Desperate, Prof Long formulated a radical plan to treat Prof Scolyer based on what had worked in melanoma, but which had never been tested in brain cancer.
For example, MCLA-158 / petosemtamab should, based on existing phase 1a and 1b data, be approved: https://beta.clinicaltrials.gov/study/NCT03526835. But, from what I understand, the FDA is going to make Merus proceed with phase 3 trials, despite the incredibly positive phase 1b and 2 data. Madness.
And they worried the experiment could kill him faster.
It's a reasonable trade-off to decide to take the risk.
Immunotherapy drugs are quite toxic, especially when mixed, so he could be poisoned
I wonder which the author is talking about, because e.g. pembrolizumab (Keytruda) is not. I assume the author isn't talking about e.g. CAR-T therapies?
I'm not sure if they've said publicly what immunotherapy they used. I have seen it referred to as a combo, so I would guess ipi/nivo - that is Nivolumab (Opdivo) + Ipilimumab (Yervoy). They've been trialling those as neoadjuvant for melanoma: https://melanoma.org.au/paper/neo-adjuvant-immunotherapy-eme...
Nivo is generally well tolerated, ipi less so. I only got to my 2nd cycle of ipi/nivo before we discontinued it. (I'd already had more cycles of nivo on a trial.) It can have neurological effects and encephalitis in rare cases, so maybe that's what they are referring to. I wouldn't say "poison" though.
As it happens, Prof Long is my medonc. We don't sit around chatting about Richard though, she's a bit busy on clinic days!
My wife recently fought and unfortunately lost a battle with metastatic melanoma.
I would agree that the nivo/ipi combo isn’t poison, but it’s no joke, and given that disease like melanoma sprouts mets like crazy, and the side effects of the treatment can result in significant side effect to critical organs.
I think it’s fine to critique the FDA process, but I also think that a conservative approach to approvals is important, because ultimately bad outcomes will cause the pharmaceutical people to get more conservative internally - imo we’re better with a external entity putting the brakes on.
It’s a tough business. I’m uncomfortable with the “fuck it give me the newest whatever” attitude that you find in online forums. I’m an IT exec, my wife was a finance professional in healthcare. It was difficult for us to navigate the decisions and risks. Most people are not well equipped to make risk decisions, and dumping experimental consent and other decisions on people facing death with adequate support is a really vicious thing to do.
One thing that Molly felt deeply was that the hope she was able to have about beating the cancer was built on the shoulders of those before her. And folks even 10-15 years ago had no hope at all. We have a duty to honor the sacrifice made and be cognizant of what is real and what is not.
Thanks for sharing, and I'm really sorry for your loss.
Yours is a really balanced take on why maybe it's not so good to have a "wild west" approach to this.
I've gone to two funerals in the past month for friends who lost battles to cancer. I can only hope we're getting closer to radically better treatments.
The most difficult thing is accepting that you cannot control the universe and you can only make the decisions that you can make at the time. With what we do professionally, sometimes we think we have power that we don’t.
My wife was blessed with being treated by an incredible team of doctors at one of the finest cancer centers in the world. They expected full recovery and were shocked when things took a turn. These things are really complex. With advances in scientific computing, genetic analysis is getting faster and better and treatments are improving.
Thats a double edged sword. “OK” in the world of a cancer patient is a relative concept. My experience with the sadness and struggle is that I will remember that these decisions are difficult, and hope is a concept can be both liberating and cruel.
IIRC former NCI head, Vince de Vita, mentions that early oncology research was pretty much right-to-try by default because they had no data on anything. And it made some people live longer because they could change strategy after the first one failed. Nowadays you have a standard care and if it fails the system will almost drop you out..
Maybe now, but it hasn't always been so. Attitudes change. If you're lucky enough to chat with someone in their 90s about dying, you may hear stories of how doctors used to "help people on their way". In other words, casual euthanasia was quietly accepted and expected.
Not quite what GP is describing, but it illustrates the point.
My mother, long since passed, was a registered nurse (and also carrying far more empathy than most human). She explained morphine pushes and “slow codes” (taking your time so people who wanted to die could) to me in my teens (early to mid 90s). Good terms of art to know when end of life creeps up on you.
There are potential trade-offs where experimental treatments which fail preclude other experimental treatments that work. Ethically this is a minefield. Personally I agree that if I have a disease I'd want to take any experimental treatment that seemed like a good idea.
I think people's action during the pandemic are a bit more responsible for additional deaths than were FDA delays.
: Rapid tests are actually quite sensitive during days ~2-4 of illness when patients are most infectious.
Was this known beforehand, or only discovered post-hoc?
From your blog:
> Regarding drugs, particularly drugs for people who are already effectively dead, like me, we should be moving closer to a surgical model.
This seems like a good idea. Though there have been some really bad surgical interventions (lobotomy, sex assignment surgery for intersex conditions or botched circumcisions).
I am sorry about your situation, but existing so many companies and startups scamming and trying to scam people I don't feel it's slow and paternalistic (here in EU is even "slower" than in USA)
Perhaps scammers should stop using health for their "getting rich fast" plots so this rules could be relaxed, but that is asking pathological narcisists to think about others which is not going to happen anytime soon :(
First, do no harm. This is a foundational tenant that permeates healthcare. As a former health system executive I have been in positition to influence decision making about high risk experimental treatments in certain cases. In the US currently, in most states, you as a patient have a more or less unlimited right to try experimental treatments if you are facing a reasonable likelihood of death otherwise. The FDA plays a very limited role in one-off situations though they are frequently made to play the villain. The reality is that there are legal avenues available much of the time that providers and companies are loathe to employ. Much of the time drug companies and doctors have lots of reasons not to want to roll the dice if they think the odds of success are low enough. The risk/reward is a very different outlook for the patient than the providers and companies that may need to be a party to the treatment. There are reprecussions to all patient deaths as a result of an experimental treatment however well intended and consented.
A complicating factor that weighs over everything is that there is a long history of terrible abuse of informed consent with less privileged patients, puerto rico is a trainwreck of abuse going back a century but there are many more. As an administrator I always felt that patients who are freely giving informed consent always have the right to try, however slim the chance of success. But, it can be brutally difficult to parse out those instances where influence, coercion or even misrepresentation are at play with a particular patient and family. Family dynamics of course can play a large role too.
Yeah, I agree with this. Ultimately the danger is that right to try essentially leads patients to deny proven methods of treatment due to coercion or being misled. If a patient refuses the usual cancer treatment and demands instead a regime of herbs and folk medicine, how do you handle that? Especially when the family then turns around and blames you.
In this scenario where you have an expert in their field knowing that the outcome for the experimental treatment could make things far worse but is willing to contribute the data to further the field anyways I think the answer is far easier to parse.
Someone close to me has ALS and their only options seem to be in Mexico and China, not anywhere in the US.
From their research, it definitely seems like the FDA is the big bad not only in preventing treatments as a default, but also by disincentivizing companies from allowing dying people to trial unapproved treatments if their condition is far gone enough that there is a low chance of success. My understanding is that this is partially because people who take treatments and die (even if they were going to die no matter what, and did not die from the treatment itself) are used by the FDA against the biotech companies when seeking approval.
I am sorry. That is a terrible disease. To my knowledge John Hopkins currently has the most promising trials for ALS but generally speaking there is not currently a full understanding of the underlying mechanisms of that disease and little, even in the most experimental ends of the pipeline, for it. I am not aware of anything that has even the slightest promise of effectiveness that would be available in mexico or china that would not be available in the US if they met eligibility criteria for currently open trials. The ACT for ALS passed in 2021, amongst other things, specifically opens what paths are available to patients with ALS and in certain circumstances offers grants.
I am sorry for your relative, but you should be aware that in ALS (and probably other diseases) a major patient organization has a financial interest in some drugs to succeed and they do not hesitate to put a lot of pressure on social media onto the FDA. As far as I know, with the same data, this drug was not authorized in the EU.
Also in ALS, there were major manipulations on social media by companies that claimed their drug was able to cure people, and to prove it they showed on social media well-known patients going to the gym and others doing motocross!
Yet these drugs never shown any benefits in phase III clinical trials...
The point that some people miss here is that it doesn't matter. If you are going to die from ALS in 2 years, are you going to feel satisfied when the FDA says "we won't let you try this; it probably won't cure you"?
Even if the FDA is this incredibly competent organization with no corruption, people should have a right to try to live. It's the most dystopian form of the nanny state mentality, IMO.
Who is going to pay for the treatments without supporting data? I don't think people have the right to demand healthcare workers to administer whatever strikes their fancy either. I know you aren't necessarily suggesting this, but I wouldn't start an IV bleach drip on someone because they have a "right to live". Time is so limited in the clinic that I don't think there is room for trying whatever the patient wants on demand. In an ideal world there should be some room for this approach, but (at least in the US hospitals I've worked at) there just isn't the infrastructure. Something with phase 2 data, sure, that seems like a good candidate for compassionate use.
ALS is devastating, I'm sorry for you and the person you are close to.
You could probably answer all of your own questions pretty easily and recognize that I'm not talking about a bleach injection.
Maybe your gripes make more sense in a socialized medicine country. Sure, they have to sacrifice people at the edges. But in the US, there's no excuse. It's like the worst of both private and public medicine.
In terms of benefitting the collective, allowing experimentation on willing subjects with terminal illnesses could really improve medicine, too. It's really just a lose-lose-lose with the current approach. Well, some people win, who manufacture the types of drugs that don't fully cure you but keep you dependent on the prescription until you die. If you don't think that's a factor in the FDA's decisions I have a bridge to sell you.
> under the care of Prof Long and a team of experts, Prof Scolyer became the first brain cancer patient to ever have combination, pre-surgery immunotherapy
Great, although it's sad that you seemingly have to be a doctor to convince another doctor to try things like this.
Now let's extend this concept to giving immunotherapy before chemotherapy, since chemotherapy wipes your immune system. It doesn't make sense to do chemo before immunotherapy when you want the immune system to attack the cancer. On the other hand, if the immune system goes on a rampage against healthy cells, then chemo could be used to wipe it again, while also stopping cancer growth.
I read articles like these, where the treatment is at least somewhat successful, and I wonder how many instances there are where they tried an experimental treatment but the patient died anyway.
My step father was diagnosed with metastasized melanoma in 2019, and was completely cured by treatments developed by professors Scolyer and Long.
He needed surgery to remove small tumors on his lungs, but the drugs made his melanoma just disappear.
He was very lucky. Not only because he was offered to take part in a trial, but also because only a small number of patients had complete success stories like his.
The link below is to a very similar case from the same trial:
It's standard protocol to take part in cancer trials after cancer stops responding to all approved treatments. Of course this article is different from organized trials.
One problem with GBM is how fast it progresses. I was my dad's caretaker when he had it, and the amount of waiting and paperwork required for most of the programs we looked at were beyond what his life expectancy was. Those that might have been possible were shut down - it was during the peak of covid. The exhaustion from the daily visits to the cancer center for radiation treatment required full head to toe PPE for both of us. Cancer itself is exhausting, but the paperwork and phone calls and pharmacies - it's too much.
I'm grateful for the work of the doctors in the article, and very hopeful that the treatment works. A close friend of mine was on a trial vaccine for his cancer, which looked promising for a while, but suddenly stopped working - the cancer was ultimately fatal.
I think trials should be offered as potential first steps, especially for aggressive cancers. Patients know the risks. They're either 100% going to die within 6 months to cancer, or, worst case, die trying to fight it, or best case, be cured.
> I think trials should be offered as potential first steps
We need really good science and statistics, far superior to p-values, to allow this potentially life saving treatment without the inevitable deaths from people at the limits returning a "not significant" finding for something that actually works.
Maybe something like allowing people who are too far gone to qualify for treatment as part of a study to instead qualify for the experimental treatment with their results only being included as a special "humanitarian" cohort.
I'd also like studies to be able to compare a treatment group against prior control groups, so that everyone today can get the experimental treatment instead of some of them being given a placebo (if there's a lack of another decent treatment to use as a control). If there's nothing effective that can be done as a control, every one should get the treatment.
The rational side of me totally agrees with everything you've said.
But the part of me that witnessed glioblastoma - I think when someone is facing that, it should be a VIP pass straight to the "whatever has even a remote chance of actually working" lobby. Which is basically what the article describes, so I'm optimistic for the doctor and his team.
Of course, not everyone is as risk tolerant as I am. My dad wanted to believe he'd be one of the rare "survivors" (I don't think it happens) using traditional radiation and chemo, and was still weighing pros and cons of other potential treatments. But I have the benefit of hindsight, and a lot more education now, and I think it's unethical to not immediately consider trial programs. The most common way to treat glioblastoma today (targeted radiation and chemo) one that only promises to give you more months of life, not years, is also the only treatment option covered by Medicare, the health insurance provider for most retirees in the United States. The uber-aggressive glioblastoma that my dad developed is what most people over retirement age get when they develop glioblastoma as well. Average lifespan from diagnosis to death: 6 months. That's if you surgically remove the tumors, a procedure not without its own risks. Risks that are usually worth it, since without surgically removing the tumors, lifespan drops to weeks.
What I'm saying is there's no path to trial programs for most of the people who'd benefit from those trials the most. It's not even on the map for them.
Trials aren't really designed to be care-giving mechanisms. It's not a goal to be easy to get into. They just need to fill the trials with eligible patients and that's it, obviously very unfortunately for a lot of folks.
> Trials aren't really designed to be care-giving mechanisms.
Sure, but they could be. Easy enough to gain profit from those who get the disease at a later date. If a current standard of care treatment is used as a control for say, half of the cohort, there could be some way to charge every participant's insurance for half the cost of the standard of care (with the other half getting the experimental treatment on a blinded basis).
1) A trial patient costs far, far, far more than the cost of caring for a patient
2) Trials are already obscenely (and increasingly) difficult to design and execute even for pure scientific ends. It’s really not trivial to add other objectives like this, even if money were totally irrelevant.
2) And thus the humanitarian part of the trial can serve dual purpose as a training exercise for the additional physicians working with the humanitarian cohort.
What kind of extra complexity other than just manufacturing more treatments? A lot of any extra complexity should be handled by the additional patient's medical providers anyway.
Depending on the rarity of the illness, this may be something that the government can easily force pharma companies to accept. They accept far more in regulatory burden and still do business.
Do you think standard of care already includes collecting the vast amount of data required to understand a treatment's effects? Medical providers aren't trained to execute clinical trials. They can do bits and pieces, but they still need extremely strong, close oversight from an actual researcher. Someone ultimately has to hold liability for trial participants too, and no one is going to take on the liability of an untrained care provider to administer a trial to a patient.
Additionally, the pharma company wouldn't allow this because in addition to the upfront design complexity, it would put the trial itself at risk. You're not really allowed to say, "just try it in a bunch of people, it's okay if untrained folks mess it up because if they do we can just throw out the data."
What did you address? It sounds like you're just saying to give the drug away for free to another cohort of people who will be producing totally useless and incomparable data.
Not opposed to that, but it's not a study cohort. It's just "give investigational drug away for free."
> You're not really allowed to say, "just try it in a bunch of people, it's okay if untrained folks mess it up because if they do we can just throw out the data."
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> It's just "give investigational drug away for free."
And here insurance regulation can also come in to play along with the pharma regulation.
Sure, none of this would be easy. But the status quo has issues too.
I don't know how Aus works, but, in the U.S., we need a much more serious right-to-try regime, particularly for fatal diseases like GBM. The FDA is way too slow and paternalistic, a topic that I've been writing about: https://jakeseliger.com/2024/01/29/the-dead-and-dying-at-the... and https://jakeseliger.com/2023/07/22/i-am-dying-of-squamous-ce... because I'm dying from a squamous cell carcinoma infestation that, it turns out, should be much more treatable than it has been so far.
For example, MCLA-158 / petosemtamab should, based on existing phase 1a and 1b data, be approved: https://beta.clinicaltrials.gov/study/NCT03526835. But, from what I understand, the FDA is going to make Merus proceed with phase 3 trials, despite the incredibly positive phase 1b and 2 data. Madness.
The FDA killed during the pandemic: https://moreisdifferent.blog/p/fda-devastation-during-the-pa... and continues to kill today.
And they worried the experiment could kill him faster.
It's a reasonable trade-off to decide to take the risk.
Immunotherapy drugs are quite toxic, especially when mixed, so he could be poisoned
I wonder which the author is talking about, because e.g. pembrolizumab (Keytruda) is not. I assume the author isn't talking about e.g. CAR-T therapies?
If you're in the US and know someone with GBM, look into DCVax: https://www.uclahealth.org/departments/neurosurgery/phase-ii....