IMMU-08. SALVAGE IMMUNOTHERAPIES FOR REPLICATION REPAIR DEFICIENT (RRD) HIGH-GRADE GLIOMA FAILING ANTI-PD1 MONOTHERAPY: AN IRRDC REPORT

Abstract BACKGROUND Although the initial response to immune-checkpoint inhibition (ICI) for patients with DNA replication-repair deficient high-grade glioma (RRD-HGG) is encouraging, role of immune-based salvage approaches those progressing on anti-PD1 monotherapy unknown. METHODS We performed an international registry study managed using central molecular, genomic, radiological review and treatment recommendations between 2015-2021. Post-progression included re-irradiation where feasible, continuation anti-CTLA4 (ipilimumab), or a MEK-inhibitor (MEKi). Outcomes (iRANO), toxicity, second progression-free (PFS2) overall survival (OS2). Companion biomarkers were centrally. RESULTS Among 75 RRD-HGG receiving PD-1 blockade, 20 are at median follow-up 44.6-months. For 55 relapsed/progressive tumors, ICI (n=38) resulted in OS2 11.6-months (51% alive) versus 1.2-months when was discontinued (n=17; no survivors, p<0.001). The combination ipilimumab/nivolumab (n=24) response/stable disease 75% 12.1-months but high autoimmune toxicities (54%). addition MEKi led 3/5 prolonged survival. improved OS2, especially tumors lower mutation burden (p=0.002), who received ipilimumab (median OS2=33-months). Several biological insights gained. Early ‘flare’ 33% combined immunotherapy radiation associated immunogenic induced signatures. responses reinvigoration peripheral immune response. Finally, delayed, sustained observed ultra-hypermutant exhibiting changes somatic mutational spectra. CONCLUSION These data suggest that continuous mutagenesis renders hypermutant susceptible checkpoint inhibitors beyond progression. additional immune/targeted agents can maximize these children young adults. Future research should focus biology-driven rational combinations also result toxicity patient benefit.