Leptomeningeal disease: a high-stakes challenge in oncology
Leptomeningeal disease, where cancer cells spread to the membranes surrounding the brain and spinal cord, remains one of oncology’s most formidable complications. Patients diagnosed with this condition often face survival measured in weeks to months, and treatment options are historically limited. In a hopeful development, researchers at Moffitt Cancer Center report encouraging early results from a phase 1B trial exploring the combination of the immunotherapy drug avelumab with whole-brain radiotherapy (WBRT). The findings, published in Neuro-Oncology, suggest this pairing can be safe and may offer clinical benefits for patients with leptomeningeal disease from various solid tumors.
What the trial looked at and what it found
The study enrolled 15 patients with leptomeningeal disease stemming from breast, lung, ovarian, pancreatic and other solid cancers. All participants received avelumab before, during, and after WBRT, with the aim of assessing safety first and foremost, while also watching for potential signals of efficacy. Key results included:
- Survival signal: 67% of patients were alive three months after treatment, with several patients surviving beyond a year.
- Safety profile: Side effects were generally manageable, and there were no treatment-related deaths.
- Immune activity: Analyses of cerebrospinal fluid (CSF) demonstrated an adaptive immune response, including reduced regulatory T cells and altered activity of immune checkpoints in CD8+ T cells and macrophages.
Although the trial was small and primarily designed to evaluate safety, the combination showed a pattern of clinical benefit that warrants further study in larger cohorts.
How the combination may work against leptomeningeal disease
Radiation therapy can increase tumor visibility to the immune system, potentially enhancing the effects of immunotherapy. In this study, CSF analyses provided a window into how the immune system responds in the central nervous system, revealing shifts in immune cell populations that could bolster anti-tumor activity. The results hint at a dynamic interplay between WBRT and avelumab that could overcome some of the immune-evasion tactics employed by cancer cells in the meninges.
Translational insights from the CSF data
Researchers highlighted how studying CSF before and after treatment yielded actionable insights into immune dynamics within the CNS. This translational work not only supports the observed safety and potential efficacy but also points to future strategies, including targeting additional checkpoints to overcome resistance.
Researchers’ perspective and quotes
Lead author Yolanda Piña, M.D., a neuro-oncologist at Moffitt, emphasized the potential impact of these early results: “Our trial shows that combining immunotherapy with radiation is safe and has signs of clinical benefit. These results set the stage for larger studies that could ultimately change the treatment landscape for this patient population.”
Senior author Peter Forsyth, M.D., chair of Moffitt’s Neuro-Oncology Department, underscored the importance of the translational findings: “By analyzing cerebrospinal fluid before and after treatment, we gained valuable insight into how the immune system responds. This work points to new therapeutic strategies, including targeting immune checkpoints like LAG3, to overcome resistance.”
Why this matters and what comes next
Given the grim prognosis facing many patients with leptomeningeal disease, these preliminary findings are notable for showing a safe path forward for combining immunotherapy with radiation. The survival signals and immunologic changes observed in the CSF offer a rationale for advancing to phase 2 trials with larger patient populations and more robust endpoints. Researchers caution that the small sample size limits definitive conclusions, but the data provide a compelling rationale to move ahead and refine the approach.
Funding and collaboration context
The study was supported by Pfizer and previously conducted under an alliance between Merck KGaA’s healthcare business and Pfizer. Additional funding came from the National Cancer Institute and the Florida Department of Health Bankhead-Coley Program, underscoring a collaborative effort to push forward promising strategies in CNS-oncology.
Bottom line
Early phase results from this Moffitt-led trial suggest that adding avelumab to whole-brain radiotherapy is a safe approach that can elicit an immune response within the central nervous system and may translate into meaningful survival benefits for patients with leptomeningeal disease. As researchers plan phase 2 studies, the oncology community will watch closely for confirmation of efficacy and the potential for broader application across tumor types.
