Single-Agent ONC201 Induces Responses in Patients with Hard-to-Treat Recurrent High-Grade Glioma

High-grade gliomas harboring the histone 3 (H3) K27M mutation are lethal brain tumors associated with a poor prognosis. At the 2019 American Society of Clinical Oncology Annual Meeting, results from a clinical trial showed that treatment with ONC201, a unique, small molecule DRD2 antagonist, resulted in durable tumor regression in adults with recurrent high-grade H3 K27M-mutant gliomas.

Data from 29 adult patients who were treated with single-agent ONC201 as of January 20, 2019, showed an objective response rate (ORR) of 27% in contrast-enhancing disease, 36% in noncontrast-enhancing disease, and 47% in either contrast-enhancing or noncontrast-enhancing disease.

The response rates are “exceedingly rare in this tumor type, with really no responses being reported in the literature in the recurrent setting,” said lead investigator Isabel Arrillaga-Romany, MD, PhD, Associate Clinical Director, Neuro-Oncology, Massachusetts General Hospital, Boston.

“There exists a subgroup of highly aggressive, high-grade gliomas that are characterized by their midline location in addition to their unique molecular signature, and that is a mutation in the histone 3 protein at position 27,” said Dr Arrillaga-Romany. These tumors are most frequently found in pediatric populations but also occur in adults, and they are invariably lethal.

ONC201 is a DRD2 antagonist and CLPP agonist that induces tumor cell apoptosis. ONC201 may work selectively in H3 K27M-mutant gliomas because of its associated dopamine receptor deregulation.

“We have shown in other gliomas, that there is a signature associated with increased sensitivity to ONC201, and that is elevated DRD2 expression and low DRD5 expression, and that is exactly what we see in the H3 K27M mutations,” Dr Arrillaga-Romany said.

A total of 27 patients were treated with ONC201 as part of 2 ongoing phase 2 clinical trials and 2 under compassionate use protocols. ONC201 was administered orally at 625 mg weekly, except for 1 patient dosed once every 3 weeks. The median age of patients was 35 years. Some 52% of tumors were located in the thalamus and 21% were located in the brain stem. Of all the patients, 48% had multifocal disease. The median number of lesions per patient was 2. Ninety percent of patients had received prior treatment with temozolomide and all patients received previous radiation at a median 8.5 months from its completion to initiation of ONC201.

Eleven of 29 patients remain on therapy with a median follow-up of 9.0 months. “Three of those patients have remained on therapy after progression due to investigator discretion, seeing that the patients have clinical benefit on therapy,” Dr Arrillaga-Romany noted.

Fifteen patients were evaluable for radiographic response; patients enrolled after December 2018 were excluded to enable a minimum of a 6-month readout for efficacy. An ORR by blinded independent central review was observed in 4 of 15 (27%) contrast-enhancing lesions, with 1 complete response, 3 partial responses, and 7 best responses being stable disease.

The ORR in noncontrast-enhancing disease was 36% (5 of 14, with 1 patient unevaluable), with 1 complete response, 1 partial response, 3 minor responses, and 4 best responses being stable disease. In considering contrast-enhancing or noncontrast-enhancing disease, the ORR was 47% (7 of 15).

In contrast-enhancing disease, the median onset of response was 2.6 months and the median duration of response was not reached with a median follow-up of 7.7 months. Some of the responses were associated with improvements in disease-associated neurologic symptoms.

At 6 months, 33% of patients were free of disease progression. Median overall survival was not reached with a median follow-up of 7.5 months.

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