NorthWest Biotherapeutics Inc (NWBO)

[Lykiri]

Chris brought in a fudster who has zero knowledge of the trial numbers

Dr Bala,

Unfortunately, there are scientists who have little knowledge of the trial data.
Read this:
Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?
Ethan Chen, Alexander L Ling, David A Reardon, E Antonio Chiocca

Published: 23 November 2023

https://academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noad211/7444576?login=false

DCVax-L: Autologous Dendritic Cells Pulsed With Autologous GBM Lysates

DCVax-L(57) was the first phase 3 clinical trial for GBM with a personalized component (Table 1). In this trial, patients underwent SOC for GBM and then received several doses of autologous dendritic cells processed and activated using patient tumor lysate as loaded vaccines.58 The injected dendritic cells then theoretically induced immune recognition of tumor antigens and increased intratumoral antitumor immunity, potentiating immune memory.
There have been 2 reports related to the results from the phase 3 trial. The first preliminary report of 331 subjects randomized after surgery and chemoradiation to receive DCVax-L and TMZ (n = 232) versus placebo and TMZ (n = 99) reported a mOS of 23.1 months for the former.(58) Two hundred and fifty out of 1599 screened patients were excluded per protocol if there was MRI evidence of early progression or pseudoprogression after standard chemoradiation, a trial exclusionary criterion that is fairly routine. This exclusion (both for the placebo and the DCVax-L group) would ensure that aggressive tumors able to evade chemoradiation would not be in the trial and perhaps make OS and PFS times longer than one would expect from a general GBM population. The mOS for the placebo group was not reported because 90% of subjects crossed over from the placebo to the DCVax-L group upon determination of progression (based on MRI) from treatment. In fact, the trial design initially allowed this crossover because the primary endpoint was PFS and not mOS. The crossover allowed in the trial underscores the need for appropriate prospective statistical designs in RCTs allowing for this occurrence. The absence of reporting of data for the placebo group also is not a common occurrence in RCTs. In this trial approximately 30% of the subjects (n = 100) initially were reported to show extended survival. This was not fully explained by known prognostic factors: only 29% were younger than 50 years of age, 65.9% had methylated MGMT, 71% had a complete resection, and only 8% of these patients had all 3 positive prognostic factors. However, the status of IDH was not reported presumably because the trial was conducted at a time (2007–2015) when IDH status was not yet fully available at all centers, and this would confound the interpretation of this survival data.

The second and final report was recently published.(59) In this manuscript, the data were reanalyzed and now the DCVax-L group exhibited a mOS of 19.3 months, almost 4 months lower than the one reported previously. To increase statistical power to the small number of control group patients that had not crossed over, the authors supplemented these with an external control population that exhibited a mOS of 16.5 months. There have been several criticisms leveled to the design and analyses of this trial, most notably the fact that the originally stated primary endpoint of PFS was not different between the groups, presumably because the possibility of vaccine-induced inflammation would have obscured the estimate of MRI-based progression.(60,61) In addition, flaws of the external controls including lack of propensity matching may confound the interpretation of the results. Lastly, the relatively prolonged time that occurred between the end of the trial and this final report is also problematic because of changes in classification of disease and patient and provider expectations related to perceived benefits of a therapy without possibility of critical peer-reviewed evaluation of the data.

Like the other phase 3 studies, though, the relative absence of biomarker data from subject tissues during study therapy limits the ability of the scientific and clinical community to know whether a biologic and immunologic effect did occur in some subjects like the ones who survived the longest (11% at 30 months). It should be noted though that the authors did show increased TILs and other biomarkers of immunological response in tumors treated with DCVax-L which correlated with survival in previous small phase 1 trials.(62–65) With this knowledge, it may have been possible to try and design trials based on this biologic and immunologic biomarker data.

DCVax-L (dendritic cell vaccine pulsed with autologous GBM lysates)
1—Reason for failure: The clinical trial primary endpoint was PFS based on MRI imaging.
Lesson learned: With immunotherapies, tumor inflammation can make MRIs difficult to interpret in terms of progression.
2—Reason for failure: The clinical trial allowed for subjects in placebo group to “cross over” to treatment group upon suspected progression.
Lesson Learned: With a high degree of “crossover,” the statistical power to evaluate OS in the placebo group was lost. Current attempts to include external control groups may be limited in being accepted by medical and regulatory community.
3—Reason for failure: Absence of biomarker data inhibits our understanding of the reasons behind the “tail” of long-term survivors in the trial.
Lesson learned: Need to include biomarker data via longitudinal sampling during the trial.