CTNI-61. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2022-11, Vol.24 (Supplement_7), p.vii86-vii87
• Main Authors: Kawakibi, Abed Rahman, Tarapore, Rohinton, Gardner, Sharon, Chi, Andrew, Kurz, Sylvia, Wen, Patrick Y, Arrillaga-Romany, Isabel, Batchelor, Tracy, Butowski, Nicholas, Sumrall, Ashley, Shonka, Nicole, Harrison, Rebecca, DeGroot, John, Mehta, Minesh, Odia, Yazmin, Hall, Matthew, Daghistani, Doured, Cloughesy, Timothy, Ellingson, Benjamin, Kim, Michelle, Umemura, Yoshie, Garton, Hugh, Franson, Andrea, Schwartz, Jonathan, Li, Sunjong, Cartaxo, Rodrigo, Ravi, Karthik, Cantor, Evan, Cummings, Jessica, Paul, Alyssa, Walling, Dustin, Dun, Matthew, Cain, Jason, Li, Jiang, Filbin, Mariella, Zhao, Lili, Kumar-Sinha, Chandan, Mody, Rajen, Chinnaiyan, Arul, Kurokawa, Ryo, Pratt, Drew, Venneti, Sriram, Grill, Jacques, Kline, Cassie, Mueller, Sabine, Resnick, Adam C, Nazarian, Javad, Waszak, Sebastian, Allen, Joshua E, Koschmann, Carl
• Format: Article
• Language: English
• Subjects: Clinical Trials: Non-Immunologic
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noac209.326

Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson’s r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPK-pathway alterations, and patients with relatively high CBF.