Breakthrough drug trial saw cancer vanish in every patient (2022) | Hacker News Reader

Breakthrough drug trial saw cancer vanish in every patient (2022)

euronews.com

145 pointswjb375 comments

For context, this study was in 2022, this drug had received accelerated approval in 2021 and was fully approved by the FDA in 2023 for mismatch repair deficient endometrial cancer. (https://www.fda.gov/drugs/resources-information-approved-dru...).

It's awesome to see the amount of progress in cancer that deeper understanding of the disease is bringing. Identifying interventions that work in a subset of patients with specific mutations, targeting them specifically, using immunotherapies, all incredibly cool and impactful.

Success with targeted therapy also hopefully paves the way towards the understanding we need for generalized solutions.

I don't think so - there is no 'general cancer', there's a lot of cancers ...

The better way of thinking about it is that this progress is allowing us to shift away from the idea of 'general' cancer or identifying cancer by tissue of origin to instead start identifying it by more useful and actionable features. So instead of talking about pancreatic cancer or colon cancer, with PD-1 inhibitors like keytruda we instead have an approval for any solid tumor that's mismatch repair deficient, something we can test for and that relates to the efficacy of a specific drug.

Really impressive results. The real victory here wasn't the breakthrough drug, which many have pointed out is another flavor of PD-1 inhibition (Nivolumab, Pembro) It's the patient selection - careful curation of MSI status with Next Gen Sequencing. Clinically it has already been implemented and is changing the outcomes of thousands of patients every year.

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

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/

thanks. yeah i dunno then

First-line nivolumab metastatic colorectal w MMR: https://pubmed.ncbi.nlm.nih.gov/34637336/

first-line keytruda metastatic colorectal w MMR: https://www.nejm.org/doi/full/10.1056/NEJMoa2017699

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.

They are https://en.m.wikipedia.org/wiki/PD-1_and_PD-L1_inhibitors

The hint is the -mab naming.

-ab means it's an antibody. There are many kinds of antibodies, not just to those two proteins.

And -mab means monoclonal antibody. But your point still stands, there is a huge number of -mab drugs out there today.

It's a really great technology, and not just for drugs. It deservedly won the Nobel Prize in Medicine in 1984.

checkpoint inhibitors are antibodies

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.

i wouldn't refer to it an an immunostimulant. it prevents tumors from hiding.

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/immunoth...

sorry about your wife. an immunostimulant is more about enraging/activating the immune system, not intervening with its capabilities

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.

Yes, it's a different term and entirely separate category of drugs.

Checkpoint inhibitors cut the brakes. This reduces their ability to detect "self," and attack blindly.

What they don't do is poke immune cells with a stick to anger them like chemoattractants and cytokines. This approach can be used to signal, "hey, the tumor is over here." Causing them to attack more intelligently.

If you would like to learn more, I would recommend the books: (a) molecular biology of cancer; mechanisms, targets, and therapeutics, and (b) handbook of therapeutic biomarkers in cancer.

Checkpoint inhibitors are immunotherapies. The checkpoints they're inhibiting are immune checkpoints.

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?

even within the same type of tissue, different patients are going to have different mutations/subclones in their tumors.

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

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?

They are:

https://www.fda.gov/news-events/press-announcements/fda-appr...

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!

different cell types express different genes at different amounts at different times

each tumor cell/ subclone has different mutations at different times

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.

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.

> 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-simpso...

Original HN post on this same subject from 2022: https://news.ycombinator.com/item?id=31630679

Thanks! Macroexpanded:

A cancer trial’s unexpected result: Remission in every patient - https://news.ycombinator.com/item?id=31630679 - June 2022 (232 comments)

I am so excited for the monoclonal antibody revolution of Medicine. Here's to them getting cheaper someday.

How expensive are they to make these days? There's also one in progress made from human stem cells that blocks a teeth-regrowth-inhibitor, causing mice and ferrets to grow more and new teeth.

It should allow human adults to grow new teeth over a period of 2~5 years, if removal of the old teeth is surgically assisted (the roots are too deep to have it work automatically, thus evolution of the blocker). Oh, and it's systemic as I understand, so usage would involve pulling all the teeth present when starting.

> There's also one in progress made from human stem cells that blocks a teeth-regrowth-inhibitor, causing mice and ferrets to grow more and new teeth.

That's quite an unexpected mix of optimistic, cute, and then disturbing right there.

> Oh, and it's systemic as I understand, so usage would involve pulling all the teeth present when starting.

Never mind, fully disturbing now. :P Though I suppose it might be interesting for folks who've already lost almost all of them...

Hey, my understanding is that they're initially targeting Japanese ~~elderly who have already lost their teeth~~ children who genetically forgot to grow at least 6 of their adult teeth (1 in 10k affected). (https://uniqa.dental/news/tooth-regeneration-drug-trials-in-...)

Also there are many people who have sustained teeth damage bad enough to normally warrant 2+ implants plus fillings for the others, and at that point, it's warranted to think about doing "wisdom teeth removal" for the remaining and growing a new set.

It's obviously not suited for replacing a single lost tooth.

Well, ferrets teeth are very close to humans, so it working for them is already highly suggestive of it working for humans. Then, the antibodies being human ones, and that they even work in mice that are very very different teeth-wise from humans, is enough to warrant trying in humans. This isn't considering the safety (no predicted collateral damage; the antibodies target USAG-1 which has purposes beyond teeth growth inhibition), but yeah.

Also see https://www.popularmechanics.com/science/health/a44786433/hu... ....

> How expensive are they to make these days?

A good question, I can't answer. But I can tell you, when my daughter had her liver transplant, they gave her an insane amount of medications for weeks. They only gave her one shot of a monoclonal antibody "Basiliximab". The syringe with it was escorted by two guards from the pharmacy.

> The syringe with it was escorted by two guards from the pharmacy.

Isn't it only, like, a few thousand dollars? By all means, be careful with it, but you don't see teams of guards at the apple store escorting hardware to the customer.

Was this maybe earlier in development and the price was much higher or something?

A few years ago the pharmacy accidentally keyed in the full price for two months (four injectors) of Humira, IIRC it was like $3k. This is in Northern Europe, probably it's more expensive in the US? Also I don't know if the price has come down since.

Of course it's also a price vs volume thing, but I heard a while back that scaling up bioreactors is the limiting factor for these monoclonal antibodies.

The cost of drugs like these is nontrivial, but much of that is dedicated to ensuring that what gets produced and delivered is actually what you wanted it to be. That is, you can make low quality mabs in a garage if you really knew what you were doing, but producing enough to sell without having patients dying of bacterial infections can't be done in a garage. Quality control combined with experienced production folks is critical.

The cell therapies are really expensive and struggling with manufacturing costs, mabs like these are priced what they are because of market forces.

As long as we don't get the cyberpunk dystopian outcomes like tailored molecules dumped in the water supply to assassinate a specific individual.

> They sent a slamhound on Turner's trail in New Delhi, slotted it to his pheromones and the color of his hair. It caught up with him on a street called Chandni Chauk and came scrambling for his rented BMW through a forest of bare brown legs and pedicab tires. Its core was a kilogram of recrystallized hexogene and flaked TNT.

-- Count Zero, by William Gibson

We're already getting this particular dystopia with computer vision systems. The systems aren't particularly good, but that doesn't entirely matter to the people setting them off: their target lists aren't particularly well-curated either. We're a few hundred years past the point where technology is ever the bottleneck when it comes to making people dead.

Extract from Self-Driving Issues by Randall Munroe. https://xkcd.com/1958

> "I guess it's just that most people aren't murderers?" "Oh, right. I always forget." "An underappreciated component of our road safety system."

Isn't that paragraph describing some kind of homing bomb that's searching for the target ("pheromones and the color of his hair")? Does Gibson have any examples of what you describe, targeted molecules?

2023 news: original paper : https://www.nejm.org/doi/pdf/10.1056/NEJMoa2201445

Are we going to see colo-rectal surgeons on the endangered species list, not to speak of other cancer specialties?

https://www.youtube.com/watch?v=W2gABYTmXos

I mean there are more maladies that affect the colon and rectum than just colon cancer, so I expect colo-rectal surgeons will survive, if with a decline in positions.

True, mechanical problems will endure, even if cancer is defeated.

Plus not everyone responds to treatment. Allergies, side effects. They may slowly age out but we will probably always see a few in the nearest large city.

This is actually one of the goals in colorectal cancer - organ-sparing treatment options. In particular, using immunotherapies in the neoadjuvant, peri-operative setting has shown tremendous benefit in colorectal cancers. Work done by Myriam Chalabi (Netherlands Cancer Institute) with the NICHE-1 study [0] and Pashtoon Kasi (Cornell) with the NEST-1 study [1] have had tremendous impacts for the up to 15% of patients who have mismatch repair deficient CRC.

[0] https://ascopost.com/issues/october-25-2022/unprecedented-wa... [1] https://www.nyp.org/advances/article/gastroenterology/ongoin...

From what I've heard, surgery to treat hand osteoarthritis is a dying sub-specialty because the drugs are so effective now (and the surgery has never been a very good solution).

* in a 5-10% subset, of a subset, of a subset of cancers.

At risk of taking the bait with this flippant comment, I’d like to highlight your critique of what others used to long for as “targeted therapy” or “personalized medicine”. I suppose we could always step backward to a world dominated by systemic cytotoxic chemo, though. Which, to be fair, still has its place.

Cancer tends to evolve at a rate that outpaces treatment innovation, and the molecular determinants can be wildly heterogenous. For example, a lung cancer patient can have half a dozen tumors that all harbor independent oncogenic drivers. It is not uncommon for a patient to undergo treatment with a target therapy and see complete tumor responses in some lesions, while others grow unimpeded.

We did not develop our own code base. Humans are a black box and drug development is HARD.

It’s not a comment on the value of the treatment, the headline is just wrong. Saying “cancer vanished in every patient” without further qualification is ambiguous, not too different from saying “illness was cured in everyone”. The correct title should have been “Success using a targeted anti-cancer therapy”.

Btw, there is still research that tries to find a general mechanism for interventions. The other day I looked at interesting work that hinged the delivery of disruptive payload on telomerase activity. Telomerase is expressed almost universally in cancer cells and in stem cells; therefore somatic cells would be spared, and it’s hoped that stem cells would be able to recover.

Anyway like you said, both approaches are meaningful, which is why it’s important to tell them apart.

Yep that's part of the advance here. Identifying what those subsets are. This drug went on to be approved for mismatch repair deficient endometrial cancers in 2023

We are going to have to cure cancer about a thousand times before we have cured it.

(2022)

Buy Phillip Morris

I don't think this is the first study where 12 patients showed full remission. Further, you'd expect that to happen by chance at the scale that we run small trials like this.

Flipping 12 coins and having them all land on heads is a 0.02% probability event. Cancer spontaneously going into remission in a patient is pretty far away from a coinflip.

That's true but this is a clinical trial where the patients are being treated- the patients were selected according to strict criteria, and received other treatments in cancer centers. It's not really just "coinflips", it's heavily biased coinflips.

Maybe I should have put this in a more productive way: I prefer studies that have a large enough n that you can actually measure the failure rate. There's a classic statistics paper where an operation was done on 3 patients and none died- the paper's title is "If nobody dies, is everything OK?" and goes into whether you can reliably conclude causal effects with very small n.

Further- let's say the drug caused remission in 50% of the patients, and the other 50% had spontaneous remission (or remissionc aused by other aspects of the treatment). Now it's not 1/2 * 12, it's 1/2 * 6 (or whatever base probability you want to choose). If you compare that probability to the number of people in clinical trials in the US, you would expect that after 30-40 years, you'd see at least one trial with 12 patients with complete remission.

(I don't actually doubt the drug is effective. We already know that. And we already know that studies this small really stretch the concepts of significance and causality).

I think most people would prefer a study with more participants, but you can’t jump to a large human trial right away

Patient recruitment is hard, but this is a phase II on an already approved drug. Typical Phase II has at least 100 patients.

Edit - also, you should go and look up the rates of spontaneous remission for colorectal cancer (e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10273780/). We're talking about 12 patients with stage 2/3 colorectal cancer, in remission with the treatment alone.

What's really cool is that papers tend to have sections where they discuss the statistics so you can use real numbers. Their null hypothesis was a 25% response rate.

"This decision rule would result in a type I error rate of 6% if 25% of the patients had an overall response and would provide the study with 84% power if 50% had an overall response. The null hypothesis was established on the basis of a study by Seligmann et al., in which the observed response to chemotherapy among patients with mismatch repair–deficient rectal cancers was 7% (8 of 115 patients)."

As other people have mentioned, this is just a variation on a theme of other successful drugs. It may well be that the odds are greater than 50% the way they selected the patients.

There's also publication and hacker News front page bias to consider in the odds making as well...

I end up seeing a lot of these discussions and you can always tell the difference between a person who doesn't know much math but works in the field, to somebody who knows a lot of math but doesn't work in the field. Experience and wisdom matter a lot wrt drug discovery and cancer treatment.

What's funny is that the paper has the statistics. The original point is sort of valid in that narrowly speaking, there's probably been other cancer trials with similar response rates. Sticking with that specific argument then yeah that claim is probably exaggerated for clicks. But that's a claim about this study compared to other studies. Doesn't have anything to do with the actual effectiveness of the drug or the statistics of the study! I don't think it's just experience and wisdom - it's also the math lol this is plenty enough to get a strong insight into causality. Colorectal cancer doesn't exactly tend to go into spontaneous remission that often...

When a press release says "all 12 patients went into full remission", you can be sure that the PR authors truly want you to believe that the drug had the effect of curing all the patients.

The press release is obviously overselling (also remission != cure), but that's separate from the statistics of the study and it's design and the significance of the results. It's almost always a safe bet to just ignore press releases entirely and jump straight to the paper.

> Flipping 12 coins and having them all land on heads is a 0.02% probability event. Cancer spontaneously going into remission in a patient is pretty far away from a coinflip.

You don't actually have to run that many trials before a 0.02% liklihood event happens by chance.

only 5000 or so trials, easy

5,000 isn’t a guarantee, but your already at 10% odds of at least one hit with 527 trials.

Considering how many of these get conducted and the odds are often better than 50/50, I expect multiple trials have cured everyone.

In the history of the world, i am pretty sure there have been more than 5000 cancer trials.

This entire chain of comments rests on the presumption of a "coin toss".

If colorectal cancers in 2nd or 3rd stage actually had a fifty-fifty chance of spontaneous remission in the real world, the disease would be a lot less scary than it is.

They don't. Spontaneous remission does happen, but isn't common. The chance that a 12-patient trial produces spontaneous remission in all 12 patients in a truly random fashion, is much smaller than 1:5000.

And the GP actually mentioned it. But everyone reacting to him still addresses the 1:5000 value. It is a nice example of anchoring as described by Daniel Kahneman - here is a number, let's cling to it.

You totally misunderstood my comment. I never meant that all 12 patients had spontaneous remission. I understand why people think that- my statement was ambiguous. What I did mean was that it's possible that some of the patients cancers went into remission for a reason that was not specific to this drug. It could be 11 people got better because of the drug- and 1 got better because they were being treated in a world-class hospital with a number of other factors that affect disease progression.

THat's how it works in clinical trials. I didn't make my statement out of ignorance- I worked adjacent to trials for decades and have seen all sorts of claims of results that didn't hold up to scrutiny.

Reply on news.ycombinator.com