Ah, that 23-patient study again.
I wouldn't draw any firm conclusions, from such a small sample size.
How many of the 23 would have had an IDH mutation?
The statistical likelihood is that it would have been just one or two!

I'm also not definitely contending anything. I simply suggesting that L may prove to be more beneficial than anything else that is available, for mutated IDH as well as for wildtype!

Perhaps we will have a better idea after the full results of the trial are released.
If we work on 5%, there will be approximately 16 out of the 331 with the IDH mutation.
And if the randomisation fell right, either by accident or active stratification, that will be about 11 in treatment and about 5 in control.

Hi ATL.
Well the results of that combo trial with Keytruda should certainly be interesting.
But I have my doubts about whether the use of Keytruda as the neo-adjuvant will actually work. It may work for a minority, but it might also introduce significant toxicity in others.
We know about the phenomenon of ICI-related hyper-progression in several other cancers, notably NSCLC; it may also prove to be a real factor in GBM.

I came across this reference recently:-

"In IDH1 wild type GBM, the median survival rate of patients with CDK4/MDM2 co-amplification is 6.6 months after diagnosis, while the median survival rate of patients without an CDK4/MDM2 co-amplification is 12.7 months"

https://www.frontiersin.org/articles/10.3389/fmolb.2020.562798/full

Well, in that one sentence, we suddenly have another biomarker expression that may have important prognostic significance in GBM!

I'm also aware that there is a putative association between MDM2 amplification and increased likelihood of ICI-related hyper-progression.

Patient experiences of Keytruda in NSCLC:-

https://www.drugs.com/comments/pembrolizumab/keytruda-for-non-small-cell-lung-cancer.html#

Perhaps you can see why I have doubts...

I imagine Kat Charles' tumour was probably mutated IDH, given her young age and the fact that it was a secondary GBM. I also imagine that she is glad she found DCVax-L rather than pursue a different option.
When did Liau and Prins suggest that L may be less effective with this classification? What lead them to make that conclusion?

Kat is only one case of course, but I don't know what else it could have been that afforded her long-term remission, other than the DCVax-L that she received.

I'm not aware of anything to suggest that L is less effective with other high grade gliomas. It's just that there hasn't been a formal trial. I know that L was only used in a handful of patients under the German Hospital Exemption scheme, but that exemption was for all gliomas. And I imagine that there is nothing to prevent L being used for IDH mutation under UK Specials, if the referring specialist believes it to be the best treatment option.

Probably yes. Virtually all primary or de novo GBMs are wild-type.
Mutated IDH almost always signifies a secondary glioma, whether or not it was recognised as a secondary glioma at the time of initial 'GBM' diagnosis.
And mutated IDH goes with younger age, better prognosis, and a pro-neural signature. But we are only talking about roughly 5% of the GBM population (the 5% that will no longer be called GBM).

Not saying it ever happened, but up until now in GBM trials, there was scope to stick a few more secondary GBMs in your treatment arm compared to your control arm, to give yourself a bit of a fair wind....

Understandably, researchers and regulators want to better categorise the heterogeneous nature of high-grade gliomas to identify which treatments are most likely to be effective in the case of each individual.
And maybe that is why regulators asked for an analysis of the L trial population to identify IDH mutation status and stratify results accordingly. This would enable a stratified comparison with the control arms of those other comparator trials. IDH wild type v IDH wildtype, and IDH mutation v IDH mutation.
Though I doubt those other comparator trials actually ever did comprehensive testing for IDH mutation status.
But an informative comparison can be made between outcomes based on mutation status just within the L trial.

Of course this is where DCVax-L aces it. Because each patient's treatment with L, is based on the unique transcriptional and molecular characteristics of that patient's tumor. And that includes intra-tumoral heterogeneity. And is therefore guaranteed to be a perfect match (especially when used as soon after resection as possible).

I can foresee that L may prove more effective with unmeth patients if TMZ is dispensed with (because it doesn't work for them), and the L injections are started straight away after recovery from surgery (possibly concurrent with some targeted RT).
But that is a side-issue.

L, being completely autologous (tailored to the individual's tumor, and using the individual's primed DC's to do the antigen-presenting) will always be superior (everything else being equal), to allogeneic approaches using synthetic or donor-derived peptides that only target a limited number of an individual's tumor characteristics.

In short, the WHO re-classifications do not make a lot of difference in the case of our trial. L remains the best treatment prospect for the 95% wild-type, precisely because it is fully personalised, and it will probably be best for the 5% mutated IDH as well.
And there is no reason why regulators shouldn't see it this way.

Additionally, L will almost certainly be the most effective option by far, for rGBM patients who weren't able to receive L at the time of initial diagnosis. (Kristyn's Dad is only here because of L.)

What LP told us all those years ago about the importance of a fully personalised approach, remains as true now as it was then.

Shenanigans at the FDA:-

"Biogen tumbles as FDA chief calls for a probe on Alzheimer’s drug approval"

https://seekingalpha.com/news/3714057-biogen-tumbles-as-fda-chief-calls-for-a-probe-on-alzheimers-drug-approval

That may indeed be the case.
Call it 'PR'ing' the hold rather than 'announcing' the hold, if you prefer.
Even then, they didn't say it was an FDA hold.
That's why we don't know the actual date of FDA initiation (if it was the FDA).
The only direct reference to the FDA was when they announced the lifting.

New enrollment never resumed, but patients already in screening continued to be randomised right up until November 2015.
So patients did, in effect, join the trial up to four or five months after the hold on new recruitment.

And we don't know for sure, but the randomisation skew suggests that perhaps all patients randomised after July or August 2015 up until Nov 2015 went to treatment, for reasons unknown.
And all randomised subjects continued to be treated per protocol, without any interruption due to the hold on new recruitment.

The hold basically resulted in a reduction of 17 patients down from 348 to 331.
It did last about 18 months, by which time NWBO had already made the decision to close any new recruitment.
We actually don't know the precise date the hold was initiated; we simply know when NWBO announced it.

She does sometimes repeat use old slides.
Not that it really matters, whether it was SPORE or Phase One.
It basically appears to be grant-funded.

I guess what we really want to know is when can we expect to see some results, who will put out the results, and who has the rights to the data, so that the data can be used to inform further proprietary development going forward.
Certainly the results should be informative, both for NWBO and Merck, whatever the outcome.

Thanks Bio. Yes, I agree it is DCVax-L.

But although the NCI still has something to do with it, it no longer appears to be part of a SPORE funded program.
Rather, it seems this charitable foundation, Phase One Foundation, have provided majority funding.
I previously gained an impression that Rob Prins is the 'lead enthusiast' for this study rather than LL, but that is just my impression.

Yes indeed. LL told us that a year or so ago.
Though it is not as clear cut as that (is it ever?)..

The SPORE site lists a study that sounds like the one we are referring to, but that states that Nivo is to be used alongside DCVax-L, as opposed to Pembro. But I think that may be the one that never took off.
So if the Pembro / L study is still SPORE funded, it ain't listed on the SPORE website page. Or I've missed it somehow.

https://trp.cancer.gov/spores/abstracts/ucla_brain.htm

Well, it's a generic description of an autologous dendritic cell therapy. So it could be any old autologous dendritic cell therapy.
Except it isn't. It's DCVax-L. We know that.
DCVax-L has been given a chemical name. It's on the EU trial site listing for the P3, if anyone is interested.

Strictly speaking there are three types of name: a chemical name, a generic or non-proprietary name, and a trade name or brand name.

https://en.wikipedia.org/wiki/Drug_nomenclature

I think you guys call that well-known painkiller Tylenol, whereas we just call it paracetomol, which is probably a reflection of brand name penetration in the US. And probably means you pay three times as much.

Perhaps a more important question is who reports the data and who owns the data of this combo study.? This will be in the contract somewhere.
One suspects this is fundamentally an exploratory study, with both firms just out to gather more data. I guess it could serve purpose as a P2.
But I remain of the opinion that it will probably serve to further demonstrate the lack of utility of ICI's for GBM.
Might be wrong of course.

'CRL'
CRL? What do they have to do with Sawston?
Answer: nowt.

If NWBO is able to begin paying the Advent wages through expanded UK Specials numbers, do you think Advent are in a position to say no?
Of course they aren't. And why would they, even if they could?
NWBO and Advent are tied at the hip.

There has to be a primary author; the one who writes the draft (after months and months of statistical analysis followed by consultations with the SAB and the Steering committee) and seeing as this is NWBO's trial, there is surely only one person who holds that responsibility. As CSO, that's Dr Bosch.
But that draft will go out for wide review, and obviously that will include LL and KA.
Not sure who will actually get listed as primary author on publication. But it will be LL or Dr Bosch, with KA coming in third.
Don't think that KA will be out of the loop, because he won't.
Just don't expect publication or dissemination next week.

I loathe making conference targets, but around about the time of SNO would be my guess. Why not SNO itself for dissemination?
It is the annual event for Neuro-Oncology after all, and so would be very fitting.

Well, it's possible he does know the unblinded results without knowing if any particular patient was treatment or control.

Why does it matter whether he knows results in detail or not?
It's almost a non-issue for me.

Oh God. Not that old chestnut....

"Unlike LC & Ex, Dr. Liau, Dr. Ashkan and Dr. Brem believe in DCVax. Who do you believe?"

Funnily enough, Ex has never said that DCVax-L doesn't work.
It's interesting, but there are only a very few board contributors, who state that they think it doesn't work at all. Three or four.

I think I've been fairly open with my opinions over the last six or seven years on just about every aspect of this long endeavour, and those opinions are all on record.
You can read my posts, or ask me any specific question, if you like.

It has superior efficacy to Optune, that's for sure!
But then that is not exactly a high bar...
And I think L will outperform L plus Keytruda. I've said that several times before.

Thankyou Lykiri.
Knew I could rely on you for stuff I've forgotten about.

It is curious how so much of current focus is outside of the US.

Ah thanks Swegen.
My memory isn't what it used to be. (Nor is nostalgia...)

Now what was I talking about?
Oh yes, the UK guy I was thinking of is on the SAB, not the Steering Committee.

Both sets:-

Steering Committee:-

Dr. Steven Bremm.
Chief, Neurosurgical Oncology, Co-Director, Penn Brain Tumor Center, Professor of Neurosurgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania


Dr. Fabio Iwamoto.
Dr. Iwamoto is a neuro-oncologist whose previous training includes a neurology residency at NewYork-Presbyterian/Weill Cornell Medical Center and a neuro-oncology fellowship at Memorial Sloan-Kettering Cancer Center. For over three years, Dr. Iwamoto was an attending physician and an investigator at the Neuro-oncology Branch, a trans-institute branch of the National Cancer Institute and National Institute of Neurological Disorders and Stroke, in Bethesda, MD. At the intramural NIH, Dr. Iwamoto was a principal investigator in early phase clinical trials for brain tumors and worked with laboratory and computational scientists on several translational projects in brain tumors.

Dr. Iwamoto was recruited to Columbia University as the Deputy Director of the Neuro-oncology Division and is actively developing the clinical and translational research components of this program. He is an expert in the diagnosis, management, and treatment of brain and spinal cord tumors as well as neurological complications of cancer.


Dr. Jian Campian.
https://oncology.wustl.edu/people/faculty/Campian/Campian_Bio.html


Dr. John Trusheim.
https://www.youtube.com/watch?v=hS2u1jvkJY4
https://www.youtube.com/watch?v=QKznRBiE-ew
https://www.futuremedicine.com/doi/10.2217/cns-2016-0032



And a recap on the SAB:-


Dr. Mac Cheever.

Dr. Martin (“Mac”) Cheever is the Director and Principal Investigator of the Cancer Immunotherapy Trials Network (CITN) funded by the National Cancer Institute (NCI). The CITN is a network of immunotherapy investigators who are well established and recognized academic leaders in the field of immunology at 32 leading research institutions across the U.S. Dr. Cheever also spearheaded the multi-year project to evaluate and prioritize the 20 most important investigational agents for immunotherapy and the 75 most promising cancer vaccine targets. Dr. Cheever previously served as the Director of Solid Tumor Research at the Fred Hutchinson Cancer Research Center, and continues to be a Full Member (Professor) there.

Dr. Cheever’s research is focused on cancer immunotherapy, including T cell therapy and the development of cancer vaccines, especially for breast cancer. He co-founded an early biotech company developing cancer vaccines, and served as Vice President of Clinical Research and Medical Affairs for 8 years. In that capacity, he gained extensive experience with design and execution of cancer vaccine clinical trials, FDA related product approval issues and collaboration with major pharmaceutical companies.

Dr. Alfredo Quinones-Hinojosa.

Dr. Alfredo Quiñones-Hinojosa is currently Director of the Brain Tumor Surgery Program at Johns Hopkins Hospital. He is also head of the Brain Tumor Stem Cell Laboratory at Johns Hopkins. In September 2016, Dr. Quiñones will become the “William J. and Charles H. Mayo Professor” and Chair of Neurologic Surgery at the Mayo Clinic in Jacksonville, Florida, in connection with $100 million in major new construction projects being undertaken there, to develop new facilities and integrated services for complex cancers and for neurologic and neurosurgical care.

Dr. Quiñones has published 295 peer-reviewed papers and over 100 book chapters (including invited reviews and letters), and has been the main editor or section editor of nine textbooks. Most notably, Dr. Quiñones is also Editor-in-Chief for one of the most well-respected and widely-read neurosurgical textbooks in the world. Dr. Quiñones is one of the few brain surgeons with multiple research grants from the National Institutes of Health, as well as the Robert Wood Johnson Foundation and the Maryland Stem Cell Foundation. Some of his major accomplishments to date include: 1) elucidating mechanisms by which brain tumors migrate and metastasize, 2) integrating the use of stem cells into local treatment of solid tumors, 3) the concomitant use of nanotechnology and focal beam radiotherapy in the systemic treatment of solid tumors, 4) the development of new imaging software to help identify areas within solid tumors with the greatest malignant potential, and 5) the development of innovative, minimally invasive approaches to brain tumor resection. Dr. Quiñones is the Principal Investigator (PI) or Co-PI on multiple clinical trials, including novel combination therapies for brain tumors (with checkpoint inhibitors and/or various other technologies), and the first trials in the U.S. of certain technologies for more complete surgical removal of brain tumors.

Dr. Quinones has been recognized with the Association of American Medical Colleges Herbert W. Nickens Award, the Johns Hopkins Hospital Department of Neurosurgery, Richard J. Otenasek, Jr, Faculty Teaching Award, the “Neurosurgeon of the Year” award from Voices Against Brain Cancer, a “Health Care Heroes Award,” a Howard Hughes Medical Institute Physician-Scientist Early Career Award and various other recognitions.

Dr. Jerome Galon.

Dr. Galon is the Director of the Integrative Cancer Immunology Lab at INSERM (the French national institutes of health). He is associate Director and co-founder of European Academy of Tumor Immunology (EATI) and board Director of the Society for Immunotherapy of Cancer (SITC). He defined the concept of cancer immune-contexture, and demonstrated the major importance of pre-existing immunity in cancer. He developed the Immunoscore system, which is receiving wide and growing attention throughout the immuno-oncology field as a potentially more accurate system for evaluating tumors and predicting clinical outcomes, taking account of both tumor characteristics and patient immune system factors. Dr. Galon heads a worldwide task force of immunologists and pathologists from 16 countries working on clinical applications and global validation of the Immunoscore system, working together with major organizations such as the Society for Immunotherapy of Cancer (SITC) and others.

Dr. Galon’s contributions have been recognized with numerous awards, including the William B. Coley Award (NY, USA), an international prize which honors the best scientists in fundamental and cancer immunology, the Rose Lamarca Award from the Medical Research Foundation, the Gallet & Breton Award from the National Academy of Medicine, and the Simone & Cino del Duca Cancer Research Award from the National Academy of Science.

Dr. Samir N. Khleif.

Dr. Khleif is the Director of the Georgia Cancer Center, the State cancer center of Georgia at Augusta University. He is a Georgia Research Alliance Distinguished Cancer Scientist and Clinician, and a professor of Medicine, Biochemistry, Cancer Biology and Graduate Studies. He also serves as the Director of the Immuno-Oncology and Immunetherapeutics Program. Dr. Khleif previously served as Chief of the Cancer Vaccine Section at the National Cancer Institute (NCI), and Professor of Medicine at Uniformed Services University of the Health Sciences. He also served as a Special Assistant to the FDA Commissioner from 2006-2009, where he led the FDA Critical Path for Oncology designed to restructure the oncology drug development process.

Dr. Khleif’s research group focuses on the development of novel immune therapies and cancer vaccines, and rational designs for combination immune therapy, based on understanding the molecular mechanisms of the interaction between cancer and the immune system (including cancer-induced immune suppression). His team designed and conducted some of the first cancer vaccine clinical trials, and they are currently developing novel combination approaches to enhance anti-tumor effects. During his tenure at NCI, Dr. Khleif was also detailed to serve for 4 years as the Director General and CEO of the King Hussein Cancer Center in Amman, expanding and strengthening the clinical operations and building that institution into a National Comprehensive Cancer Center of Excellence. Dr. Khleif serves on the board of the Society of Immune Therapy of Cancer (SITC), and he is a member of the National Cancer Policy Forum of the National Academy of Medicine where he leads the Immunotherapy Task Force. Dr. Khleif is the chair or member of many national committees on immuno-oncology and cancer research. He is the recipient of many awards including the National Cancer Institute (NCI) Director Gold Star Award, and the Public Health Service (PHS) Commendation Medal.

Dr. John Smyth.

Dr. Smyth was appointed the first Chair of Medical Oncology in Edinburgh and, over the course of 30 years, has developed multidisciplinary oncology to create the Edinburgh Cancer Research Centre, combining laboratory and clinical research with teaching and training, and serving a population of 2 million. Dr. Smyth’s research expertise is in experimental therapeutics, from drug design through all phases of pre-clinical evaluation and clinical trials, with his major research focus on the development and evaluation of new anti-cancer drugs. He Chaired the Expert Advisory Group for Oncology & Haematology for the Commission on Human Medicines, and served for several years on the UK Committee on Safety of Medicines, as well as on the Scientific Advisory Group for Oncology for the European Medicines Agency (the Europe-wide regulatory body). Dr. Smyth also has extensive experience participating in the independent monitoring of clinical trials of checkpoint inhibitor drugs. His work has also focused on the affordability of cancer related healthcare.

Dr. Smyth has published over 300 papers and been involved in 47 books and chapters. He served as Editor-in-Chief of the European Journal of Cancer for a decade, from 2001to 2010. He is a fellow of the Royal College of Physicians of Edinburgh and London, and fellow of the Royal Society of Edinburgh, and is a past president of the European Society of Medical Oncology and the Federation of European Cancer Societies.


That is a lot of expertise.

Yep. A UK chap who had past connections with European regulatory affairs.
Though I've forgotten who the hell he was...
Where's Lykiri when you need him?
What has your question got do with Tony boy?

I doubt he will be seen in a live studio ever again.

It's perfectly possible that any necessary convincing was done way back.
Otherwise, how do you explain the new endpoints?

Thanks Lykiri.
Bang goes my theory that he would turn up in a role in respect of Sawston and / or Advent .
Probably because he doesn't want to change personal base from the US.
That's my rationalisation anyway....

"So LL presenting public information, similar to what Senti and ATL have both posted, shows she has the data,

Can we also then deduce that Senti and ATL (and who knows how many others here) are in the loop?"

Nothing that LL has publically presented definitively shows that she has seen a prelim data analysis of unblinded data.
Though of course I expect she has seen the unblinded data, if not the analysis. She doesn't need to know how the data will be analysed, or what statistical techniques are being employed.
But I would expect her to know the basic results at least.

In answer to your own question; no, of course we can't make such deductions.

Yep, I reckon that is what he said, or at least what he meant.
Somewhere between the two. And he might only be talking about UK subjects, or UK plus German subjects, because he would have greater knowledge of them.

All good..

Hi abc.
I'll listen again, but perhaps it could have been; 'a quarter or a third'.
A 'quarter of a third' doesn't really make sense to me.

I believe that, in a wide-ranging podcast, he is simply giving an approximation of what he is seeing in patients who received a 'personalised immunotherapy'.
A positive and encouraging approximation, in my opinion, but personally, I don't see a need to extract too much ultra-specific meaning by parsing every word.

Don't forget that he is probably the main referrer of patients for treatment under UK Specials (and the surgeon for these).
So he will also know how these patients are progressing. Even though UK Specials treatment hasn't been running that long, he will know what proportion of patients remain progression-free at certain milestones. It appears that if you get to 3yrs without progression, you will probably get to 5yrs and more.

So he may have 'rolled in' his experience with UK Specials somewhat, when talking about his belief that personalised immunotherapy is 'the key'.
Plus the UK patients in the trial might have done just a little bit better anyway. And if so, that might be reflected in his remarks.

And if I caught him right, his first mention was 'a quarter to a third'.

I believe a 'commercial' price is chargeable.
i.e. one that allows for a reasonable margin.

Hi CT.
Yes, once Sawston is licensed as a manufacturing facility, the manufacture for treatment under UK Specials will move from CCGTT in London (where Mark Lowdell is the nominated qualified individual)) to Sawston.

This is in advance of any actual regular drug approval.
And from that point (Sawston being licensed), there will be the scope to basically treat any number of patients, who are legitimately referred under the provisions of the UK Specials scheme.

One could reasonably envisage the referrals (and numbers treated) going up 5 or 10 fold over the following few months, as there will be no limits on manufacturing capacity, and, hopefully, less Covid restrictions in operation.

Not totally sure of international rules. But I believe that a citizen from abroad (diagnosed with GBM), could come to the UK and have an appointment with a UK consultant with the relevant specialisms, and be referred for treatment under UK Specials. (Obviously we are talking mainly about patients with the necessary private financial resources.)

Worthwhile revenue...

I get this weird feeling of deja vu right now, but what the hell....

So you got the 962 by deducting those that didn't have GBM.
And you are stating that the majority of these 962 (less the randomised 331), were excluded due to disease progression.

So that is 631 (with confirmed GBM) who were excluded.

We are both looking at the same table from JTM!
And it clearly states that there were exactly 250 subjects that were excluded due to disease progression or pseudo-progression.
And if it was half progression and half pseudo-progression, that would take it down to 125, excluded due to disease progression.
Even if most of them were genuine progression, say 175, that is still nowhere near a majority of 631..

All these comparator trials did the same thing of excluding subjects who progressed during concurrent chemorad.

Do you think that Novocure didn't exclude those with disease progression?
Of course they did.

The only difference is, that they allowed in subjects whom they had ascertained were experiencing pseudo-progression, by waiting until a follow-up scan or scans was able to make the distinction.

If you think that DCVax-L does nothing, then presumably you think that Optune is even less effective.

(More deja vu...)

Ok. Seeing as the rest of your post is predicated on the above stat that you quote, where did you get your figures from?

If you can't adequately evidence the stat, then the rest of the post pretty much falls by the wayside.

The BLA has to include all of the CMC Process Validation data.
If they want to use Flaskworks from the get-go, straight after approval, then all the Flaskworks process validation data has to be in the BLA. And that means doing all your comparability studies, before you submit the BLA.

If you've got an hour or more to spare, then this FDA video outlines expectations / requirements.

Or this timepoint:-



I expect UK and European requirements are broadly similar.
I'm assuming this is what is currently engaging most of their time and energy. It all has to be done before regulatory submission, if they mean to start their commercial manufacture in the way that they intend to carry it on. Otherwise you have to do a post-approval supplementary submission and then wait for that to be approved.
And getting on with all this, is more important than rushing out a topline announcement that is likely to come across as somewhat ambiguous and confusing to the average reader.

DCvax-L is a cell-based therapy.
What do you think it is?

It's often referred to as a vaccine.
Though I really don't know why. It doesn't immunise or inoculate against a possible future pathogen.
It's a treatment or therapy for an existing cancer.
I guess it's purely related to the delivery method.
And I don't suppose they are going to start calling it something else at this stage, just to please me.

Your link doesn't demonstrate anything to suggest that there is any inherent weakness in an autologous cell therapy that just happens to be injected.
In fact the therapy that that article is touting as somehow superior, also appears to be injected, and is also described as a vaccine!
So do you think it won't work for that reason?

Yep.
I don't know why I even mentioned median OS!

Yes, you are more right on this one than I was.
I thought they cracked on straight after recovery from surgery.
I really should have checked better, before stating what I did.
Seems like it is anything between two weeks and six weeks, depending on which source you read.

Moffitt say the following:-

"Chemotherapy is one of the main forms of treatment for glioblastoma. In most cases, patients start chemotherapy two to four weeks after surgery, at the same time as or shortly after radiation therapy."

The median appears to be about a month or so:-

https://academic.oup.com/neuro-oncology/article/20/7/966/4861801

Well, I expect when the time comes, all reviewing regulators will make appropriate adjustments to make the comparisons as accurate as possible.

NWBO did quote OS data from surgery in JTM, so the SNO update a year later, must also have been from surgery.
So any informal cross-trial comparisons (such as on here), that has been made based on that blinded data, should have been done with adjustment.

But there has been no further blinded data since then, and (obviously) nothing unblinded as yet.
As you say, patients outside of a trial aren't randomised, so they can't use randomisation date for those patients, if they go to patient registries to calculate 'normal' survival averages.
And I haven't picked up that they will formally make those comparisons anyway. And making comparisons with the general GBM population is also fraught with confoundment. For a start, the general GBM population are older than are typically seen in a clinical trial. And not all of the general population are treated by top surgeons and NO's in top hospitals.
So the regulatory reviews will make the focus of comparison against the closest comparable trial's control arms.
And they are the ones that LL has employed in the table.

It doesn't really matter if that final analysis uses surgery or randomisation. If you are, say, 4 months better than the comparators on median OS, then you are 4 months better on median OS than the comparators, whichever startpoint you use.
(Though it does affect 'relative' and 'absolute' calculations a bit).
Having said that median OS is not the best metric to define DCVax-L. Because you miss the all-important long tail.
We have long known this.

DCVax-L is 100% certain to show a huge statistically significant advantage over the comparators on OS, measured by RMST (area under the curve) and at all milestone time points from OS36 and beyond, whatever clock start is used.

So the start point issue isn't really an issue anyway!

Concurrent chemorad would normally start within a few days of surgery, while still an in-patient. So the the 6 weeks concurrent would normally be over between 6 and 7 weeks from surgery.

Well yes, the CT site does state that for the PFS primary (as was). But that was for the two arms of the trial.
Obviously if you're doing the external comparator thing, you have to make appropriate and accurate adjustment, so that a PFS (or OS) comparison is as fair as you can make it.
And there is some adjustment to be made, as the Liau table shows.
But Ex was overstating things with the '3 months plus' bit.

Oh yes. The Gilbert 'dose-dense' v 'standard' maintenance chemo had to be randomised straight after the 6 weeks concurrent chemorad, because the whole trial was about which schedule of follow-on maintenance chemo was better.
In fact I think they also randomised some during the 6-weeks concurrent.
So that trial was definitely not '3 months plus' to randomisation, as Ex suggested.

Hi ATL.
Basically, it takes a deep dive into each trial to see exactly when they randomised. And nobody sets the clock running any time later than randomisation.

So I'm questioning Ex's assertion that all the comparator trials didn't randomise until '3 months plus' after diagnosis or surgery.

He is basically suggesting that NWBO is making their stats look 3 months better by backdating to diagnosis / surgery.

What I'm suggesting is that it is not at all that cut and dried.
And less than the '3 months plus' that he is suggesting.
Because most of these trials were randomising straight after the 6 weeks concurrent (or earlier).
Which is likely 6-7 weeks from surgery, as your cited table suggests. Not the 3 months plus that Ex states.
Optune were randomising as early 43 days from diagnosis, which must have been before the end of concurrent chemorad.


I haven't done all the checking myself of each trial (nor will I probably do so).
But I just like to query Ex when he makes a broad brush statement, that isn't completely accurate.

Perhaps we should list all the trials we are talking about.

You're not wholly wrong on this occasion, but you're not wholly right either!