NorthWest Biotherapeutics Inc (NWBO)

[ae kusterer]

Is this true? If it is, you really are a piece of garbage and should be ashamed of yourself!!!
"Dr." Matt Williams is not a medical doctor. He's a PhD in computational physics. He runs the
largest Optune clinic in the UK.

— Hspooner (@Hspooner665) November 30, 2022

As some of you know, we have concerns about the recent @NWBIO DCVax trial in GBM

We have now clarified these in our submitted comment, joint from 8 UK centres. Our patients deserve better.@braintumourrsch@BrainTumourOrghttps://t.co/icfyymEYvB

— Matt Williams (@matthwilliams) November 30, 2022

This you? Do you really run the largest Optune clinic in the UK? Do you not consider that a conflict of interest? How do you sleep at night? $NWBOhttps://t.co/217qN9Tfpe

— Joey Carroll (@TVsJoeCarroll) December 1, 2022

exwannabe

Re: lutherBlissett post# 540761

Wednesday, November 30, 2022 12:25:54 PM

Post#
540785
of 541103
November 30, 2022
The need to report as-planned analyses and the weakness of historical controls

Matt Williams, MbChB FRCR PHD | Imperial College Hospitals NHS Trust

We would like to congratulate the authors on conducting a large, multi-centre, international study in patients with Glioblastoma (GBM). However, due to the methodology used it is difficult to conclude that the experimental arm, addition of autologous tumour lysate-pulsed dendritic cell vaccine (DCVax), improves the outcome beyond standard of care in newly diagnosed Glioblastoma.

Our main concern with the methodology is the change in comparison arm. In the original version of the protocol provided, the primary and secondary endpoints were specified as PFS and OS, compared between the treatment cohort and the placebo cohort. The published study compared treated cohort with external controls. This change in comparator partway through the trial is not highlighted in the methods section of the final publication. The explanation given in the paper about PFS being confounded by immune-mediated effects does not explain the switch from comparing the randomised arms to using external controls. Although one possible reason could be to account for the number of patients in the control arm crossed-over to active treatment, we are not aware of any treatment, for any solid tumour, where treatment at relapse produces comparable survival to use in the upfront setting.

This is particularly problematic because the trial mandated exclusion of patients with significant residual disease, bilateral disease or early disease progression. In fact out of 1599 patients screened, 1268 were excluded for a range of reasons including disease progression and early clinical deterioration (Liau JTM 2018). While the matched cohort included some trials that excluded early progression, not all did, and since these were different trials, patients may have been excluded using different definitions of early progression from that used in this trial. In addition, there is evidence of general improvement in OS in patients with GBM enrolled in trials: for example, the median OS in the control studies for patients with MGMT methylated GBM receiving chemo-radiotherapy with Temozolomide is quoted as being 21.3 months; we note that the recent NOA-09 study had a median OS of 31 months in that same group of patients, emphasising the importance of using data from contemperaneous randomised controls. The general effect is these would be to increase the survival rate in the trial arm, irrespective of the effect of DCVax.

It is particularly interesting that the greatest benefit may be in the older age group, and confined to the subtotally resected (OS 17.5mo vs 14.2mo in subtotally resected historical controls), rather than completely resected (20.3mo vs 20.4mo). Furthermore it is interesting to note the benefit reported in the second line setting against externally matched controls. This hypothesis generating data does warrant further exploration.

We recognise the benefits of novel trial designs to accelerate advances. For example, the flexible nature of the multi arm multi stage design has been successfully used in other cancers. (SydesTrials 2012). However, as per the GBM AGILE platform study, it important to retain a contemporaneous control arm (Alexander Clin Can Res 2018).

We recommend an addendum clarifying the change in trial design, and reporting the results as specified in the initial protocol.


Dr. Matt Williams, London
Dr. Paul Sanghera, Birmingham
Prof. Susan Short, Leeds
Dr. Anup Vinayan, London
Dr. Juliet Brock, Oxford
Dr. Chris Herbert, Bristol
Dr. Joanne Lewis, Newcastle
Dr. Shaveta Mehta, Liverpool
(All UK Cancer Centres; truncated for length)

https://www.finder.bupa.co.uk/Consultant/view/165944/dr_paul_sanghera (radiologist)

CONFLICT OF INTEREST: None Reported