Abstract Purpose: Existing salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median survival of approximately 9 months. Given the complex molecular heterogeneity of GBM, single-target approaches have consistently failed as a treatment strategy. We conducted a phase 1 clinical trial to assess the feasibility, safety, and efficacy of a genomically-tailored multi-agent regimen in 30 adults with surgically-treated rGBM. Patients and Methods: Adults with IDH-wildtype glioblastoma (n=29) or grade 4 IDH-mutant astrocytoma (n=1) were consented and underwent clinically-indicated surgery for recurrent disease. Comprehensive genomic profiling was performed on the recurrent tumors, and results for each patient were discussed at an individualized molecular tumor board to determine a personalized treatment regimen combining up to 4 FDA-approved drugs, including one cytotoxic agent as backbone. Results: A total of 12 drugs were used in 18 combinations – the most common regimen was lomustine, afatinib, and abemaciclib (n=8). The most common toxicities included cytopenias, rash, and gastrointestinal symptoms, requiring frequent dose reductions. Measured from surgery at trial enrollment, progression-free survival at 6 months (PFS-6) was 40%, overall survival at 9 months (OS-9) was 73%, and median OS was 12.7 months. After trial therapy, genomic profiling performed on subsequent recurrent tumor specimens identified genetic evolution corresponding to putative treatment resistance mechanisms. Conclusions: Implementation of individualized treatment regimens in a timely fashion was feasible for patients with surgically resectable rGBM. Overall efficacy was not significantly improved compared to a contemporary patient cohort treated without experimental regimens, with full dosing of most combination therapies limited by toxicities.
Chen et al. (Fri,) studied this question.
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