"To date, no prospective trials have directly compared ibrutinib with venetoclax as NA1 in R/R CLL. It remains a key unanswered question as to which of these two NAs optimises the balance of safety and efficacy when utilized as the NA1 in R/R CLL.
To address this, we report a large, international study to establish the efficacy of ibrutinib and venetoclax ± anti-CD20 as NA1 in R/R CLL. To our knowledge, this is the largest series comparing these two approaches as NA1."
"In conclusion, venetoclax and ibrutinib-based therapy as NA1 provide comparable OS outcomes in R/R CLL patients treated outside of trials. Our data suggest a significant PFS advantage for venetoclax-treated patients as NA1, a finding that requires independent validation and reassessment for patients treated at first relapse outside of clinical trials. The selection of either as the NA1 should therefore be based on individual patient factors, drug access, deliverability and patient preference. "
* "Finally, the patient numbers in the venetoclax are small compared to ibrutinib and we acknowledge analyses may be underpowered to detect differences if they exist."
I can tell you now the trial you mention never will happen. Or rather not a simple randomised one. There are some combo trials going ahead such as flair that will give us some ideas. But who is going to fund a huge head to head proper study?
This paper linked in the article has the right idea. It is retrospective and not large enough though. .
And the data in the paper even though small is very encouraging for venetoclax, also now things are a bit more mature with ibrutinib use (for which it has a reasonably large dataset) it seems like discontinuation rates have gone down. Some may remember in early non trial use discontinuation rates were a lot higher than this
Ideally what we need is a huge blood cancer prospective registry. It could be run by a patient group and be patient led with doctor input or be doctor led with patient input. Typically these registers are one or the other unfortunately but it would be theoretically possible to do both.
The idea is this members of a forum site like this would be invited to join a registry. This would have the following goals
1. To prospectively collect data about watch and wait both initially and between treatments and look for more evidence about what predicts progression ( but this would also include incidence of symptoms, infections, quality of life, ability to work, and death rates when untreated
2. To prospectively collect data about treatment response progression and Overall survival for patients who are treated in our outside trials (note that as combinations and sequences become more and more complex outside of trials some form of systematic data is required. (This would include reasons for treatment and might help to confirm whether in the new landscape earlier treatment or retreatment is indicated than per current guidelines)
3. To match patients against clinical trials. Eg if a sponsor wanted to recruit patients who have been on ibrutinib for over a year, to see if their new drug added could send the person to MRDU the database owner (who wouldn’t be an individual company) could send a message to everyone in the database that matched the precise criteria.
This data would be invaluable and the same framework could be used for all blood cancers perhaps with some adjustments where relevant.
To make it work you would need to ensure proper consent and ethics were in place. And in addition it would be wise to attempt to get a doctors perspective too captured.
If the database used surveys for things like fatigue level etc you could also have it print out a report to take with you to your consultation or even email ahead so the doc knows just how bad the fatigue is compared to last year etc etc and how many infections you’ve had this would allow for more efficient use of the time in the consultation to elaborate specific questions the doc or patient had, we could even document fatigue in part by things like step count for those who track it.
The data base could be lead by the patient groups but have doctor input where that is possible. Clearly there’d also need to be a way to ensure that deaths were reliably tracked which would require a friend or next of kin for every member on the database having consent to inform of this. And /or docs being involved.
We’d also need to commit to a six monthly update or something like that wirh a simple electronic questionnaire. And if people stopped responding to that we couldn’t assume they were dead but they’d just count as lost to follow up unless death could be confirmed.
I have seen this kind of registry work wonders in other disease areas and really shape the treatment of a rare disease. Think of it as a souped up version of that questionnaire being run for various nice like bodied. But it would generate tons of data like the lines of this paper you mentioned.
But we could also look at things like do patients who get vaccinated against pneumonia benefit by a reduced death rate? We might need thousands to show that. But you can certainly look for correlations and such like. It’s a form of big data.
It’s Tragic that companies like amazon can figure out whether if you buy toy cars it makes you more likely to watch the Grand Tour but we are not even scratching the surface of what is possible with heath data.
In an ideal world it would be even more sophisticated and draw in data from nhs symptoms about Hosptal admissions but to be honest that data is not great easy or cheap to get.
This all might sound like pie in the sky. But imagine if a consortium of patient charity groups was formed to cost up the creation of the database and small fees to remunerate doctors for their time in filling in the electronic forms. Then that group would approach a consortium of pharma companies to invest in it. The current companies have shown themselves willing to pay togeher a bit by more than one company giving free drug to the same trial eg flair.
A lot of companies are keen on big data and natural history data. As are NICE and other such bodies. We’d have immense clout if the data was so much more robust. Eg being able to model clearly how many lives a new treatment would save.
Increasingly it’s recognised that if you design a clinical trial well and design a registry well you often get similar results. It’s a great way to confirm if the results in the real world mirror the studies. And it’s also a great way to quantify the frequency of side effects and complex things like clonal evolution.
I know this seems a huge grandiose idea but it really is something that would be possible to do And would lead to huge benefits.
If for example even a tenth of all our members signed up for this it would probably be the largest set of prospective CLL data in the world.
If most of them did well then we’d really be talking.
I should note also that such a registry could also include retrospective data on patients at the point they signed up it’s just not going to be as compelling as the forward looking data.
You are absolutely correct. Unfortunately, the last time I checked, there was not even a registry of all the clinical trials. In some cases unfavorable results have been buried and favorable ones published. A commplete registry of trials plus the kind of real-world registry you suggest would yield remarkable knowledge comparing the options doctors suggest to their patients.
Clinical trials dot gov is a registry of all the drug trials and certainly pharma companies are required to publish details of all their trials there as they are going on, getting an NCT number and ethics approval, and without that the journals won’t publish the data. So I think the times of clinical
Trials happening in secret are gone tho it’s perhaps possible a few academic trials get missed tho again without that number and ethics the wont be published.
Clinical trials dot gov also had a results section and you are legally required to publish the results there at least within a certain. Time of the study ending. Note that journals often won’t take “negative” trials so it’s true that if you only look at publications some trials won’t be there or might be delayed.
In the past pharma companies weren’t required to declare all trial results to the FDA and so could do say six trials and on out submit the two that were positive! These days that’s not the case. By the way often we are a bit naive about so called failed trials ae we sometimes thing that means we have shown the drug failed which it doesn’t. we should make more use of meta analysts which allows us to look at the results of several trials togeher and we might find that the trends were all in the same direction so if pooled the negative trials become positive.
Famously there were lots of small clot busting trials done over decades and if we had done a meta analysis after each was published we would have realised that saved lives sooner than we eventually did for heart attacks.
You also have to remember that pharma companies save money by killing unhelpful drugs quickly so if a failed study happens or odd side effects you will often find it kills a drug and perhaps we lose drugs which are helpful.
Some of you might be aware that recently venetcolax was put on hold in a different cancer because a study seemed to suggest it might be causing more harm than good in that indication. Sadly if that had happened before the very positive CLL studies the drug might have been cancelled and we’d have missed out on what seems to be the most effective drug we have for CLL.
There’s always a balance between efficacy and side effects. And as someone who’s helped to run a lot of these trials they are much harder to do well than you think!
That's good to know. Clearly my research on this is out of date. I confess I have not been as active in the field as I was, having retired in 2006. I recall that it used to be different. Thanks for the important update.
You are right. It was previously different. It’s great that things have tightened up. Ironically the pressure is higher now on the companies than it is on the individual academic studies. I think they should have to follow the exact same rules.
I agree. I have seen academic studies that needed a lot of tightening. This, of course, is ironic. In theory academic studies ought to be peer reviewed and free of the bias that might affect corporate research. Unfortunately this is not always the case. At least it was not when I looked at this. University research is often funded by the pharmaceutical companies or by medical device manufacturers or other entities that have a stake in the outcome.
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