TRK Inhibitor Active in Treatment-Refractory Glioblastoma

HOUSTON — A fourth of patients with TRK fusion primary central nervous system tumors responded to the TRK inhibitor larotrectinib (Vitrakvi), including almost 40% of pediatric patients, pooled data from two studies showed.

Overall, 15 of 55 (27%) patients had objective responses, including three complete responses. The 38 pediatric patients included in the analysis had an objective response rate (ORR) of 37%. Among 39 patients with measurable disease at baseline, the ORR was 38%, increasing to 52% in the pediatric subgroup.

The 38 pediatric patients had a 24-month disease control rate of 74%, a median duration of response of 17 months, a median progression-free survival (PFS) of 20 months, and a 3-year overall survival (OS) rate of 64%, reported Sébastien Perreault, MD, of CHU Sainte Justine in Montreal, at the Society for NeuroOncology annual meeting.

“Larotrectinib had a manageable safety profile in all patients with TRK fusion primary CNS tumors,” said Perreault. “Five patients entered ‘wait-and-see’ [treatment pause] and did not have documented progression. These results support the wider adoption of next-generation sequencing panels that include NTRK gene fusions when testing for CNS tumors.”

The analysis included patients from two multicenter, open-label trials of larotrectinib in various types of TRK fusion tumors, one involving pediatric patients and the other with adults and children. CNS tumors represented in the analysis were 32 high-grade gliomas, 15 low-grade gliomas, and eight other types of tumors. The 55 patients included 16 with non-measurable disease at baseline.

In the pediatric study, five patients paused treatment for a median of 20 months, and none had documented disease progression, said Perreault.

Adverse events (AEs) were primarily grade 1/2, and no patients discontinued treatment because of AEs.

ATM Pathway Inhibitor

An investigational ATM pathway inhibitor has shown preliminary activity in combination with radiotherapy in patients with glioblastoma, according to a phase 0/Ib study.

Among 21 patients treated to date with AZD1390, 15 with recurrent disease had a median OS of 13.8 months and median PFS of 10.8 months. Landmark analyses showed a 12-month OS rate of 57.1% and 6-month PFS rate of 50%. Six patients with newly diagnosed MGMT-unmethylated tumors had a 6-month PFS rate of 83%, and median PFS had yet to be reached.

“There were no notable or unexpected toxicities, and the drug was quite well tolerated, as expected,” said Yoshie Umemura, MD, of the Ivy Brain Tumor Center at Barrow Neurological Institute in Phoenix. “The drug was well penetrating into the central nervous system, even at low doses.”

“The survival analysis is still pending,” she added. “However, I would like to note that these findings, in conjunction with a separate phase I study in glioblastoma, have led to a randomized controlled phase II/III study.”

Development of AZD1390 originated from evidence that ATM inhibition may potentiate radiotherapy by preventing acute-phase DNA damage repair. The trial included a pharmacokinetic threshold for entry into the clinical-efficacy component.

Drug concentrations were assessed serially after tumor resection, followed by ex vivo exposure to a 5-Gy radiation dose. Samples that achieved a pRAD50 “trigger” level as compared with non-irradiated tissue qualified patients for clinical evaluation of the drug plus intensity-modulated radiotherapy.

Sonodynamic Therapy

A novel device that delivers non-ablative low-intensity ultrasound passed a first-in-human test in patients with recurrent high-grade glioma.

Used in conjunction with the oral sonosensitizing agent 5-ALA, the sonodynamic therapy led to a median OS of 15.7 months in 12 patients with treatment-refractory glioma compared with 6.8 months in a historical control group. Average and median PFS were 6.2 and 5.5 months, respectively, as compared with 1.8 months in the historical controls.

“If you look at survival with lomustine for recurrent glioblastoma or bevacizumab [Avastin], you see essentially a doubling of median survival,” said Michael Schulder, MD, of the Zucker School of Medicine at Hofstra/Northwell in Lake Success, New York. “I think these are very exciting results with a therapy for diffuse disease, that is repeatable for patients with persistent disease. We’re excited about moving forward with a randomized controlled trial next year, and Alpheus Medical is going to be looking at applying this technology elsewhere in the body.”

5-ALA selectively accumulates in tumor cells as protoporphyrin, a naturally occurring autofluorescent compound, Schulder noted in his introductory comments. The substance has been approved in the U.S. since 2017 for use in conjunction with fluorescence-guided surgery for glioblastoma. However, use of light-activated 5-ALA to treat brain tumors has been restricted to small tumors because of limited tissue penetration and treatment complexity.

Sonodynamic therapy involves administration of oral 5-ALA, followed by external application of low-level ultrasound energy to 10 brain regions. The energy is delivered via individual electrodes, and application to each region lasts approximately 12 minutes. Patients return for 2-hour treatment sessions at 4-week intervals. Schulder said Alpheus has developed a new treatment helmet that will improve patient convenience.