I think Drs. Liau, Ashkan and Bosch did a good job explaining the trial, how they chose the comparison data and how they addressed potential bias. IMO the only clear bias is being expressed by certain anonymous message board posters....
April 11, 2023 Authors' Response Marnix Bosch, BS, MBA, PhD | Northwest Biotherapeutics, Inc We appreciate the comments made by Dr. Matt Williams and colleagues, and their recognition that novel trial designs can accelerate advances. They acknowledge our rationale for moving away from a progression free survival (PFS) endpoint which is confounded by immune mediated effects, while they question why external controls were needed for the overall survival (OS) endpoint. As explained in our paper, the reasons included substantial depletion of the control arm due to the crossover trial design allowing control patients to receive DCVax-L following recurrence. The rationale did not require that patients crossing over from placebo achieve any treatment effect, as erroneously implied by Williams, because receiving DCVax-L at any time point automatically disqualified these patients from being true controls for a survival endpoint.
Regarding in-/exclusion of patients, as previously reported, the screening process began before the initial surgical resection, and the largest exclusion of patients was because they were found not to have glioblastoma, and the next largest exclusion was because the patient’s tumor was too small to provide sufficient tumor protein to meet eligibility criteria. Additionally, although there was an intent for near gross total resection at screening, we still included patients if this goal was not met (i.e., patients with significant residual disease after surgery).
Williams observes that not all the comparator trials excluded patients with early progression. As explained in our paper, we too noted this and checked for bias by conducting sensitivity analyses specifically on this factor. These analyses found that the hazard ratio remained the same with those trials excluded, and the OS benefit of DCVax-L remained statistically significant.
We agree with Williams that it is important for comparison data to be contemporaneous. This was an express factor in the selection of the external controls for our trial by independent experts. Williams suggests that the NOA-09 study with an mOS of 31 months in MGMT methylated patients may be a more appropriate comparator than the mOS of 21.3 months seen in the 5 large contemporaneous trials we used as comparators for our study. However, the NOA-09 trial enrolled only a selected subset of MGMT methylated patients, and is not representative given the chosen cutoff in the MGMT assays. As the authors of the report on the NOA-09 trial themselves recognize: “Median overall survival in the temozolomide group [i.e., control group] of our trial was greater than that of comparable historical groups of patients with tumors with methylated MGMT …”. So far, the NOA-09 trial has proven to be an outlier, and it is therefore a less appropriate comparison for our trial than the 5 large contemporaneous trials we used.
We agree that the DCVax-L trial results include some interesting (and clinically useful) observations, such as the greater relative benefit seen in older patients and in patients with subtotal resections, in addition to the encouraging overall results. We look forward to further exploring these findings.
Linda M. Liau, MD, PhD, University of California, Los Angeles, USA Keyoumars Ashkan, MD, FRCP, FRCS, Kings College Hospital, London, UK Marnix L. Bosch, PhD, Northwest Biotherapeutics, Inc
Dr Liau reported serving on the board of directors of ClearPoint Neuro outside the submitted work and having a patent pending for combinations of inhibitors with dendric cell vaccines to treat cancer. Dr Ashkan reported receiving grants from Northwest Biotherapeutics during the study conduct.
CONFLICT OF INTEREST: Dr Bosch reported being an employee of and owning shares in Northwest Biotherapeutics, Inc. and reported having patent 13/492693 pending.
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