EXTH-42. Lost in translation: Do preclinical studies predict clinical failure in GBM?

Abstract Despite intensive research over the past two decades, all glioblastoma (GBM) Phase 3 drug trials have been negative. The utility of the preclinical studies used to inform development for 10 Phase 3 trials was evaluated by four criteria: 1) drug distribution to the brain, 2) tumor location (flank vs. intracranial), 3) GBM xenograft source (patient-derived (PD) vs. cell line-derived (CD)), and 4) magnitude of survival extension. For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%. B/P for imatinib was 1-3% and the other four drugs ranged from 25% to 51%. Except for enzastaurin, all drugs were studied in orthotopic tumor survival studies. The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide. However, only veliparib and sunitinib were studied in orthotopic PD models, and a single CD model (U87 or D54) was used exclusively for four drugs (enzastaurin, nimotuzumab, sunitinib, marizomib). In summary, 6 of 10 drugs had unknown or very poor brain distribution, 8 of 10 drugs were tested exclusively in CD models, which have questionable translational value, and 3 of 10 drugs had nominal activity (<50% survival prolongation) in preclinical survival studies. The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into advanced clinical testing.