IMMU-13. Dual CTLA4/ PD-1 blockade improves survival for replication-repair deficient high-grade gliomas failing single agent PD-1 inhibition: An IRRDC study

Abstract

BACKGROUND: High-grade gliomas (HGG) with replication-repair deficiency (RRD) harbour high mutation burden (TMB) and are rapidly fatal following chemo-radiation approaches. Although hypermutation results in objective responses and prolonged survival in >30% of patients undergoing PD1-blockade, salvage following failure of PD1-inhibition remains a challenge. METHODS: We performed a real-world study of Ipilimumab (anti-CTLA4) in combination with Nivolumab/Pembrolizumab for patients failing single-agent PD1-inhibition. RESULTS: Among 68 consortium patients with relapsed HGG treated with single-agent PD1-inhibitors, progression was observed in 43 (63%). Ipilimumab was added to 20/43 (46.5%), 14 (32.5%) received best supportive care (BSC), and 9 (21%) received miscellaneous therapies. For patients receiving CTLA4/PD1-inhibition, median age at progression was 12.3-years (IQR: 9; 15.6). Time from anti-PD1 initiation to progression was 8-months (IQR: 3.8; 18.5). Germline predisposition was observed in all patients (CMMRD: 70%, Lynch: 25%, polymerase-proofreading deficiency: 5%). All HGG were hypermutant (median TMB: 182 mutations/Mb; IQR: 15.6; 369.4). Centralized radiology review revealed objective responses in 3/20 (15%, all ultra-hypermutant: 320, 496, 834 mutations/Mb), stable disease in 5 (25%), and 12 (60%) eventually progressed (iRANO). Following failure of PD1-blockade, estimated progression-free and overall survival at 18-months for patients receiving CTLA4/PD1-inhibition were 11% and 25%, respectively. Importantly, survival was superior to patients receiving BSC (median OS <1-month versus 12-months on CTLA4/PD1-inhibition; p<0.001). All patients receiving BSC died within 3.5-months, while 4/8 survivors were alive for >1-year on the anti-CTLA4/PD1combination (range:1-48 months). The combinational immunotherapy resulted in significant autoimmune toxicity in 11/20 (55%), warranting immunosuppressive therapy in all, and treatment abandonment in 6 patients. CONCLUSION: Combined CTLA4/PD1-blockade after failure of single-agent PD1-inhibition revealed objective responses and prolonged survival in an otherwise rapidly-fatal disease. This needs to be assessed in the context of significant autoimmunity, supporting the need for the current prospective trial (NCT04500548), and novel strategies to limit treatment-related toxicity.

Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome

“…However, we also note that there may be a need for sustained immune surveillance in these patients with germline genomic instability, as interruption of immunotherapy was clinically correlated with recurrence/progression at multiple time points in both patients. This can be challenging with the use of combinatorial ICIbased treatments, like anti-CTLA4 and anti-PD1, especially in CMMRD https://doi.org/10.1038/s41698-024-00597-8 patients where even non-malignant cells in the body accumulate mutations and MS-indels at high rates, leading to high rates of autoimmune toxicities in a recently published study, was also seen in our patients 19,26 . Hence, while combinatorial strategies can be effective salvage options upon failure of checkpoint-inhibitor monotherapy, it can be challenging to continuously deliver existing combinations in CMMRD patients.…”

“…Focal radiation was administered to sites of disease recurrence in combination with bevacizumab, and nivolumab was reinitiated. Ipilimumab was added post-radiation, but the treatment had to be interrupted for thrombocytopenia 19 . Autoimmune toxicity and concomitant hematological malignancy were excluded by exhaustive investigations.…”