The Lynx Group

Selective, Small-Molecule DRD2 Antagonist Induces Tumor Regression in Recurrent High-Grade Glioma

August 2019, Vol 10, No 4 | Payers’ Perspectives In Oncology: ASCO

Chicago, IL—ONC201, a small-molecule DRD2 antagonist, results in durable tumor regression in adults with recurrent high-grade H3-K27M gliomas, reported lead investigator Isabel Arrillaga-Romany, MD, PhD, Associate Clinical Director, Neuro-Oncology, Massachusetts General Hospital Cancer Center, Boston, at ASCO 2019.

Data from 29 adults who received treatment with single-agent oral ONC201 as of January 20, 2019, showed an objective response rate (ORR) of 27% in contrast-enhancing disease, 36% ORR in non–contrast-enhancing disease, and 47% ORR in contrast-enhancing or non–contrast-enhancing disease.

These response rates are “exceedingly rare in this tumor type, with really no responses being reported in the literature in the recurrent setting,” said Dr Arrillaga-Romany. There are no therapies for recurrent high-grade gliomas that can improve survival.

“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 [H3] 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 induced tumor-cell apoptosis. ONC201 may work selectively in H3-K27M mutation–positive 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,” she said.

Durable Response in Phase 2 Studies

A total of 27 patients (median age, 35 years) received treatment with oral ONC201 as part of 2 ongoing phase 2 clinical trials and 2 patients under the compassionate use protocol. ONC201 625 mg was administered weekly, except for 1 patient who was dosed once every 3 weeks.

In all, 52% of tumors were located in the thalamus and 21% in the brain stem; 48% of patients had multifocal disease. The median number of lesions per patient was 2. Overall, 90% of patients had received temozolomide ­(Temodar), and all patients had received radiation at a median of 8.5 months from its completion to the initiation of ONC201.

Of 29 patients, 11 continued to receive treatment with ONC201, with a median follow-up of 9 months. “Three of those patients have remained on therapy after progression due to investigator discretion, seeing that the patients have clinical benefit on therapy,” said Dr Arrillaga-Romany.

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

The ORR of the patients with non–contrast-enhancing disease was 36%, with 1 complete response, 1 partial response, 3 minor responses, and 4 best responses of stable disease. In considering contrast-enhancing and non–contrast-enhancing disease, the ORR was 47% (7 of 15 patients).

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 progression. The median overall survival was not reached, with a median follow-up of 7.5 months. Both studies are ongoing.

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