Introduction
Leptomeningeal disease, in which cancer cells invade the membranes surrounding the brain and spinal cord, remains one of oncology’s most daunting challenges. Patients face rapid neurological decline, and survival is often measured in weeks to months. In a phase 1B study from Moffitt Cancer Center, researchers explored whether combining the immunotherapy drug avelumab with whole-brain radiotherapy could offer a safe and potentially effective option for this hard-to-treat condition. The findings were published in Neuro-Oncology.
What is leptomeningeal disease?
Leptomeningeal disease (LMD) arises when malignant cells disseminate through the cerebrospinal fluid and settle on the brain and spinal cord membranes. Its aggressive biology and diffuse spread make it resistant to many standard therapies, leaving few proven treatment avenues and a generally poor prognosis for affected patients.
The trial at a glance
The study enrolled 15 patients with LMD stemming from breast, lung, ovarian, pancreatic and other solid tumors. All participants received the immune checkpoint inhibitor avelumab in conjunction with a course of whole-brain radiotherapy, administered before, during, and after immunotherapy. While the trial’s primary aim was safety, researchers also gathered valuable data on clinical outcomes and immune biology from the cerebrospinal fluid (CSF).
Key findings
Survival signals
Three months after starting treatment, 67% of patients were alive, with a subset remaining alive for more than a year. Although the small sample size limits definitive conclusions about efficacy, these survival signals offer encouragement for the approach and justify further investigation in larger cohorts.
Safety and tolerability
Safety outcomes were favorable: no treatment-related deaths occurred, and adverse events were manageable and consistent with what is typically seen with immunotherapy and radiotherapy. The absence of severe, therapy-related mortality supports pursuing a phase 2 trial to better define tolerability across a broader patient population.
Immune activity in the central nervous system
Translational analyses of CSF revealed an engaging immune response within the CNS. Researchers observed a reduction in regulatory T cells and notable changes in immune checkpoint activity among CD8+ T cells and macrophages, indicating an active, adaptive immune environment in the leptomeninges following therapy. Yolanda Piña, M.D., the study’s lead author, emphasized that these findings demonstrate immune mobilization against cancer cells in the CNS and help explain the observed clinical signals.
Expert perspectives and translational insights
Peter Forsyth, M.D., chair of Moffitt’s Neuro-Oncology Department and senior author, highlighted the importance of the CSF analyses. “By analyzing cerebrospinal fluid before and after treatment, we gained valuable insight into how the immune system responds,” Forsyth said. He also noted that the translational data point toward new strategies, including targeting additional checkpoints such as LAG3 to overcome resistance in this disease setting.
Implications and next steps
Researchers caution that the study was small and designed to assess safety rather than efficacy. Nevertheless, the combination’s survival signals and observed immune activity provide a strong rationale for advancing to a phase 2 trial. Such a study would more rigorously evaluate efficacy, help identify which patients may benefit most, and refine combination approaches with immunotherapies for LMD. The trial was supported by Pfizer and by collaboration between Merck KGaA and Pfizer, with additional backing from the National Cancer Institute and the Florida Department of Health Bankhead-Coley Program.
Limitations and context
As with any early-phase, small-sample study, results must be interpreted with caution. Patient heterogeneity, tumor type, and prior treatments can influence outcomes. These findings serve as a stepping stone toward more definitive investigations that could reshape how leptomeningeal disease is treated in the era of immunotherapy and precision radiotherapy.
