Good morning all
This post highlights an interesting discussion on the current SOC ("Standard Of Care") treatment for Biliary Cancer - and contrasts that SOC with Imugene's Vaxinia - which now has a "Fast Track" designation by the FDA for development as a potential treatment of Biliary Cancer.
Preliminary Note 1:
I'm using @memememe 's product specific threads again, to keep this separate from the more general "Ra! Ra!" and "Boo! Boo!" discussion on the multibaggers thread - entertaining though that is....
Preliminary Note 2:
As others have pointed out (again my apologies - but I can't recall who found it first) - there is a Poster presentation on Imugene's CF33-HNIS (the Vaxinia Oncolytic Virus) happening this Thursday 18 January (USA time) in San Francisco at the ASCO Gastrointestinal Cancers Symposium. The link to the Abstract is here: https://meetings.asco.org/abstracts-presentations/229209. It is part of "Poster Presentation Session A" which is scheduled for 11:45am - 1:15pm on the 18th.
It is possible that we may receive updated data on the MAST study in this poster. I'm a bit doubtful, because submissions for the event closed on 19 September and the "Late Breaking Data Submission Deadline" was 19 October, but it is still possible. Once a poster is accepted, I'm sure they can still add to the results, as long as they are not changing the topic. Anyway - we will know soon enough. "Regular Abstracts" are being released online at 5pm on 16 January (San Fran time), but "late breaking" abstracts will be released at 7am on the day of presentation. So - if the Poster contains significant new information then presumably IMU will make an Announcement to the ASX when the Abstract is released. Sydney is currently 19 hours ahead of San Fran time so that would be at Midday Sydney time on Wednesday 17th (if it's a "regular abstract") or pre-market open on Friday 19th if it's a "late breaking abstract."
Now - to the main point of my post - Vaxinia as a potential treatment for Biliary (Bile Duct) Cancer. Why did the FDA give it "Fast Track"?........
Back on 28 November IMU announced that they have received "Fast Track" designation from the FDA for the MAST trial of Vaxinia - with specific reference to Vaxinia as a potential treatment for Bile Duct cancer. (I will shorten this to BC for "Biliary Cancer."). IMU is now proceeding to enrol an additional 10 BC patients in the MAST trial - to see if the initial Vaxinia results in BC indicate a genuine effectiveness (and not pure chance).
And what were those initial results? Well - when the initial MAST trial results came out on 6 November we were told that it included two BC patients. One of those patients had achieved a "Complete Response" (ie no detectable cancer) and the other had achieved "Stable Disease." That's only a sample of 2 patients of course, but BC is regarded as a gastro-intestinal cancer type and there were 6 patients with gastro-intestinal cancers in the MAST results (2 x BC; 2 x Colo-rectal Cancer; 1 x Pancreatic Cancer; 1 x Liver Cancer). Across that group the disease control rate (Stable Disease, Partial Response or Complete Response) was 75%.
Yeah I know - 75% of 6 patients is 4.5 patients, but presumably it was either 4 patients or it was 5 of them. Either way - given that this was Vaxinia as a mono-therapy, and only at low to mid range dose levels - the results were very encouraging. Certainly the FDA thinks so - because 3 weeks later they gave IMU the Fast Track designation.
But why did they do that? I mean - the initial MAST results are a very small sample. Well - I've just been doing some background reading which I think helps explain exactly why the FDA now sees Vaxinia as a high priority for further testing and development.
The lead author of the upcoming ASCO Poster Presentation is Daneng Li, an MD and Associate Prof at City of Hope. (You can read his profile here: https://www.cityofhope.org/daneng-li. )
Back on 23 July last year Dr Li was the Moderator of a discussion on "Evolving Therapies in Biliary Tract Cancers". The discussion brought together a group of Oncologists to discuss approaches to treatment for a specific case study - a 72 year old man diagnosed with Cholangicarcinoma (another name for BC)
You can read the full discussion here if you like. I recommend it! :
https://www.targetedonc.com/view/li-assesses-evolving-therapies-in-biliary-tract-cancers
And this is why I think the discussion is highly relevant to Imugene's expansion trial of Vaxinia against BC, and the FDA decision to grant Fast Track designation for that:
Reading through the discussion, you will see that it centres around the practitioner's experiences with the current "Standard Of Care" for BC - which is now regarded as a combination of 2 Chemotherapy drugs (gemcitabine and cisplatin - or sometimes oxaliplatin) plus 1 MAB Immunotherapy drug - Durvalumab (Brand name Imfinzi) which is a PD-L1 Checkpoint Inhibitor drug made by Astra_Zeneca.
This SOC treatment has come about as a result of the Stage 3 "TOPAZ-1" Clinical Trial conducted by Astra-Zeneca.
But just how good were the TOPAZ-1 results?
Well - you can read all that here: https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200015 but I can summarise it for you. In the TOPAZ-1 trial, 341 patients were treated with Chemo plus Durvalumab, and 344 patients were treated with Chemo only. The 2 year survival rate for the Chemo only patients was just 10.4%, and for the Chemo plus Durvalumab patients that went up to 24.9%. So that's a good increase - but it also tells us that even under the current "Standard Of Care," three quarters of all BC patients are likely to die within 2 years - and that is truly dismal.
Yes - there were some also some success stories! Out of the 341 patients who received Chemo plus Durvalumab, a total of 7 achieved a "Complete Response" (apparent elimination of the cancer) - which is fabulous for the lucky 7. In the Chemo only group, there were just 2 Complete Response patients.
But here is another way of looking at it - the lucky 7 Complete Responders comprised just 2.1% of the Chemo plus Durvalumab group. Remember that figure....
Now look at the Safety data for what Clinicians like to euphemistically call "Adverse Events." What does that data tell us? Well - "Grade 3 or 4 adverse events occurred in 256 patients (75.7%) in the durvalumab group " The corresponding figure for the Chemo only group was also very high - at 77.8%.
So this tells us that patients with the new SOC treatment (or the old Chemo only treatment) have a better than 75% chance of a serious adverse reaction to the treatment. And how bad can that be? Well - check this: "The number of deaths due to adverse events was 12 (3.6%) in the durvalumab group and 14 (4.1%) in the placebo (Chemo only) group."
Remember that earlier figure for Complete Response? It was just 2.1%. So on the new "Standard Of Care" treatment a patient has a 2.1% chance of achieving a "Complete Response" and seeing their cancer disappear - but they actually have a 3.6% chance of dying as a direct result of the treatment! It's a pretty grim statistic.
Okay - so neither of those outcomes (complete response or death from treatment) is a high likelihood - but the fact remains that the chance that the treatment itself will kill you is 71% higher than the chance that it will eliminate your cancer!
Sure - we do need to bear in mind that at the less extreme ends of the scale, in the middle there is the bulk of patients who are likely to live longer as a result of their treatment, even if their cancer doesn't disappear. However - remember that 75% of all patients do experience a grade 3 or 4 "adverse event" - so we also have to consider quality of life issues for all patients, even for those who live a little longer as the result of their treatment. That's certainly something the FDA will be considering too.
Which takes us back to the case study discussion moderated by Dr Li.... (Here is the url again: https://www.targetedonc.com/view/li-assesses-evolving-therapies-in-biliary-tract-cancers )
The topic comes up of how long to continue the chemo, and whether - or when - to continue with the Durvalumab MAB immunotherapy alone. One practitioner comments: "I keep it going unless the patient has intolerable [adverse] effects or progressive disease. It’s a discussion between the patient and the physician, where you tell them, “We could keep going, or we could stop here and give you a break.” Most of them opt to continue, but some, especially those with [adverse] effects, do want to have a break."
Dr Li from City of Hope responds: "Yes, that’s a great point; I have certainly heard that. Physicians will say that the patients are pretty beaten up after 8 cycles, so it’s a good time to give them a break and keep them on maintenance durvalumab."Cry comment: Chemotherapy is not fun. Patients are "pretty beaten up" and some just cannot continue. Even though they want to overcome their cancer, they just "do want to have a break."
Then they talk about "Hepatotoxicity" - damage to the liver as a result of treatment:
"you don’t know [whether the] hepatotoxicity is from [the] immunotherapy or [ from] cancer. Sometimes it’s hard to tease those out. When the patient’s liver function [test result levels] start to go up and there may be a little ascites here and there, you don’t know what’s going on—whether it’s the immunotherapy, toxicity, or cancer progression."
A colleague responds: "For the concern of progression vs autoimmune hepatitis, the picture of the liver dysfunction is a little different [between those scenarios]. If you look at it carefully, maybe you can tell the difference. Liver disease progression or even bile duct blockage will be more cholestatic and have more of an alkaline phosphatase elevation. But, with autoimmune hepatitis, you usually get just liver enzyme elevation, which…is a problem, but…one way to tell the difference is to take a careful look."My comment: The CART immunotherapy drug can damage your liver - (those Grade 3 and 4 "Adverse Events" again). But there can be other causes of liver damage too - and the Oncologists clearly find it very hard to determine whether it's the cancer causing liver toxicity, or a blockage in the bile duct, or the treatment itself!
And their summary: "I think that for BTCs in general, the prognosis is still poor for most patients, given the late diagnosis. With the addition of durvalumab, there is a small group of patients, maybe 10% or 15%, who have durable responses. But the rest of them still don’t do very well..... It's a tough disease. "All of which gives us (and the FDA) very good reason to consider the contrast with Vaxinia.
All patients on the Vaxinia MAST trial came into that trial with progressive disease. All patients on the MAST trial had been through at least two prior forms of treatment, and failed on both (Progressive Disease). We can be very confident that both of the BC patients on the MAST trial have been through Chemo, and possibly a MAB immunotherapy as well. There were therefore not only in "progressive disease" but also "pretty beaten up" (to quote Dr Li) by the prior treatment before they started with Vaxinia. For that reason you would have to regard them as pretty poor candidates for a treatment which (in part) relies upon the patient having a well functioning immune system. (Vaxinia does directly kill cancer cells, but it also makes cancer cells visible to the immune system, for further attack by the immune system. Both effects are critical to success).
Despite this poor prognosis, and despite receiving just a mid range dose of Vaxinia, one of the two BC patients on the MAST trial had a complete response (all cancer eliminated) and the other achieved stable disease. That's only a sample of two - but the results for the gastrointestinal cancer group as a whole (75% disease control rate) indicates that it possibly/probably wasn't just chance.
Equally compelling for the FDA - and for anyone concerned with safety and quality of life issues - we know that 75% of patients on the Standard Of Care have a Grade 3 or 4 "Adverse Event" - a bad reaction to the treatment - and 3.6% of then will die from their treatment.
By comparison - none of the 28 MAST study patients have had a severe adverse event. 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 )..
So - Vaxinia in Biliary Cancer:
- very encouraging signals of clinical effectiveness, in a disease where over 75% of patients on the current Standard Of Care 75% will die within 2 years.
- incredible safety and minimal side effects - which means great quality of life - when the SOC has a 75% Grade 3 or 4 "Adverse Event" likelihood, and 3.6% of SOC patients will actually die as a direct result of their treatment.
- no toxicity from Vaxinia - so no complication for the Oncologist, trying to work out if liver damage is due to the disease or the treatment
- Incredible ease of administration - a direct injection to the tumour (or maybe an even simpler IV injection) compared to hours long and repeated infusions of toxic Chemo and MAB drugs. Cheaper, much less arduous for the patient.
- Vaxinia is a cheap and easy to make drug. Durvalumab - a main part of the current SOC - is produced in mammalian (Chinese hamster ovary) cells by recombinant DNA technology. A course of Durvalumab plus Chemo is estimated to cost $217,000 USD (Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950513/ )
Which makes it easy to see why the FDA has granted "Fast Track" status to Vaxinia. The current "Standard Of Care" sets a pretty low bar for achievement. Vaxinia already looks likely to clear that bar easily.
By how much, and how certain can we be?
The next set of data from the MAST trial will start to answer those questions, but we are off to a wonderful start.
And all this is just about a single use for Vaxinia - as a treatment for Biliary Cancer. The MAST trial is already showing that Vaxinia looks likely to be effective across a huge range of solid cancers.
My opinion - you ain't seen nothin' yet!
Cheers
Dave 
(20min delay)