Findings from a phase I study suggest that delivering high concentrations of the chemotherapy 5-FU directly to brain tumors via the retroviral vector vocimagene amiretrorepvec, or Toca 511, may benefit patients with recurrent high-grade glioma. This investigational treatment was well tolerated and induced robust, durable responses lasting a median of 3 years.

Using a retroviral vector to deliver high local concentrations of chemotherapy to the brain may benefit patients with recurrent high-grade glioma (HGG), a particularly aggressive cancer including glioblastoma and anaplastic astrocytoma, for which few treatment options exist.

Vocimagene amiretrorepvec (Tocagen), also called Toca 511, selectively replicates in cancer cells, inducing them to produce the enzyme cytosine deaminase (CD), explained study investigator Clark Chen, MD, PhD, head of neurosurgery at the University of Minnesota Medical School in Minneapolis. Approximately 1 month after patients receive an injection of Toca 511 at the tumor site, they take the prodrug 5-FC in pill form. Upon circulation to the brain, 5-FC is converted by CD into the chemotherapy 5-FU.

Study results on Toca 511′s clinical potential in HGG were first published last year. At the 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 26–30 in Philadelphia, PA, Chen highlighted a subset of 23 patients in that phase I dose-escalation trial, most with glioblastoma, who received higher doses of Toca 511. The median overall survival (OS) was 14.4 months. Five complete responses were seen, and the median duration of response was 35.7 months.

Three-year survival is rare with HGG, so “this is a pretty striking signal,” Chen said. “The fact that glioblastoma very seldom leaves the brain is an attractive feature, in a way, because we can use Toca 511 to generate chemotherapy where it really matters. As well, patients are spared the toxicity of systemic 5-FU.”

Chen noted that the findings compared favorably with historical data from a study in which patients with glioblastoma were given lomustine, another chemotherapy. There, the median OS was 8.4 months, and the duration of response ranged from 2.8 months to 9.6 months.

Toca 511 was very well tolerated overall—mild fatigue and diarrhea were the main side effects, Chen reported, and “virtually no hematologic toxicities” were seen, unlike with lomustine.

Interestingly, Chen added, two patients recorded as having achieved partial responses were, over time, reclassified as complete responders, suggesting an immunologic component to Toca 511. Preclinically, his colleagues have shown that the high local concentrations of 5-FU generated through Toca 511 eliminate immunosuppressive myeloid cells, which may help establish a more conducive milieu for T cell–driven antitumor immunity.

Toca 511 has earned Breakthrough Therapy and PRIME designations from the FDA and the European Medicines Agency, respectively. Chen and his colleagues have also identified an mRNA expression signature, termed survival-related neuronal subtype (SRNS), which they think may be associated with longer survival following treatment.

“It could help us figure out who is more likely to benefit from this therapy,” he said of SRNS, but added that further validation is needed. The investigators hope to provide this validation, as well as to confirm Toca 511′s early efficacy and safety data, in an ongoing global phase II/III trial. –Alissa Poh

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.