So, do these results prove activity of DCVax-L in glioblastoma? The answer to this question is clearly: no, they do not. Indeed, there is a trend towards the recognition of the validity of external controls for comparison, but it really requires a near total similarity between trials or datasets—from the way diagnoses are made, the trial design, inclusion criteria, endpoints and the centers participating.4,5 And here, major differences are present.
The study (NCT00045968) was initially designed in 2007 as a prospective multicentric placebo-controlled randomized phase III trial. Patients with newly diagnosed glioblastoma were to be randomized in a 2:1 ratio to standard radiochemotherapy with either placebo or DCVax-L. With cross-over to the active treatment for the patients in the control arm at the time of progression being part of the study protocol, the primary endpoint had to be progression-free survival (PFS). The trial was conducted at 94 sites in 4 countries (US, Canada, UK, and Germany) and enrolled a total of 331 patients (232 patients randomized to the DCVax-L group, and 99 patients randomized to the placebo group) over a period of eight years (August 2007 until November 2015), with the vast majority of patients (n = 303, 91.5%) accrued between 2012 and 2015. An initial report on the trial in 2018 reported only on the combined overall survival (OS) data of both study arms and failed to report on PFS, the primary study endpoint.3 The argument for not publishing the primary endpoint was an ambiguous statement about an expert panel being required because of the complex determination of progression. Nonetheless, the authors concluded that the patients in this trial were living longer than expected. Now, more than four years later, a second report is available, which is surprisingly named “A Phase 3 Prospective Externally Controlled Cohort Trial”. This is a remarkable title, as the investigators have re-analyzed the OS data of the study against published external controls and present this as a prospective trial. It is obvious, however, that this is not a prospective analysis but a post hoc retrospective analysis: the investigators had seen the data, both of their own study and of the cohorts taken for comparison and then decided to go ahead with cross-trial comparisons. The authors state that the PFS endpoint became infeasible because of pseudo-progression issues, however, to the best of our knowledge in no other study that issue has resulted in abandoning the primary endpoint. Fortunately, the numerical PFS data are now presented: the median PFS was 6.2 (95% confidence interval CI 5.7–7.4) months for patients receiving DCVax-L and 7.6 (95% CI 5.6–10.9) months for the placebo group and not statistically significantly different (P = .47). Thus, the clinical trial did not reach its prospectively defined primary endpoint and with that, the investigators de facto declare the randomized trial in its original and prospective
design to be negative.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076936/
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