2483 - Response to ONC201 by Prior Radiotherapy Regimen in Recurrent H3 K27M-Mutant Diffuse Midline Glioma

I. Arrillaga-Romany¹, S. L. McGovern², J. E. Allen³, S. Gardner⁴, A. M. Haggiagi⁵, Y. Odia⁶, S. C. Ramage³, P. Y. Wen⁷, and P. Lee⁸; ¹Massachusetts General Hospital, Boston, MA, ²Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, ³Chimerix, Inc, Durham, NC, ⁴New York University, Grossman School of Medicine, New York City, NY, ⁵Columbia University Irving Medical Center,, New York City, NY, ⁶Florida International University, Herbert Wertheim College of Medicine, Miami, FL, ⁷Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, ⁸Chimerix, Durham, NC

Purpose/Objective(s): ONC201 (dordaviprone), an oral, blood-brain barrier penetrant, small molecule ClpP agonist and DRD2 antagonist, has demonstrated efficacy in patients with recurrent H3 K27M-mutant diffuse midline glioma (DMG). This analysis evaluated the efficacy of ONC201 in these patients by front-line radiotherapy (RT). Materials/

Methods: This analysis was conducted as part of an integrated analysis of five previously conducted studies of single-agent ONC201; primary outcomes, including safety endpoints, were previously reported (Arrillaga-Romany, et al, 2024, JCO). Eligible patients had measurable H3 K27M-mutant DMG by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria, performance score =60, and were =90 days from radiation. Pontine and spinal tumors were not eligible. The first 50 eligible patients were evaluated. Radiographic endpoints were assessed by dual-reader, blinded independent central review.
Results: Among patients with RT dose reported (84%, 42/50), most patients received 54-60 Gy (92.8%, 39/42); two patients received <54 Gy and one received >60 Gy. Most patients received RT with concurrent chemotherapy or targeted therapy followed by adjuvant (CRT+Adj, 70.0%, 35/50). Other regimens included RT with concurrent chemotherapy or targeted therapy without adjuvant (CRT, 16%, 8/50), RT followed by adjuvant (RT+Adj, 8%, 4/50), and RT alone (6%, 3/50) Of these, pediatric patients (age <18 years, n=4) received CRT+Adj (n=1), RT+Adj (n=1), or RT alone (n=2). The majority of patients administered CRT and/or Adj had received temozolomide (91.2%, 43/47). Among 10 patients with radiographic responses by RANO-HGG criteria, seven had received between 54-60 Gy of RT and two received <50 Gy; one responder did not have RT dose reported. By regimen, seven responders had received CRT+Adj, two had received CRT, and one had received RT+Adj. One responder previously treated with RT+Adj had received proton therapy. ONC201 was well tolerated with treatment-related treatment-emergent adverse events (TR-TEAEs) occurring in 20% of patients, the most common of which was fatigue (n=5; 10%). No grade 4 TR-TEAEs, deaths, or discontinuations occurred.
Conclusion: Radiographic responses to ONC201 in patients with H3 K27M-mutant DMG were observed irrespective of prior standard RT dosing modality. Additionally, responses to ONC201 were observed both in patients receiving prior photon and proton radiation therapy. The phase 3 ACTION trial (NCT05580562) is currently evaluating ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma following standard front-line RT.