Proton craniospinal irradiation with bevacizumab and pembrolizumab for leptomeningeal disease: a case report

Leptomeningeal disease (LMD) remains a challenging condition with a dismal prognosis. In this case study, we report partial response of LMD in a patient with metastatic large cell neuroendocrine carcinoma following treatment with proton craniospinal irradiation (CSI), bevacizumab, and pembrolizumab. Two years after the initial diagnosis, he presented with LMD. He underwent proton CSI with bevacizumab followed by combination therapy with pembrolizumab and bevacizumab. He had a partial disease response with progression-free survival after LMD diagnosis of 4.6 months. He unfortunately developed pembrolizumab induced hypophysitis, after which he experienced rapid neurologic clinical progression. Overall, this novel combination led to a durable partial response which warrants prospective evaluation. Patients with leptomeningeal disease have few therapeutic options and poor treatment outcomes. Single-agent therapies have not yet been as successful in improving patient survival. In this paper, we discuss how combination therapy with proton craniospinal irradiation, bevacizumab, and pembrolizumab led to neurological improvement and disease regression. These results show that this novel combination may lead to a significant benefit not seen previously with these individual drugs given alone. We hope to lay a foundation for a novel therapeutic approach in a critically high need disease which has previously been thought to be resistant to radiotherapy or immunotherapy. The novel combination of proton craniospinal irradiation, bevacizumab, and pembrolizumab led to neurological improvement and disease regression in a patient with leptomeningeal disease, which has previously been thought to be resistant to radiation and immune checkpoint therapy.