A phase Ib, window-of-opportunity study of neoadjuvant avelumab and hypofractionated proton beam therapy for recurrent radiation-relapsed meningioma.

2015 Background: Effective treatments for recurrent meningiomas following radiation therapy (RT) are limited. Inhibitors of the programmed-death-1 (PD-1) or programmed-death ligand-1 (PD-L1) pathway have shown modest activity for these tumors in single-arm phase 2 studies. This study aims to evaluate the immunological effects of combining anti-PD-L1 (avelumab) with proton beam therapy (PBT) for recurrent radiation-relapsed meningiomas. Methods: Recurrent grade 1-3 meningiomas that failed prior surgery and RT were treated with neoadjuvant avelumab (10 mg/kg IV biweekly for 6 doses) plus hypofractionated PBT (20 Gy over 5 fractions), followed by surgery and additional adjuvant avelumab (up to 6 doses). Blood samples were collected pre-avelumab, at week 4, and before surgery. Eligibility criteria include age ≥ 18 years, KPS ≥ 60, surgery suitability, dexamethasone dose ≤ 4mg daily, normal organ function; no prior anti-PD1/PDL1 therapy, and absence of autoimmunity. RNA-sequencing (RNAseq) and multiplex immunofluorescence (MxIF) were performed on pre- and post-avelumab tumor tissues; blood samples underwent multiplex flow cytometry (MxFC). Results: Between March 2018 to March 2023, 9 patients (22% grade 1, 56% grade 2, and 22% grade 3) were enrolled in the study. All completed neoadjuvant therapy, one forwent surgery due to dramatic radiological response, and two did not complete adjuvant avelumab (due to patient preference and infusion reaction). There was no dose-limiting toxicity or unexpected toxicity. After a median follow-up of 43.0 month and a minimum follow-up of 21.7 months, 8 patients have progressed, and 2 patients with progression have died. The median progression-free survival (PFS) was 19.1 months (95% CI: 15.2-23.0), with the median overall survival not yet reached. Three patients demonstrated notably prolonged PFS (37.7, 58.5 months, and ongoing). RNAseq showed significant increase in T-cell and macrophage gene expression in post-treatment tissues compared to pre-treatment. MxIF revealed a marked increase in T-cell and CD68+ macrophage infiltration in the long-PFS patients’ post-treatment tissues, a pattern not observed in the short-PFS patients. Particularly, the long-PFS patients’ post-treatment tissues displayed increased infiltration of CD68+HLADR+ macrophages, likely of M1-phenotype. In contrast, the pre- and post-treatment tissues from the short-PFS patients predominantly featured CD206+ macrophages, likely of M2-phenotype. A trend towards increased number of primed T cells in the peripheral blood was observed in the long-PFS patients at week 4. Conclusions: Avelumab combined with RT may induce an immunological response in some radiation-relapsed meningioma patients, leading to prolonged remission. Further investigations with larger prospective studies and predictive biomarkers are warranted. Clinical trial information: NCT03267836 .