Phase II Study of ONC201 in Neuroendocrine Tumors including Pheochromocytoma-Paraganglioma and Desmoplastic Small Round Cell Tumor

Peter M Anderson, Matteo M Trucco, Rohinton S Tarapore, Stacey Zahler, Stefanie Thomas, Janette Gortz, Omar Mian, Martin Stoignew, Varun Prabhu, Sara Morrow, Joshua E Allen, Peter M Anderson, Matteo M Trucco, Rohinton S Tarapore, Stacey Zahler, Stefanie Thomas, Janette Gortz, Omar Mian, Martin Stoignew, Varun Prabhu, Sara Morrow, Joshua E Allen

Abstract

Purpose: Tumor dopamine-like DRD2 receptor expression is higher in pheochromocytoma-paraganglioma (PC-PG) compared with other cancers. ONC201 is a bitopic DRD2 antagonist with preclinical ONC201 activity in desmoplastic small round cell tumor (DSRCT).

Patients and methods: Patients (N = 30) with neuroendocrine tumors were treated on this investigator-initiated trial (NCT03034200). ONC201 dose and schedule were 625 mg orally weekly in cohorts A (PC-PG) + B (other neuroendocrine tumors) and 625 mg orally on 2 consecutive days each week in cohort C, which included 5 responding patients. The primary endpoint was radiographic response measured using RECIST. Secondary endpoints included progression-free survival, overall survival, and safety.

Results: In arm A (n = 10; all PC-PG), 50% (5/10) exhibited a partial response (PR) and 2 additional patients had stable disease (SD) >3 months. Median duration of therapy for arm A patients was 9 months (range: 1.5-33 months) with 5 patients treated >1 year. In arm B (n = 12), there were 1 PR (DSRCT) and 2 SD (DSRCT; neuroblastoma) >3 months. Median duration of therapy in arm A was 18 months (range: 1-33 months) and arm B was 3 months (range: 1.5-33 months). Arm C PC-PG (N = 8) showed 1 PR and 7 SD at 3 months, with median duration of therapy >10 months. There was no decline in Karnofsky performance status at week 12 for 28 of 30 patients and no dose modification due to treatment-related adverse events.

Conclusions: Oral ONC201 was well tolerated in patients with metastatic neuroendocrine tumors and associated with clinical benefit, including tumor responses, particularly in some patients with DSRCT and the majority of patients with PC-PG. See related commentary by Owen and Trikalinos, p. 1748.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
TCGA analysis of DRD2 mRNA of the dopamine-like DRD2 receptor shows PC-PG to be highly elevated compared with normal cells and is associated with approximately 3–10 × higher expression than all other cancers tested. High DRD2 expression at the protein level has also been confirmed in PC-PG compared with normal adrenal or nerve tissue (25).
Figure 2.
Figure 2.
ONC201 is a DRD2 antagonist and ClpP agonist that causes increased integrated stress response and cell death pathways and decreased cell survival pathways in cancer cells compared with normal cells.
Figure 3.
Figure 3.
Phase II study of ONC201 in neuroendocrine tumors was a phase II open-label design. +Progression was as defined by RECIST (28).
Figure 4.
Figure 4.
Best response by RECIST: A, PC-PG tumors had responses to both weekly and 2 consecutive days/week dosing. B, Other neuroendocrine tumors had a greater proportion with tumor shrinkage using 2 consecutive days/week dosing (red). All responses in roll-over patients (blue hatched) occurred prior to 2 consecutive days/week dosing. C, PC-PG tumor responses depicted over time.
Figure 5.
Figure 5.
Duration of ONC201 therapy and overall survival: A,N = 14 PC-PG 5/14 were treated > 1 year, 4 continue ONC201. Patients without an arrow (5/14) died of tumor progression; 9/14 metastatic PC-PG remain alive. B,N = 16 other patients with neuroendocrine tumor: 2 patients with DSRCT were treated >1 year; 6/16 other patients with metastatic neuroendocrine tumor are currently alive; 10/16 died of tumor progression.

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