SYST-14 CLINICAL EFFICACY OF ONC201 IN RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA (DMG) PATIENTS

Abstract

Abstract BACKGROUND H3 K27M-mutant DMG predominantly affects children and young adults; no effective therapy is known. ONC201 is a first-in-class, anti-cancer DRD2 antagonist and ClpP agonist. METHODS Fifty pediatric and adult patients with recurrent H3 K27M DMG who received oral ONC201 monotherapy in clinical trials and expanded access were selected for a planned efficacy analysis. Eligibility criteria included measurable contrast-enhancing disease by RANO-HGG criteria (excluding pontine and spinal cord tumors), KPS/LPS≥60, ≥90 days from prior radiation, and adequate washout from prior anti-cancer therapy. The primary endpoint was overall response rate (ORR) by RANO-HGG criteria. Secondary endpoints included duration of response, time to response, progression-free survival (PFS), overall survival (OS), corticosteroid response rate, performance status response rate, and ORR by RANO-LGG criteria. Radiographic endpoints were assessed by dual-reader blinded independent central review. Data cutoff was May 31, 2021. RESULTS ORR was 20.0% (95%CI, 10.0–33.7) by RANO-HGG criteria. Median duration of response was 11.2 months (95%CI, 3.8–not reached) and median time to response was 8.3 months (range, 1.9–15.9). PFS at 6 months was 35.1% (95%CI, 21.2–49.3). The ORR was 26.0% (95%CI, 14.6–40.3) by RANO-LGG criteria. Fifteen patients (30.0%; 95%CI, 17.9–44.6) achieved an objective response by RANO-HGG and/or RANO-LGG criteria. Of 15 patients receiving ≥4 mg daily dexamethasone at baseline, 7 (46.7%; 95%CI, 21.3–73.4) achieved ≥50% confirmed reduction in dose. Of 34 patients with baseline KPS/LPS <80, 7 (20.6%; 95%CI, 8.7–37.9) achieved a confirmed performance status improvement. With a median follow-up of 18.8 months, median OS was 13.7 months (95%CI, 8.0–20.3) and OS at 24 months was 34.7% (95%CI, 20.7–49.2). Twenty-five patients had serious adverse events with one possibly related to ONC201 by investigator assessment. CONCLUSIONS ONC201 monotherapy exhibits durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.