Phase 2 Trial of PD-1 Inhibitor Sintilimab in Recurrent/Progressive Meningioma.

BACKGROUND: Systemic therapeutic options for meningiomas remain limited. Emerging evidence indicates meningiomas harbor an immunosuppressive microenvironment and programmed cell death ligand 1 (PD-L1) expression is significantly upregulated in both tumor cells and tumor-infiltrating immune cells. Here we conducted a single-arm, single-center, open-label, phase 2 clinical trial (NCT04728568) evaluating the programmed cell death receptor-1 (PD-1) inhibitor sintilimab in patients with recurrent/progressive meningiomas following standard surgery and/or radiotherapy. METHODS: Forty patients (9 grade 1, 18 grade 2, and 13 grade 3) received intravenous sintilimab (200 mg every 3 weeks). According to Response Assessment in Neuro-Oncology for meningioma (RANO-meningioma) criteria, the 6-month progression-free survival rate (PFS-6) was used as the primary endpoint. Secondary endpoints included the 12-month progression-free survival rate (PFS-12), PFS, overall survival (OS), and safety. Peripheral lymphocyte subpopulations, tumor-infiltrating lymphocyte (TIL) densities, and tumor mutational burden (TMB) were evaluated as immunocorrelated biomarkers. RESULTS: Patients with grade 1 exhibited a PFS-6 of 67.0%, a PFS-12 of 56.0%, and the median PFS was 14 months (95% CI: 0, 31.5). Grade 2/3 patients showed a PFS-6 of 42.0%, a PFS-12 of 19.0%, and the median PFS was 5.0 months (95% CI: 3.46, 6.54). The median OS was 27.0 months (95% CI: 17.26, 36.73) in grade 2/3 patients. The best outcome among all patients was stable disease (SD). Sintilimab was well tolerated without severe adverse events. A patient with a high TMB (13.14 muts/Mb) had a pseudoprogression with sintilimab and maintained stable disease among subsequent treatments. Among 3 patients with matched pre-/post-treatment tumor samples, 2 showed increased PD-1+ T cell expression after sintilimab. CONCLUSION: Sintilimab failed to improve PFS-6 in both grade 1 and grade 2/3 recurrent/progressive meningiomas in this single-arm, single-center, and small-sample trial. When evaluating PD-1 inhibitor treatment for recurrent/progressive meningioma patients, who generally have a longer expected survival and high TMB, the use of the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria may be more appropriate to avoid overlooking potential clinical benefits.