Abstract Aims DNA replication repair deficiency (RRD) renders high-grade gliomas (HGG) sensitive to immune checkpoint inhibition (ICI). Clinical benefit can be offset by immune-flare in 30% of patients. Traditionally, this is treated using corticosteroids. This affects ICI efficacy and adds toxicity. We evaluate VEGF-targeting using bevacizumab as a steroid-sparing strategy to manage this neuro-inflammatory complication. Methods We performed a retrospective chart review of patients in the International RRD Consortium (IRRDC) with RRD-HGG treated with ICI, who received bevacizumab to manage immune-flare (2016-2025). Exome sequencing was utilized to characterize tumor mutational burden (TMB) and identify driving germline/somatic mutations in mismatch repair and polymerase genes. The primary endpoint was safety of using bevacizumab with ICI in this pediatric and young adult cohort; the secondary endpoint assessed its utility in facilitating corticosteroid tapering, mitigating iatrogenic morbidity, and maintaining ICI continuity. Results Over 10 years, 181 patients with RRD-driven HGG were treated using ICI. Fourteen patients (median age years=13; range =4-30; CMMRD n = 6, Lynch n = 8) received bevacizumab. Median TMB was 26.5 mut/Mb (range=4-836). 14.4 % were on anti-PD1/PDL1; 42.8% were on checkpoint combinations. 64.2 % received bevacizumab within 3-months of radiotherapy. 35.7% received bevacizumab alongside steroids; 64.3 % received bevacizumab instead of steroids. Bevacizumab was well-tolerated in conjunction with ICI, with no grade 3/4 treatment-limiting toxicities. Proteinuria was managed conservatively. Steroids were completely stopped in all patients on concomitant treatment, with reversal of steroid-related morbidity (weight gain, hyperglycemia). Radiological improvement in T2/FLAIR signals was reported in 28.5 %. Clinical improvements were reported in 42.8 %. Patient-reported benefits included visual improvement and ability to return to school. Conclusion Bevacizumab served as a steroid-sparing bridge that mitigated systemic corticosteroid toxicity and allowed continuation of ICI treatment. Anti-VEGF treatment should be considered the standard-of-care in managing immune-flare in RRD-HGG treated using ICI in lieu of corticosteroids.
Yenidoğan et al. (Tue,) studied this question.