ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma

Abstract

Purpose: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG.

Methods: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review.

Results: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred.

Conclusion: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Trial registration: ClinicalTrials.gov NCT03416530 NCT03295396 NCT05392374 NCT03134131 NCT02525692.

FIG 1.

CONSORT diagram. CUP, compassionate use program; DIPG, diffuse intrinsic pontine glioma.

FIG 2.

Change in tumor size by RANO-HGG criteria in the efficacy population. (A) Swimmer and (B) spider plots of patients in the efficacy population assessed by BICR while receiving monotherapy ONC201. Three patients did not have on-treatment MRIs available for BICR; one patient censored before first on-treatment MRI because of concurrent therapy; one patient did not have measurable target lesion by BICR. ^aChange >100%. BICR, blinded independent centralized review; CR, complete response; MRI, magnetic resonance imaging; NE, not evaluable; NR, not reached; PD, progressive disease; PR, partial response; SD, stable disease; SPD, sum of products of perpendicular diameters (target-enhancing lesions per BICR).

FIG A1.

ONC006 CONSORT diagram. DIPG, diffuse intrinsic pontine glioma; H3, histone 3.

FIG A2.

ONC013 CONSORT diagram. DIPG, diffuse intrinsic pontine glioma; H3, histone 3.

FIG A3.

ONC014 CONSORT diagram. DIPG, diffuse intrinsic pontine glioma; H3, histone 3.

FIG A4.

ONC016 CONSORT diagram. CUP, compassionate use program; DIPG, diffuse intrinsic pontine glioma; H3, histone 3.

FIG A5.

ONC018 CONSORT diagram. DIPG, diffuse intrinsic pontine glioma; H3, histone 3.

FIG A6.

PFS by RANO-HGG in the efficacy analysis population (n = 50). PFS, progression-free survival; RANO-HGG, response assessment in neuro-oncology high-grade glioma. Shaded areas indicate 95% CI.

FIG A7.

OS in the efficacy analysis population (n = 50). OS, overall survival. Shaded areas indicate 95% CI.

FIG A8.

Best percent change in tumor size in the efficacy population (RANO-LGG). Swimmer plot of patients in the efficacy population with measurable target-enhancing lesion by BICR at baseline and postbaseline evaluations. Three patients did not have on-treatment monotherapy MRIs available for BICR; one patient censored before first on-treatment MR; one patient did not have measurable target lesion. ^aChange >100%. BICR, blinded independent centralized review; MR, minor response; MRI, magnetic resonance imaging; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SPD; sum of products of perpendicular diameters (target nonenhancing lesions per BICR).

FIG A9.

Best percent change in tumor size by baseline performance score. ^aChange >100%. Only patients with measurable target-enhancing lesions at baseline and postbaseline are included (n = 45). KPS, Karnofsky performance score; LPS, Lansky performance score; SPD, sum of products of perpendicular diameters (target-enhancing lesions per blind independent central review).