SNO summary: Durable responses with Toca 511 + Toca FC

I already posted on this data at the end of October, but here is my long form write-up.

Durable responses observed in IDH1 wildtype and mutant recurrent high grade glioma (rHGG) with Toca 511 & Toca FC treatment

Timothy Cloughesy of UCLA presented updated results for the phase 1 trial of tumor resection followed by injection of Toca 511 into the tumor resection cavity.  This trial (NCT01470794) treated 56 patients with recurrent glioblastoma or anaplastic astrocytoma (WHO grades 3 and 4).  

Pooling results across all three phase 1 dose escalation trials (n=127 patients), Toca 511 was found to be well tolerated, with only 25% of patients experiencing grade 1 or 2 treatment-related adverse events (including fatigue in 11%), and 7% of patients experiencing a grade 3 or higher treatment-related adverse event (including one case of headache, one case of fatigue, and two cases of vasogenic cerebral edema). Administration of the fluorouracil prodrug, Toca FC, was also associated with a low incidence (3.3%) of grade 3 or higher treatment-related adverse events.  Only three out of 122 patients discontinued therapy due to adverse events associated with Toca FC.

In the NCT01470794 trial of resection followed by injection of Toca 511 into the resection cavity, 46/56 (82%) of patients had recurrent glioblastoma, and the remainder had anaplastic (grade 3) or other gliomas.  50% were at first recurrence, 23% were at second recurrence, and 27% were at third or more recurrence.  

This trial included the endpoint of durable response rate, defined as a response lasting at least 24 weeks (5.5 months).  Remarkably, all responders (6 out of 53 patients evaluable for efficacy, 11.3%) are in complete response and still alive, with a median duration of response of at least 35.1 months (nearly 3 years). An additional 18.9% had stable disease as best response, for a clinical benefit rate of 30.2% (response plus stable disease).

In the subset of patients (n=23) treated with higher doses of Toca 511 and meeting the eligibility criteria for the ongoing phase 3 Toca 5 trial (at first or second recurrence, no prior Avastin, and tumor no larger than 5 cm), there were 5 out of 23 patients (21.7%) with durable complete response lasting for a median of 35.7+ months.  An additional 21.7% had stable disease as best response, for a total clinical benefit rate (response + stable disease) of 43.5%.  In this subgroup of 23 patients, three of the complete responders had wild-type IDH1, and two had anaplastic astrocytoma with mutant IDH1. These responses occurred gradually over 6-19 months, consistent with an immunologic mechanism of action.  Median survival from Toca 511 treatment in this subgroup is 14.4 months, which compares favorably with historical benchmarks of 9-10 months for recurrent GBM with standard treatments.

The safety profile, increased median survival relative to historical benchmarks, and relatively high rate of complete durable responses lasting for a median of at least three years is encouraging.  The randomized phase 2/3 Toca 5 trial for recurrent glioblastoma or anaplastic astrocytoma (NCT02414165) recently re-opened in November 2017 to new recruitment and the phase 1 Toca 7 trial for newly diagnosed high grade glioma (NCT02598011) is scheduled to open sometime in 2018.