Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

Abstract

Background: Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient.

Methods: In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC.

Results: Among 56 patients, durable complete responses were observed. A subgroup was identified based on Toca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival.

Conclusions: Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

Figures

Fig. 1

Top panel: timeline of Toca 511 delivery, Toca FC dosing, and MRI. Bottom panel: independent radiology review determined radiographic response after Toca 511 + Toca FC therapy. The left temporal tumor is shown to be progressing prior to surgical resection. After surgical resection, residual tumor remains, which continues to grow postoperatively. Following Toca FC administration, there is gradual decrease of the tumor to a partial response and then to a complete response (see Supplementary Fig. S2 for complete series).

Fig. 2

Swim lane demonstrating responses are durable (≥24 wk) and associated with long-term survival.

Fig. 3

Summary of RNA and DNA sequencing results from patient tumors. (Left to right) The barplot shows the total number of high confidence mutations called from exome sequencing data by MuSE (Mutation calling using a Markov Substitution model for Evolution). The first 3 left columns summarize results from RNA sequencing: molecular subtype (mesenchymal—red, classical—black, neural—green, proneural—blue), and IDH1 R132H/S mutation (orange). The next 4 columns show response (CR—green, stable disease—purple, progressive disease—orange), clinical features, including eligibility for phase III trial (phase III eligible subgroup—yellow), tumor grade at study entry as determined by clinical site pathologist (WHO grade IV = gray, grade III = black), and number of recurrences (1 or 2—light brown, >2—dark brown). Patients are ordered by duration of survival post resection and Toca 511 treatment. Patients alive at last contact are indicated by light blue bars.