Phase 2 study of nivolumab for patients with meningiomas refractory to surgery and radiotherapy with immune-related response criteria.

2084 Background: The majority of meningiomas, which are the most common central nervous system (CNS) tumors, are benign and often cured by surgical resection alone. However, 20%–30% of meningiomas can be malignant tumors of CNS WHO grade II or III that are refractory to repetitive resection and radiotherapy. Moreover, a proportion of grade I meningiomas is associated with an aggressive clinical course reminiscent of grade II tumors. Reports of effective medical therapy for those tumors are extremely rare. Methods: A single-arm, open-label, phase 2 study was conducted to evaluate the efficacy and safety of nivolumab for meningiomas refractory to surgery and radiotherapy. Nivolumab (480 mg) was administered intravenously every 4 weeks and continued until tumor progression or unacceptable toxicity for up to 365 days. The primary endpoint was the objective response rate (ORR) determined by a central independent review committee. With a one-sided significance level of 5%, a power of 80%, a threshold response rate of 5%, and an expected response rate of 20%, the required sample size was calculated to be 27 patients using the exact binomial test. Considering a 10% attrition rate, the target sample size was set at 29. To avoid premature discontinuation of potentially effective immunotherapy, response was evaluated based on the iRANO (meningioma) criteria, which is based on the RANO (meningioma) criteria (Neuro Oncol 21(1):26-36, 2019) with the integration of the immune-related response criteria outlined previously (Lancet Oncol 16(15):e534-e542, 2015). Archival tumor specimens from all 29 cases were obtained for biomarker analyses. Results: A total of 29 patients started the study therapy. Response assessment by the central review committee was performed for 28 patients: grade I meningioma in 5, grade II in 19, and grade III in 4 by definition of the 2016 WHO criteria. The best overall response was PR in 1, SD in 13, and uPD/cPD in 14. The ORR was 3.6% and progression-free survival at 6 months was 23.9%. Biallelic inactivation of the NF2 gene was detected in 20/27 cases (74%), whereas biallelic inactivation of the CDKN2A gene was identified in 7/27 cases (26%). One patient who had multiple grade I meningiomas with biopsy-proven lung metastases showed near CR following initial radiological progression. The TMB of the tumor was 8.1/MB. Next-generation sequencing found that none of the tumors had mutations of the DNA mismatch repair genes. Nivolumab was well tolerated. Conclusions: Although nivolumab monotherapy failed to meet the prespecified primary endpoint, our study demonstrated that a subset of patients could benefit from the therapy and that immune-related response criteria are necessary to evaluate immunotherapy for meningiomas. Clinical trial information: jRCT2031190074 .