Sorafenib and temsirolimus demonstrated limited activity with high rates of toxicity among patients with recurrent glioblastoma, according to a study published in Cancer.1

Sorafenib and temsirolimus target VEGFR-2 and mTOR, respectively, both of which are implicated in glioblastoma proliferation. For this phase 1/2 study (ClinicalTrials.gov Identifier: NCT00329719), patients were enrolled into a phase 1 dose-finding study or a phase 2 component. Eligible patients had recurrent glioblastoma after surgery or radiotherapy plus temozolomide and had previously received 2 or fewer systemic chemotherapy regimens.

The phase 1 study used a 3+3 dose escalation design to determine the maximum tolerated doses (MTDs) of sorafenib and temsirolimus. No dose-limiting toxicities (DLTs) were observed in patients at dose level 0 (sorafenib 200 twice daily and temsirolimus 25 mg weekly), but DLTs including grade 4 gastrointestinal perforation and grade 3 vomiting, nausea, and fatigue were observed once doses were increased to sorafenib 400 mg twice daily and temsirolimus 25 mg weekly.

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In the phase 2 component, the median overall survival was 6.3 months vs 3.9 months for VEGFi-naive patients vs patients previously treated with a VEGFi, respectively.

Among the first 41 evaluable patients for phase 2, 7 patients (17.1%) in the VEGFi-naive arm had a progression-free survival (PFS) of 6 months and met the predetermined threshold for treatment success. Among patients previously treated with a VEGFi, only 4 patients (9.8%) of 41 had a PFS of 6 months, which did not meet the success threshold.

Over 75% and 73.9% of VEGFi-naive and prior VEGFi patients, respectively, had at least 1 grade 3 or worse adverse event.

The authors concluded that “significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy.”

Reference

  1. Schiff D, Jaeckle KA, Anderson SK, et al. Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572. Cancer. 2018 Jan 3. doi: 10.1002/cncr.31219 [Epub ahead of print]