Lung cancer pill cuts risk of death by half
theguardian.com
theguardian.com
This is a drug that targets lung cancer (~12% of cancers) and only one type of lung cancer (non-small cell lung cancer, ~80% of cases). It targets a particular mutated gene that occurs in about 30% of that subtype. And then, about 50% of those patients respond.
So do that math, and you end up seeing that treating one of the most common mutations in one of the most common cancers with what is considered very high efficacy still only helps with about 1.4% of all cancers. This is actually an enormous number for this kind of treatment, and there is a long tail of rare cancers that are going to be much harder to find targeted therapies for.
That all said, this currently appears to be an enormous success story, and the kind of treatment options that have been enabled by genomic sequencing of cancers, followed by many years of drug development and clinical trials. It's fantasically exciting to see us continue to chip away at the problem but by bit and grant people longer lives as a result!
Signed, a guy who spent most of his PhD studying cancer.
Simultaneously, one of the largest criticisms of osimertinib in resectable NSCLC has been that some oncologists got overexcited about the DFS results and patients have been unfortunately not receiving the traditional standard of care adjuvant therapy (old school platinum based drugs) which have a proven overall survival benefit (until today osimertinib did not, it now possibly does).
Targeted gene-directed therapy is cool but conventional chemotherapy is still really important.
ICIs are magic when they work.
And thanks for trying to question my expertise. Please look up the no true Scotsman fallacy and see if that may apply here.
They share the same DNA in the sense that every cell in that body does. But the different types of cancers have different mutations per cell type and the increasingly precise identification of those is the basis of the recent new treatment options. Histological classifications become less and less relevant, instead mutations and subtypes of mutations give directions for treatment paths. So I think that statement is a bit confusing.
What do you mean by "histological classification" because every interpretation I can think of is very incorrect.
If you mean diagnosing the type of cancer (e.g. clear cell renal cell carcinoma) we've already been using molecular markers for over a decade now.
Since you mention "describing the look": mitotic rate and local staging (depth of invasion, lymphovascular invasion, perineurial invasion) matter far more than any DNA/type of cancer and this isn't changing at all nor will it ever change.
Do you mean this literally or figuratively? Isn't one of the serious problems with tumors that the mutation rate inside them goes through the roof? (And then they eventually figure out how to be metastatic?)
The headline here is really strong -- and the actual abstract is much more sober: "5-year OS rate was 88% with osimertinib vs 78% with placebo" [Full abstract is here: https://meetings.asco.org/abstracts-presentations/219805 ]
P.S. Hi Chris! (I think I picked up a summer student from you last week!)
Interested to see their detailed results but I’m mildly suspicious this will be AstraZeneca PR buffing underwhelming results.
Think about that... If the committee whose job is approving this medicine get results in on Friday, but don't sit down to approve it till the following Monday, then 4098 people die unnecessarily.
As soon as we have compelling data some discovery (medical or otherwise) might help lots of people, it should be almost a manhattan project type effort to get it into the hands of everyone worldwide asap.
For example 780,000 people died of polio between 1988 and today. Yet for all that time there has been a cheap, low risk, well tested, near 100% effective vaccine (many in fact). And polio is probably one of the better cases because governments and charities have been pushing it pretty hard.
Edit: Also, polio eradication efforts where a Manhattan project style heroic effort.
The system is actually really fast at getting promising cancer therapies into the hands of patients, especially when there aren't good alternatives.
Even if something isn't yet approved and the patient is ineligible for a clinical trial, an intervention can be offered to patients under compassionate grounds/special access.
regulations that are too loose may cause suffering and death while regulations that are too strict will delay or block prevent helpful treatments.
regulating healthcare is extremely difficult and largely a thankless job.
one solution is to approach national healthcare like national security and let people volunteer for treatments like volunteering for the army.
in short, overstate risks but let patients decide.
adopt cigarette-simple consent forms that state in bold words that an experimental treatment is likely to cause death or crippling side-effects like paralysis, blindness, stroke, Alzheimer's, or worse.
perhaps require multiple signatories from family members to guard against irrational behavior.
this protects the FDA while minimizing barriers to innovative therapies and treatments.
Then you have to battle the people selling highly marked up snake oil as an 'experimental' treatment - when every expert could tell you this treatment is already well known to be ineffective.
Isn't that easily solved by requiring all experimental drugs and procedures to be provided free of charge with the cost footed solely by the provider?
on the one hand, you may throttle promising treatments and on the other hand, you may increase useless treatments.
publishing results is one way to mitigate snake oil, though this obviously doesn't eliminate the problem.
the general framework is to maximize transparency and freedom.
letting people volunteer for national healthcare like they can for the national army increases freedom, but we must also increase transparency to combat snake oil.
This actually seems large to me.
Although that is suspiciously large. Looking at the numbers I think it should be much lower. A 51% reduction doesn't mean it helps 51% if the people. In this case it looks like about 10% of the people are effected given the 88% vs 78% survival rates, right? Maybe something like .28% of all cancer?
This looks as enough close to personalized therapy for me. There are prediction tools available online.
https://nextgen-tools.iedb.org
I even coded my own peptide prediction tool a few years ago:
https://padiracinnovation.org/News/static/design-your-own-pe...
Unfortunately stage 4 cannot be cured, and at some point tagrisso stops working. My understanding is the cancer mutates and eventually develops resistance. Then she will go on chemo and her quality of life will go down.
I am thankful for modern medicine that we get some extra time with her.
There are also radioligand therapies like lutetium 177 but they haven't been sequenced on chemo naive patients yet. So soc is chemo first.
I don’t think this is published yet and I’m not familiar with prostate ca treatment literature so take this with a grain of salt.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627907/
https://clinicaltrials.gov/ct2/show/NCT04647526 this one was supposed to publish some preliminary results in q1 2023 but i don't see any updates :/
Non-inferiority studies aren't sufficiently powered to answer the question but up-front Docetaxel is pretty old-school. My urology days are long behind me now but even in my residency abiraterone/enzalutamide had taken over as in:
> https://clinicaltrials.gov/ct2/show/NCT04647526 this one was supposed to publish some preliminary results in q1 2023 but i don't see any updates :/
This is the trial I was referring to, I don't think they're done with the analysis/writing yet.
I have no numbers or data hence my casualness but our nucs physician was really excited 5 years ago and lukewarm when I recently asked him if they were finally taking over mCRPC care over a beer.
Again grain of salt, but my impression from that convo was it's going to end up another line of therapy (mCRPC treatment is a game of kicking the can down the road as long as possible).
Why would we give higher dose of the cure at start ? Wouldn’t the body handle it ?
Eventually it will metastasize so some other part of the body and THAT will give symptoms.
When my Mum was diagnosed the Dr. said the bad news is you have cancer in the bones in your neck. The really bad news is that it started in your lungs, and it's way, way to far along to do anything about.
Cancer sucks.
We also have great non-invasive curative treatment options like stereotactic radiation.
It's fairly rare though, the quoted numbers from SEER are 14% but from a clinical perspective most of us that deal with lung cancer feel that's discordant with our practices and likely an overestimate.
In either case, smoker or non-smoker you're far more likely to develop NSCLC with adenocarcinoma being more common than squamous cell (typically only in smokers for the latter but still less common than adenocarcinoma).
The typical adenocarcinoma most people get has a doubling time of roughly 1-2 years.
I double checked, only 2.5% of SCLC incidences is from non-smokers.
Died on less than 2 months after that. It sucks.
My Mum was told that people with her diagnosis survive on average one year. She fought hard through radiation and years of chemo, and made it just less than three years after the diagnosis. Through most of it she was waking me up at 6am to go for a sunrise walk on the beach. I hope I can be that strong one day.
https://www.cdc.gov/cancer/lung/basic_info/screening.htm
https://www.uspreventiveservicestaskforce.org/uspstf/recomme...
Do you smoke? quit smoking. Do you live in areas with lots of air polution? High levels of radon where you live? Move.
Do you work with a bunch of carcinogenic chemicals? Find something else to do.
You can also get a gene test do see if you're suspectable to certain cancers.
But most importantly: listen to your body. If you feel that something is wrong, take it up with your doctor.
I’ve been told brake (or tire) dust is the newest suspect for why young never-smokers are developing lung cancer (combined with certain relatively prevalent mutations).
Outside of that, it’s a crap shoot. My mom in law didn’t have either risk factor. PET scans can pick up but each one exposes you to radiation which can also cause cancer. So they generally don’t screen for low risk patients.
Osimertinib did $5.44B in global sales last year, leading AstraZeneca’s oncology portfolio [0]
[0] https://www.astrazeneca.com/content/dam/az/PDF/2022/fy/Full-...
"After five years, 88% of patients who took the daily pill after the removal of their tumour were still alive, compared with 78% of patients treated with a placebo. Overall, there was a 51% lower risk of death for those who received osimertinib compared with those who received placebo."
So 88% instead of 78% without the pill were still alive five years on. I assume that is the maximum range they could test. How was the 51% then calculated?
Edit: thank you all for the explanation. That makes a lot of sense!
The true value could easily be 51% if the percentages reported in the Guardian were rounded.
So, for 100 untreeated patients 22 would die. Now for these 100 placebo patients, if they took the pill, they would die 12 (another assumption that the two populations are the same).
The reduction is (22-12) / 22 = 10/22 is the risk of death if untreated.
The complementary percentage is
12/22 approx 51%.
However this does not come with confidence intervals.
I actually think the other explanations are wrong. They are probably reporting the Hazard Ratio, which is more often used as primary outcome for efficacy of drug than 5 year survival. (See for example: https://en.wikipedia.org/wiki/Hazard_ratio)
The hazard ratio, under some assumptions, tries to estimate the relative risk of dying per unit of time. The benefit of this measure is that there is not some artificial cutoff (the difference between a death at 4 years and 364 days and 5 years and 1 day is neglible).
How big a check would a government have to do to just "buy" the rights to a drug ? (Both in the "legal" and in the "an offer the CEO can't refuse" version ?)
the government programs carry a lot of weight as a large client but are currently barred from negotiating on prices
part of some US universal healthcare proposals are to just allow existing government programs to negotiate on prices, while simultaneously extending coverage to more people
The price in the US seems to be around double in the US. But maybe that just pharma companies do PPP adjusted pricing? e.g. it seems to cost ~1500 in India for instance. Americans are simply much richer and also significantly more on healthcare than people in other countries.
That seems like a monthly price? The treatment regimen in this study is daily for 3 years.
It's hard to find out what drug prices really cost as there are a lot of discounts and negotiations behind the scenes but the best source in this instance would be a cost-effectiveness study which uses local data and happens to be a hot-topic in every national cancer society so is widely available.
EU and US pricing isn't too far off with both being ~130k USD a year give or take.
> it seems to cost ~1500 in India for instance.
There were generics, and there probably still are in parts of the world but they're technically "illegal". AstraZeneca shut down a few and there are pending countersuits against them.
https://www.fiercepharma.com/pharma/astrazeneca-staves-last-...
(1) https://www.cdc.gov/cancer/lung/basic_info/risk_factors.htm#....
'When the person stops using tobacco, nicotine levels in the brain drop. This change triggers processes that contribute to the cycle of cravings and urges that maintains addiction. Long-term changes in the brain caused by continued nicotine exposure result in nicotine dependence, and attempts to stop cause withdrawal symptoms that are relieved with renewed tobacco use.'
https://www.camh.ca/en/health-info/mental-illness-and-addict...
The DFS numbers are not new and known, the reason this is in the news as it’s the first report of OS numbers from the initial ADAURA trial.
I can’t be definitive without seeing the data yet but:
1. Osimertinib is not that new, in the context of curative intent disease (i.e. resectable stage II-IIIA) it is currently (ideally) used post adjuvant chemotherapy (the only treatment to date with an overall survival benefit).
We need clarification on what the placebo arm is and what the subgroup analysis showed. What it should be (and presumably) is an “active surveillance protocol” where patients underwent short course adjuvant platinum based therapy and then followed with imaging. Recurrences are then treated with systemic or locoregional therapy.
As this is an update of the ADAURA trial we know that only 40% of patients received the standard of care platinum adjuvant therapy, this article claims an OS benefit was seen in all groups but we don’t have the numbers for the subset of patients who received appropriate adjuvant treatment.
2. Main criticism of the ADAURA trial thus far has been that the results only report “disease free survival”, while that intuitively makes sense as a metric what we really care about is “overall survival”. There are several reasons but to keep it simple this is now the third generation tyrosine kinase inhibitor, the first 2 also had DFS improvements (albeit not as dramatic) but failed to show OS benefits.
3. Osimertinib is expensive. Following the ADAURA protocol (3 years of adjuvant therapy) would have an incremental cost (ICER) somewhere around ~$3-450,000 per patient. “Willingness to pay” is variable, in most places it’s $50,000/quality adjusted life year. Some in the US are pushing for this to be ~$190,000/QALY (3x GDP).
Based on extrapolated DFS and earlier OS data in the last year it was estimated that the OS would be around 5-6%, based on this threshold a system would need a willingness to pay of ~$320,000/QALY. Conversely, to meet the GDP threshold above OS would need to be ~20%.
In a recent Canadian economic analysis they modelled 6% OS at 10 years and arrived at a ICER of ~$40,000 suggesting this protocol makes economic sense. To my knowledge this is the first report suggesting cost effectiveness and contradicted the Health Canada modelling.
4. Based on this news article, there was an absolute reduction in OS of 10% at 5 years which seems underwhelming given that we know most of the patients did not receive adjuvant platinum based chemotherapy, the OS in the subgroup that received both treatments is what matters here.
From the US analysis, this would still not meet the willingness to pay threshold. The Canadian one would need to be re-run with 5 year numbers to see what the ICER is.
Overall, it’s potentially a very positive result but at face value the OS numbers seem less impressive than anticipated.
If someone has the $ and an EGFR ex19 mutation there is definitely benefit but it remains unclear whether this is cost-effective for a system vs other treatment options we have.
(N.B. These numbers are approximate from my recollection of the literature but I can dig up references if something seems off. For background I’m a radiologist focused on oncologic imaging, this has been a hot topic in rounds/case conferences for a few years now hence my familiarity.)
AstraZeneca’s patent expires in 2035 and as a cash cow ($2B in revenue) I would expect they continue to aggressively fight competitors in court.
Imatinib (the 1st gen drug of the same class) went generic a few years ago and is 99% cheaper now.
I assume we’ll see something similar with osimertinib but I can’t comment on whether there’s any secret sauce that makes it different.
Perhaps one of the pharma/biochem HN commenters can offer more insight.
> After five years, 88% of patients who took the daily pill after the removal of their tumour were still alive, compared with 78% of patients treated with a placebo.
...which is still remarkable, but doesn't sound quite as good as "cutting by half".
45% reduction in 5-year mortality. Quite close to “cutting by half”
I’d read some research about this a couple years ago and didn’t remember seeing anything about effects on the cardiovascular system but that does seem like a possibility
My chance of living 5 years goes from 78% to 88% by taking an expensive pill everyday with side effects? That's not an amazing thing. If it was 78% to 95% with one or two pills, or a positive healthy lifestyle change, then that's something.
I'm going to push back and say this is garbage. The fact that this is being billed as "thrilling" and "incredibly positive" makes me want to puke. This is par for the course in the cancer industry.
I'm going to call this what it is: an advertisement for two crappy new lines of business. First, we have a new genetic testing business: "Not everyone diagnosed with lung cancer is tested for the EGFR mutation, which needs to change, Herbst said, given the study’s findings." Cha-ching!
Then, we have the actual new business of the pill. What are they going to charge, $50,000 a year?
Imagine if you could choose 2 options:
1. Take a pill everyday. Have side effects. Pay $250,000 2. Don't take a pill. No side effects. Keep the $250,000
If that was the choice I'd bet people in group #2 live longer.
This isn't science or medicine, this is advertising.
Pardon my bluntness, but sometimes anger is necessary to get people to wake up.
Reducing the likelihood of death by a half is still something... Of course yeah, the price is pretty insane but besides that it's still a great achievement and a significant step in the right direction.
However, I'm usually not wrong about these things. This pattern is so common in big pharma it's an easy bet right now.
Based upon the limited information released I would bet:
1) it has high odds of being very lucrative for a small number of people
2) it will be a net negative for patients^
^ Patients would be better off with more money and using an alternative treatment strategy. This drug is priced at $12,750 per month, according to Wikipedia.
You really need not be apologetic, being too 'open' to repeated nonsense from the same entities (big pharma in this case) is not a good thing either.
You're still a bit too cynical but there are some nuggets of truth in what you're saying.
With regards to mutation testing: I'm not sure where this Hopkins guy is getting his data from but mutation testing for lung cancer is already standard of care, it's been part of the NCCN guidelines for > 5 years at least.
EGFR is not the only driver mutation and osimertinib is not the only drug that can be used, even for EGFR.
Molecular marker and genetic testing of cancer is unequivocally to the benefit of patients and is not a BigPharma scam, it also has little to do with this specific drug other than that this is one of many gene-directed cancer therapies.
> 2) it will be a net negative for patients^ > ^ Patients would be better off with more money and using an alternative treatment strategy. This drug is priced at $12,750 per month, according to Wikipedia.
Be careful with generalizations like this. This drug is very signficant, you just have to select patients appropriately.
There is no doubt osimertinib works well, if you have unresectable/non-curable lung cancer it can potentially buy the patient an extra couple of years (median ~8 months) over previous generation TKIs and even longer versus conventional chemo. These patients used to just die within a few months 5-10 years ago.
This article, and the trial it talks about, is about adjuvant therapy (i.e. after the surgery) in patients with locally-advanced but curative intent disease that at baseline have pretty good good survival so in this specific use-case your criticism of cost-effectiveness is a reasonable one.
Consider a 45 year old with an EGFR mutation and stage IV lung cancer (unfortunately common these days), an extra 8 months-3 years is immensely significant for them and their families and this is a miracle drug.
On the other side of the spectrum, for a 75 y/o with stage II cancer who underwent curative-intent treatment (i.e. this study population), the argument is much weaker given the costs vs low absolute risk reduction over a long time period. I broke down the financials in another comment.
You're probably right that the numbers won't add up in this trial for this specific patient population, the article + PR releases so far do smell a bit like AstraZeneca buffing somewhat underwhelming results (expectation was that overall survival would look better than 10%) to sell more of an expensive drug, but you're overgeneralizing and it is a very good treatment option in well selected patients. It will also be a great adjuvant treatment option whenever this becomes cheaper like 1st-gen TKIs are now.