Pilot report of an anti-PD-1/VEGF bispecific antibody for treating recurrent H3K27M-mutant diffuse midline gliomas.

BACKGROUND

H3K27M-mutant diffuse midline gliomas (DMGs) are highly aggressive, immunosuppressive tumors that are resistant to conventional therapies. Median overall survival is typically 8-11 months after diagnosis; fewer than 10% of patients survive beyond 2 years, and the 5-year survival rate is generally below 1%. Ivonescimab, a novel bispecific antibody that simultaneously targets PD-1 and VEGF, may help overcome this resistance by restoring T cell immunity and normalizing tumor vasculature. We report the first use of ivonescimab as salvage therapy for recurrent DMG.

METHODS

Two patients with recurrent H3K27M-mutant DMG who experienced rapid progression after standard first-line chemoradiotherapy received off-label ivonescimab (10 mg/kg) plus chemotherapy intravenously every 3 weeks for 5-6 cycles.

RESULTS

After only three cycles, MRI revealed marked tumor shrinkage and substantial improvement in Karnofsky Performance Status (KPS). At treatment completion, both patients achieved partial remission (PR, tumor volume decreased at 66.7% and 68.7%, respectively). Both patients maintained progression-free survival (PFS) of more than 8 months and overall survival (OS) of more than 16 months, and both were alive more than 10 months after recurrence. Furthermore, treatment was well tolerated, the most common adverse event was fatigue, hematology toxicity and nausea vomiting, and no grade 3 or higher adverse events were observed.

CONCLUSIONS

These preliminary findings demonstrate the tolerability of concurrent anti-PD-1/VEGF bispecific antibody with chemotherapy for recurrent DMG, who do not fit for reRT, and suggests that combination therapy may offer survival benefit. However, larger and more rigorous studies are needed to validate these initial observations and to define the efficacy and safety of this strategy in the clinical management of DMG.