Immu-24. salvage immunotherapies for replication repair deficient (rrd) high-grade glioma failing anti-pd1 monotherapy: a report from the international rrd consortium

Abstract BACKGROUND Initial response to immune checkpoint inhibition (ICI) for DNA replication-repair deficient high-grade glioma (RRD-HGG) is encouraging. However, clinical/biologic implications of immune-directed approaches after failing ICI-monotherapy remain unknown. METHODS We performed an international study of patients managed using central review/treatment recommendations (2015-2021). Salvage after anti-PD1 failure included re-irradiation where feasible, and addition of anti-CTLA4 (ipilimumab), or a MEK-inhibitor (MEKi). Outcomes included radiological response (iRANO), toxicity, second progression-free (PFS2) and overall survival (OS2). Companion biomarkers were performed centrally. RESULTS Twenty among 75 patients treated on anti-PD1 monotherapy are progression-free at a median follow-up of 44.6-months. For 55 patients with relapsed/progressive tumors, continuation of ICI (n=38) resulted in median OS2 of 11.6-months (51% alive) versus 1.2-months when ICI was discontinued (n=17; no survivors, p< 0.001). Addition of ipilimumab (n=24) resulted in response/stable disease in 75% with median OS2 of 12.1-months. High autoimmune toxicities (54%) were observed, particularly in constitutional mismatch-repair deficiency patients. The addition of MEKi led to response in 3/5 patients with prolonged survival. The addition of re-irradiation improved median OS2, especially in tumors with lower mutation burden (p=0.002), and those who received ipilimumab (median OS2=33-months). Several biological insights were gained. Increased CTLA4 expression explained responses to ipilimumab. Re-irradiation responses were attributed to the absence of radio-resistant indel signature (ID8). Early radiological ‘flare’ was observed in 33% on combined immunotherapy and re-radiation. MEKi responses were associated with reinvigoration of peripheral immune response. Finally, delayed, sustained responses were observed in ultra-hypermutant RRD-HGG exhibiting changes in somatic mutational spectra. CONCLUSION These data suggest that the continuous mutagenesis renders hypermutant RRD-HGG susceptible to checkpoint inhibitors beyond initial progression. The combination with re-irradiation and additional immune/targeted agents can maximize survival in these children and young adults. Future research should focus on biology-driven rational immunotherapy combinations that also result in lower toxicity to maximize patient benefit.