Good morning GMT (and good morning to everyone else too)
We are all waiting patiently (or impatiently in some cases) for the next data cut from the Vaxinia MAST trial. I've been too busy of late to post much here on HC but I have been doing some more thinking about the initial Vaxinia MAST trial results and recent comments from others here about the potential for "off label" use of Vaxinia if/when IMU can get FDA approval for use against a single cancer type (eg Bile Duct cancer).
In the process I came across your own post from 11 January( https://hotcopper.com.au/threads/ann-imugene-presentation-to-jpmorgan-healthcare-conference.7795582/page-43?post_id=71825510 ) and I realise that my recent thoughts are closely related to the question you asked back then about patients dropping off the trial, and to your own suggested answer. Here is what you wrote:
"I wonder if, with the CR and PR now confirmed, we are likely to now see less patients move off treatment as the trial progresses? Hard to tell I guess given each individual's own unique set of circumstances, but you have to wonder if the improvement in responses and/or the higher doses will encourage patients to stick with the treatment a little longer."
Your question was prompted by this chart from the presentation to the JP Morgan Health Care Conference in January
(The full presentation can be downloaded from the bottom link on this page: https://www.imugene.com/investor-presentations )
So - here are my thoughts:
I think we have good reason to expect that interest in off-label use of Vaxinia would be very strong. The reason - it has such an impressive safety and tolerability profile.
When asked about this in the Investor "MAST Study Update" Webinar, Leslie replied that some of the patients experienced... "fatigue... almost like flu like symptoms, but all manageable, and they go away, more importantly." (You can hear it yourself on the webinar video from 25:10 onwards - available on the IMU website at https://www.imugene.com/videos )..
Chemo, and most immunotherapy treatments, come with all kinds of nasty side effects and significant risks of major "adverse events." My post of 15 Jan looks at the current SOC for Cholangiocarcinoma - a combo of Durvalumab and chemo which had a 75.7% frequency of Grade 3 or 4 adverse events when it went through its Stage 3 clinical trial, including 3.6% fatality due to the treatment. omg.....
That's probably worse than the SOC for many other cancer types, but chemo is generally a horrible experience, and even blockbuster immunotherapies like Keytruda come with very real risks eg severe Cytokine Release Syndrome
So a clinician is likely to look at Vaxinia and say: well - it shows a really strong disease control rate, and it has almost no risk of major adverse effects. It's also a one off administration - easy to do - and it won't interfere with, or prevent, other treatments. It shouldn't complicate monitoring and adjusting treatment either - because any "adverse events" are highly unlikely to be a result of the Vaxinia treatment. So.... why not "just do it" ?
If Vaxinia can get approval in a single indication, I can certainly see Vaxinia being picked up as an additional/combo treatment in a very wide range of other solid cancer types.
Assuming of course that further data from the MAST trial is as good as, or better than, what we have seen so far. We just have to wait and see for that - but the progression to 1 billion PFU tells me that the data has continued to improve.
Here is a related thought I have been considering since the initial MAST trial results were released - and this is the part related to your question, friend GMT:
I've just suggested - above - that Vaxinia will be extremely attractive for off label use as an additional therapy to be used concurrently with the various SOC's, because it is so easy to use and it is a "one off" treatment. So if and when Vaxinia is granted approval in one indication - that gives it a big advantage for off label use in others.
However, like you, I did notice in the MAST trial interim data (the left hand chart above) that a high number of patients are being marked as "off treatment." Some may have just died as a result of their disease - because they are all very unwell people - but I think most of this is that many of the "off treatment" patients have simply moved on to a different form of treatment. Once they do that, my assumption is that it becomes impossible to attribute any further clinical outcomes to the earlier Vaxinia treatment, so they have to be removed from further assessment in the MAST trial and marked as "off treatment." It is quite possible - maybe even likely - that some of these patients show later improvement/clinical benefit, but the MAST trial cannot capture or include that data. It would just not be scientifically valid.
So human psychology is probably hindering the MAST trial. Why?
Well - as I understand it - through this dose escalation phase the treatment for each patient consists of one single injection of Vaxinia, at whatever dosage level has been set for the cohort.
And that's all. There really can't be anything else.
Then the patient is monitored - with the first scan happening 6 weeks after the treatment....
Compare that to most (or even all?) other cancer drug treatments. Most (or all?) other treatments consist of an ongoing course of drug or chemo. So - depending on what it is - every day or every week or every month the patient is receiving something. And they know they are receiving that treatment. Even with radiation therapy - it will probably be a few times a week for at least a month or two.
If Vaxinia "works" then this ease of administration is a MASSIVE advantage in the future, if and when it gains FDA approval - but in a clinical trial which depends upon patient retention I think it could actually be a real disadvantage, because of human psychology. These people know they are very very unwell indeed and that their life is hanging in the balance. Most people in that situation will be desperate to try anything at all which might improve their chances. That's why they will have "signed up" for the MAST trial in the first place. Other treatments have failed and they are desperate!
I know I would be too.
So - after all the excitement and hope of a new treatment - what they get is one injection. Then they are told to wait..... and not do anything else. Which is a really hard ask!
I mean - they don't even get a scan until 6 weeks later, and we know that due to pseudoprogression it is likely that most patients will show no improvement at 6 weeks and may even appear - by tumour size - to be getting worse. How many of those patients will be tempted to seek out and try another treatment, rather than wait longer?
I think the answer is "a lot" and that is what we are seeing in the chart above. Some Oncologists may well say "you have already tried everything else" - and that may be true in many cases - but some patients will persuade their Dr to let them try something else, or they will just Dr shop until they get an Oncologist willing to give them an extra option.
In the initial data cut (see chart above) we see that 2 patients went "off treatment" before their first scan. They may have simply succumbed to their disease before they could get a result from Vaxinia but maybe they just felt they could not "wait" to see if it worked - and they managed to get onto another form of treatment.
Another 8 patients reached their first scan - which showed "progressive disease" - and then dropped off. It is highly likely that they were in the same situation. Spooked by the "progressive disease" result - they jumped ship.
What leaps out at me though is this:
Every patient who got to their second scan showed as Stable Disease, or achieved a Partial Response (major reduction in tumour) or a Complete Response (elimination of tumour).
And yes - 8 of them then went "off treatment" - but for the reason I gave above I think that is entirely understandable. It certainly can't be taken as evidence of treatment failure. I think it is far more likely to be just fear and an entirely understandable desire to do absolutely everything possible to get better.
So we may continue to see a large "off treatment" rate in the data, because of human psychology. I think it tells us that the trial results - good though they are - do not reflect the true magnitude of the clinical benefit of Vaxinia.
I can't think of anything IMU can do about that beyond very careful screening and detailed education of trial participants - which I'm sure they will be doing.
And yes - the more the data builds, the more confidence people taking Vaxinia (and their Oncologists) will have in its effectiveness.
So yeah - for my money, the data so far is good, but the best is yet to come.
Best wishes to all
Dave
(20min delay)