I'm coming to this party a little late. I was out and about yesterday when the actual conference Poster became available, so I'm just looking at it now.
And yes! That diagram of the study design is extremely interesting.
As you say, friend Gossy, this is firm evidence that they intend to investigate higher dosage levels beyond the current 3 x 108. We know that Prof Fong saw no toxicity in mice until he reached 109, and the average human is a bit more than 2,500 times the mass of a lab mouse, so 109 or even 3 109 should be safe for a human. (The actual exact process of comparing dosage across species is much more complex, but the huge mass difference does give IMU a big window to increase beyond mouse levels).
They really do want to find the genuine Optimal Biological Dose - and that means increasing dosage until the additional effectiveness of increased dose drops away (OBD is the point at which the curve of Increasing effectiveness flattens out) or until you reach a dose limiting toxicity. In her recent interview LC hinted that they might go higher than the current 3 x 108. Now we are seeing that possibility shown on the poster.
It seems great news to me, because it would mean that the current dose level of 3 x 108 is producing a significant increase in effectiveness - and still with no significant toxicity. So the next step would be to go to 109 - one billion PFU - and see if that produces even greater effectiveness. If it doesn't, or if they start to see real toxicity, then they drop back and 3 x 108 is confirmed as the OBD for all subsequent patients. And yeah - if 109 also produces a significant additional benefit, then there is a possible escalation to 3 x 109.
Each step up in dose imposes a delay. The FDA requires them to wait at least 3 weeks on the Mono therapy arm (and 6 weeks on the combo arms) before increasing the dose - just to be sure that current patients don't develop an unexpected negative reaction. However - we all want the most effective possible result from Vaxinia, so each dose escalation is really a major victory.
And then there is the bottom line of that study design diagram....
When they originally announced the expansion cohort for Biliary Cancer, as a response to the first cut of the effectiveness data back in early November, it was clear that BC was just the "first cab off the rank." There has been a bit of speculation here on HC as to what would be next. That's why I've expressed a strong interest in seeing a chart that shows response by cancer type. At present, we only know the specific examples they have given - eg the 2 x BC cancer results, and the fact that we now have 2 x Melanoma PR results.
Now the study design chart tells us that they are looking at a second expansion cohort - this time for Metastatic Head and Neck Squamous Cell Carcinoma. Which is a skin cancer category - but not actually the same as Melanoma. I'm curious about that. They have announced 2 PR results for Melanoma, and made no previous mention of Metastatic Head and Neck Squamous Cell Carcinoma, but it's the latter category that is now listed for an expansion
Here's an educated guess: We know that they chose Biliary Cancer as the first expansion cohort because they expect Vaxinia to be effective in BC AND because the current Standard Of Care treatments in BC are NOT very effective. Indeed - that is exactly why the FDA has now granted them Fast Track for Vaxinia against BC. There are no really effective options to treat BC.
Malignant Melanoma is no joke either - and it kills more people than Squamous Cell Carcinoma - but treatments for Melanoma have made enormous advances in recent years - particularly through Immunotherapy. Checkpoint Inhibitors (Opdivo, Keytruda) have been a big breakthrough, and the median survival rate for advanced and inoperable Melanoma has improved from 6 months to 6 years. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954703/#:~:text=The%20use%20of%20immunotherapy%20in,advanced%20inoperable%20stage%20IV%20disease
By contrast, Metastatic Head and Neck Squamous Cell Carcinoma still has a dismal prognosis. The median survival is just 6 - 15 months. Source: https://www.uptodate.com/contents/treatment-of-metastatic-and-recurrent-head-and-neck-cancer/print#:~:text=The%20prognosis%20of%20patients%20with,the%20management%20of%20these%20patients.
It can occur in all kinds of "hard to reach" places inside the head and neck. Check the diagram in this article: https://www.nature.com/articles/s41572-020-00224-3 That can limit surgery options, but intra tumoral injection of Vaxinia could till be possible or - where that is too hard - we are starting to see IV Vaxinia generating a clinical benefit. Also - the metastatic disease can crop up in distant locations. When that happens, the outcomes are even worse - but that's also a situation where IV Vaxinia could potentially help.
Checkpoint Inhibitors have not been so successful with Head and Neck Squamous Cell Carcinoma. Pembrolizumab (Keytruda) gave a only 20% response rate, and that was only in patients where the disease was PD-L1 positive: Source: https://ascopubs.org/doi/full/10.1200/EDBK_157801#:~:text=In%20a%20large%20phase%20IB,%2Dpositive%20or%20HPV%2Dnegative.
So..... Vaxinia has the same method of action across different cancer types. They may be reasoning that if it works against Melanoma (as seems to be the case) then it is likely to work against Squamous Cell Carcinoma - and they are choosing Metastatic Head and Neck Squamous Cell Carcinoma because that version has such poor outcomes with current treatments.
As @Zior says above "To be going after some of the poorest prognosis conditions first will ultimately, in my opinion, lead to capitulation across the solid tumour field in general."
Anyway - that's my best (self) educated guess.
@WellsEicke - you ask if Mesothelioma may be next? It's a really good question. As @@Zior says, we just can't know and Zior doesn't want to guess. All we know so far is that Yuman verbally reported a clinical benefit for a patient with Testicular Mesothelioma. We don't even know if there are any patients on the trial with the more common lung or intra-peritoneal Mesothelioma. We do know that Mesothelioma is a horrible disease with no cure and a 5 year survival rate of just 10%. The median survival is just 4 - 18 months, depending on the stage and type. Source: https://www.pennmedicine.org/cancer/types-of-cancer/mesothelioma/prognosis#:~:text=Mesothelioma%20Survival%20Rate%3A%20The%20mesothelioma,disease%20is%20just%2010%20percent.
I have professional experience arranging care for people living with Mesothelioma, and I have been how ineffective the current treatments are. Rates of Mesothelioma have dropped since action was taken to remove asbestos from widespread use, but it can take decades to appear so people exposed in their workplace many years ago are still being diagnosed, and will be for years to come. We are also seeing cases of mesothelioma from people exposed while doing home renovations.
Like Zior - I won't guess and say "yes" - but I will say that Mesothelioma would be a really really great cancer type for an expansion cohort IF the Vaxinia Trial shows evidence that it can be effective against the disease. It's a shocking disease with no good treatment - so the FDA would definitely give it Fast Track if Vaxinia seems to show effectiveness. An expansion cohort in Mesothelioma would also, I think, get a lot of attention - because Mesothelioma is one of those diseases that a lot of people are very aware of - in this country at least. (Respect to the memory of Bernie Banton!). Right now, all we know about Mesothelioma and Vaxinia is Yuman's verbal mention last year of the one case. This is - again - why I would love to see a chart of response to Treatment by cancer type.
The Fast Track for BC, and the plan for other possible expansion cohorts, illustrates just how clever Imugene has been by persuading the FDA to agree to a Phase 1 "Basket Trial" against any solid cancer type. Amazing!
The protocol for doing this goes back to changes made by the FDA in 2019, in recognition of legislative changes aimed at speeding up drug research.
"ABasket Trial involves a single investigational drug or drug combination that is studied across multiple
cancer populations defined by disease stage, histology, number of prior therapies, genetic or other
biomarkers, or demographic characteristics. It is usually designed as a single-arm, activity-estimating
trial with overall response rate as the primary endpoint. A strong response signal seen in a sub-study
may allow for expansion to generate data that could potentially support a marketing approval."
What we are seeing with the Vaxinia MAST trial is a further development of this concept. Instead of a "single arm" trial through, Imugene has four trial arms going! IT and IV in Monotherapy, and now IT and IV in combo with Keytruda.
Also - and this is has been a huge time saver - they have been a "Basket Study" right from the start as a Stage 1 Dose Escalation trial.
This is a major innovation. In the advice from the FDA (see reference above) the "FDA strongly recommends that the recommended phase 2 dose (RP2D) of each investigational drug be established before evaluation in a master protocol." (I have added the emphasis in bold).
ie. The FDA has previously been "strongly" recommending that a Dose Escalation trial happens before a drug is trialled in a "Master Protocol" as a basket study across multiple cancer types.
If Imugene had followed that advice, we would have spent the last 2 years dose escalating as a monotherapy only, in a single cancer type application. We would have no evidence yet of clinical benefit for any other cancer type and no evidence of potential combination therapy benefit. There would be no plan for an expansion (a sub-study as the FDA calls it) into Biliary Cancer with prospects for that to then generate a registrational study - or the same for Metastatic SC Head and Neck Cancer.
In fact - there would have been no Basket Trial at all until the Phase 1 Dose Escalation trial was completed - which could easily be another year. Then a submission for a Basket Trial would have been put to the FDA.... to be considered..... then arranged..... then started..... then run to the point where we start to see results. Add another 2 years for all that at least.
By my reckoning, the MAST trial study design has cut at least 5 years from the development process for Vaxinia. This is why Yuman is so ecstatically happy about his collaboration with Imugene.
And this was not Imugene "going rogue" and ignoring the FDA. IMU has made it very clear that each step of this process has been carefully discussed with the FDA. We have had to take their word for it, but the FDA approved the MAST trial, and further proof of the pudding is that the FDA has now granted them Fast Track for BC.
The FDA knows what we have, they are being consulted at each step, they are watching very closely, and they will support success.
Best of all - the entire Vaxinia MAST trial is inherently an extremely "Fast Track" process. Posters who are impatient for results and outcomes just do not understand how fast this is actually happening compared to usual drug development trials.
Best wishes to all
Life is short. Stop reading this now and go get yourself a good weekend!
Cheers
Dave
IMU Price at posting:
10.5¢ Sentiment: Buy Disclosure: Held
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