-agnostic_cancer_drug https://en.wikipedia.org/wiki/Tissue-agnostic_cancer_drug If by "game" you mean rigorous regulatory process to ensure safety and efficacy, then yeah. Different monoclonal antibodies even with the same target can behave differently. You'd have to specifically design a trial and seek approval for an indication like the one you described. Which people have done and are doing. It's an exciting field of research!
Kalanos 2y ago

vikramkr 3y ago

The targeting here is definitely the point, its the core hypothesis in the abstract. In general this increased targeting ability has been enormously powerful in solving the response rate problem you mentioned. Fundamentally the problem isnt that the response rate is low accross the board, it's that it's incredibly high in a small subset and incredibly low in the rest. Figuring out that subset is basically wins all around - you can identify the actual subpopulation You're treating so your study is better powered (less noise from people who wouldn't be responsive), you can codevelop a diagnostic to identify chance of response, you don't treat and give side effects to patients who won't respond, also saving costs. This is a bit of a weird post and comment thread because this is an older paper about a technology that is genuinely very successful, but it's being responded to as if it's one of those random mouse trials of a brand new therapeutic strategy. This drug already had accelerated approval and was on the market when this trial was run! In case the rest of the world missed the memo - some of those mouse trials y'all read about in the early 2000s or so? Yeah they worked in humans too. This is one of them.

inglor_cz 3y ago

Just like with other tools, good selection matters. When working with screws, you don't want just any screwdriver, you want the right size. It is my impression that in this trial, the main idea was to improve the fit between patient and therapy.

xk3 3y ago

> at a sample size of 12... they could have gotten lucky right?? this seems like Simpson's Paradox https://robertheaton.com/2019/02/24/making-peace-with-simpsons-paradox/ https://robertheaton.com/2019/02/24/making-peace-with-simpso...