5 ms·

“Statistically significant and highly clinically meaningful” perhaps, but not so much that they can say what that actually means. My understanding is that of a

“Statistically significant and highly clinically meaningful” perhaps, but not so much that they can say what that actually means. My understanding is that of all cancer drugs approved by the FDA between 2000-2016 (around 90 drugs), the median life extension was just over 2 months...

jncfhnb 3y ago
The distribution skews right on these things. Median probably is not the right way to think about it
- pauln99 3y ago
  Maybe I've misunderstood, but for the average person that's even worse news, right? Two months was from clinical trials where there's no doubt that the "thumb is on the scale" in a host of ways, creating an exaggerated estimate of efficacy that would be realised in the real world. The reality is closer to no life extension, with the remaining lifespan is spent sicker than you'd have been without the drugs.
  - icegreentea2 3y ago
    Imagine a toy scenario where a cancer will kill 80% of people with it at exactly 3 years, and all 20% remaining will uh live full lives (so say another 20 years). If you created a drug that shifted the ratio to 60/40, and measured right at the 5 year mark. In a population of 100 untreated people, you'd get like 4080 total months lived (80x36 + 20x60). In a population of 100 treated people, you'd get like 4560 months lived (60x36+40x60). That's only generating an extra 4.8 months of life per person treated. However, you've doubled the number of people alive at the end of trial. Now obviously this is a toy example that's probably a bit exaggerated, but this type of behavior is exactly why median/average life extension is an inadequate measure alone.
  - s1artibartfast 3y ago
    >The reality is closer to no life extension, with the remaining lifespan is spent sicker than you'd have been without the drugs. I dont think that is true at all. The data is pretty clear that lifespan is significantly increasing. >Over time, the mean overall survival has improved from two months in 1973 to five months in 2015. Regarding long-term survival, a clear rise in 2yS is noted, increasing from 2.6% in 1973 to 12.9% in 2013 (latest year of which 2yS data can be calculated; Figure 1 and Tables 1 and 2), occurring mostly after the mid-1990s. A more modest increase is seen in the 5yS, from 0.7% in 1973 to 3.2% in 2010. >https://www.researchgate.net/publication/348455938_Long-Term_Survival_of_Patients_with_Metastatic_Non-Small-Cell_Lung_Cancer_over_Five_Decades https://www.researchgate.net/publication/348455938_Long-Term...
    - pauln99 3y ago
      I'm sorry, but two months to five months after 50 years and hundreds of billions of dollars. That was hardly the promise of the "war on cancer"!
      - s1artibartfast 3y ago
        To be fair, there are other cancers that are essentially cured. Lung cancer is a particularly nasty one for a number of reasons. It's hard to fight with the laws of physics or biology, so I'm curious who promised you something else. In general though, I tend to agree that in the US we spend far too much on what essentially boils down to performative end of Life Care. If you ask someone if they would rather spend $200k for 2 months or leave it to their family, I think most people would pick the second option. When someone else is paying, they choose the first option.
        pauln99 3y ago
        "This year marks the 50th anniversary of the “War on Cancer” declared by Richard Nixon, a former President of the United States of America. By signing into law the National Cancer Act on December 23, 1971, Nixon hoped this action to be the landmark legislation taken by his administration. Nixon apparently had confidence that cancer would be conquered in 5 years." You're right, there are a small handful of unusual cancers that we have cures for, and that's great. And some small progress has been made overall. But a lot of money has been spent, and it has been half a century or more, and we don't have much to show for our efforts.
ndr 3y ago
Sad stats truth: statistical significance does not say much about effect size, and it's misinterpreted by ~half articles. See https://www.nature.com/articles/d41586-019-00857-9 https://www.nature.com/articles/d41586-019-00857-9 for more
- losvedir 3y ago
  That's why the "highly clinically meaningful" part of the quote is there.
AtlasBarfed 3y ago
I think that is a perverse incentive of Medicare so it gets covered in treatment. The may work better, but the drugs only run the studies to that threshold. My mom died of lung cancer like 10 years ago and the immunotherapy drugs like keytuda all has those disclaimers. Her pd1 wasn't a good fit, but some like Jimmy Carter responded really well
s1artibartfast 3y ago
Yes, but this isnt as negative as it sounds. That 2 months average is often driven by more people alive at the end of a 2 year trial. Also, 16 years of 2 month extensions ends up being quite meaningful.
- pauln99 3y ago
  To be clear, those aren't 16 years of accumulating improvements. The median life extension - across all 90-odd drugs - was two months.
  - s1artibartfast 3y ago
    I understand that specifically is for stage 4 non small cell lung cancer, but I don't think it's appropriate to cherry pick a single example. There are other cancers and stages we're much more progress has been made.
arrosenberg 3y ago
Anecdotal, but Keytruda was approved in 2019 when my dad was diagnosed. He got 4 extra years (3.8 of which were pretty high quality) that I can assure you he would not have gotten without it. The progress on lung cancers specifically has advanced quite a bit in the last 10 years.
e40 3y ago
In this case, the extension is often far longer. See comment by @kkio. Our oncologist has people that have been on it for years, as well.
jseliger 3y ago
My understanding is that of all cancer drugs approved by the FDA between 2000-2016 (around 90 drugs), the median life extension was just over 2 months... An exciting, underrated possibility: therapies in conjunction with each other, even if the therapies are initially studied in isolation. Single-agent chemo doesn't work for many cancer types, but multi-agent chemo often does. The same may be true of the small molecules, antibody drug conjugates (ADCs), and monoclonal or bispecific antibodies being tested now. I have squamous cell carcinoma initially of the tongue, and now of the head, neck, and lungs (https://jakeseliger.com/2023/07/22/i-am-dying-of-squamous-cell-carcinoma-and-the-treatments-that-might-save-me-are-just-out-of-reach/ https://jakeseliger.com/2023/07/22/i-am-dying-of-squamous-ce...), and I'm on a clinical trial monotherapy at UCSD called MCLA-158 / petosemtamab. But, if I live long enough, which isn't super likely but isn't impossible, there's a decent shot that the FDA will finally approve Moderna's mRNA-4157 personalized vaccine for melanoma—hopefully in 2025. If I can get mRNA-4157 off label and combine it with pembrolizumab (Keytruda) and petosemtamab (assuming the latter is approved, too), that combo may be much more potent than any of the three in isolation, and I've already failed pembro as a monotherapy and pembro + carboplatin + paclitaxel. And if that combo doesn't work, or has some unexpected negative effect (including death), well, I'm going to die anyway, and the risk seems worthwhile. As another commenter observed, the median can be skewed by the number of people who don't respond; among those who respond to a given drug, some don't respond, but some live surprisingly long.

jncfhnb 3y ago

The distribution skews right on these things. Median probably is not the right way to think about it

pauln99 3y ago
Maybe I've misunderstood, but for the average person that's even worse news, right? Two months was from clinical trials where there's no doubt that the "thumb is on the scale" in a host of ways, creating an exaggerated estimate of efficacy that would be realised in the real world. The reality is closer to no life extension, with the remaining lifespan is spent sicker than you'd have been without the drugs.
- icegreentea2 3y ago
  Imagine a toy scenario where a cancer will kill 80% of people with it at exactly 3 years, and all 20% remaining will uh live full lives (so say another 20 years). If you created a drug that shifted the ratio to 60/40, and measured right at the 5 year mark. In a population of 100 untreated people, you'd get like 4080 total months lived (80x36 + 20x60). In a population of 100 treated people, you'd get like 4560 months lived (60x36+40x60). That's only generating an extra 4.8 months of life per person treated. However, you've doubled the number of people alive at the end of trial. Now obviously this is a toy example that's probably a bit exaggerated, but this type of behavior is exactly why median/average life extension is an inadequate measure alone.
- s1artibartfast 3y ago
  >The reality is closer to no life extension, with the remaining lifespan is spent sicker than you'd have been without the drugs. I dont think that is true at all. The data is pretty clear that lifespan is significantly increasing. >Over time, the mean overall survival has improved from two months in 1973 to five months in 2015. Regarding long-term survival, a clear rise in 2yS is noted, increasing from 2.6% in 1973 to 12.9% in 2013 (latest year of which 2yS data can be calculated; Figure 1 and Tables 1 and 2), occurring mostly after the mid-1990s. A more modest increase is seen in the 5yS, from 0.7% in 1973 to 3.2% in 2010. >https://www.researchgate.net/publication/348455938_Long-Term_Survival_of_Patients_with_Metastatic_Non-Small-Cell_Lung_Cancer_over_Five_Decades https://www.researchgate.net/publication/348455938_Long-Term...
  - pauln99 3y ago
    I'm sorry, but two months to five months after 50 years and hundreds of billions of dollars. That was hardly the promise of the "war on cancer"!
    - s1artibartfast 3y ago
      To be fair, there are other cancers that are essentially cured. Lung cancer is a particularly nasty one for a number of reasons. It's hard to fight with the laws of physics or biology, so I'm curious who promised you something else. In general though, I tend to agree that in the US we spend far too much on what essentially boils down to performative end of Life Care. If you ask someone if they would rather spend $200k for 2 months or leave it to their family, I think most people would pick the second option. When someone else is paying, they choose the first option.
      - pauln99 3y ago
        "This year marks the 50th anniversary of the “War on Cancer” declared by Richard Nixon, a former President of the United States of America. By signing into law the National Cancer Act on December 23, 1971, Nixon hoped this action to be the landmark legislation taken by his administration. Nixon apparently had confidence that cancer would be conquered in 5 years." You're right, there are a small handful of unusual cancers that we have cures for, and that's great. And some small progress has been made overall. But a lot of money has been spent, and it has been half a century or more, and we don't have much to show for our efforts.

ndr 3y ago

Sad stats truth: statistical significance does not say much about effect size, and it's misinterpreted by ~half articles. See https://www.nature.com/articles/d41586-019-00857-9 https://www.nature.com/articles/d41586-019-00857-9 for more

losvedir 3y ago
That's why the "highly clinically meaningful" part of the quote is there.

AtlasBarfed 3y ago

I think that is a perverse incentive of Medicare so it gets covered in treatment. The may work better, but the drugs only run the studies to that threshold. My mom died of lung cancer like 10 years ago and the immunotherapy drugs like keytuda all has those disclaimers. Her pd1 wasn't a good fit, but some like Jimmy Carter responded really well

s1artibartfast 3y ago

Yes, but this isnt as negative as it sounds. That 2 months average is often driven by more people alive at the end of a 2 year trial. Also, 16 years of 2 month extensions ends up being quite meaningful.

pauln99 3y ago
To be clear, those aren't 16 years of accumulating improvements. The median life extension - across all 90-odd drugs - was two months.
- s1artibartfast 3y ago
  I understand that specifically is for stage 4 non small cell lung cancer, but I don't think it's appropriate to cherry pick a single example. There are other cancers and stages we're much more progress has been made.

arrosenberg 3y ago

Anecdotal, but Keytruda was approved in 2019 when my dad was diagnosed. He got 4 extra years (3.8 of which were pretty high quality) that I can assure you he would not have gotten without it. The progress on lung cancers specifically has advanced quite a bit in the last 10 years.

e40 3y ago

In this case, the extension is often far longer. See comment by @kkio. Our oncologist has people that have been on it for years, as well.

jseliger 3y ago

My understanding is that of all cancer drugs approved by the FDA between 2000-2016 (around 90 drugs), the median life extension was just over 2 months... An exciting, underrated possibility: therapies in conjunction with each other, even if the therapies are initially studied in isolation. Single-agent chemo doesn't work for many cancer types, but multi-agent chemo often does. The same may be true of the small molecules, antibody drug conjugates (ADCs), and monoclonal or bispecific antibodies being tested now. I have squamous cell carcinoma initially of the tongue, and now of the head, neck, and lungs (https://jakeseliger.com/2023/07/22/i-am-dying-of-squamous-cell-carcinoma-and-the-treatments-that-might-save-me-are-just-out-of-reach/ https://jakeseliger.com/2023/07/22/i-am-dying-of-squamous-ce...), and I'm on a clinical trial monotherapy at UCSD called MCLA-158 / petosemtamab. But, if I live long enough, which isn't super likely but isn't impossible, there's a decent shot that the FDA will finally approve Moderna's mRNA-4157 personalized vaccine for melanoma—hopefully in 2025. If I can get mRNA-4157 off label and combine it with pembrolizumab (Keytruda) and petosemtamab (assuming the latter is approved, too), that combo may be much more potent than any of the three in isolation, and I've already failed pembro as a monotherapy and pembro + carboplatin + paclitaxel. And if that combo doesn't work, or has some unexpected negative effect (including death), well, I'm going to die anyway, and the risk seems worthwhile. As another commenter observed, the median can be skewed by the number of people who don't respond; among those who respond to a given drug, some don't respond, but some live surprisingly long.