Promising early results for avelumab plus radiation in leptomeningeal disease
In a small but encouraging phase 1B study, researchers at Moffitt Cancer Center report that the immunotherapy drug avelumab, when given with whole-brain radiotherapy, may offer a new, potentially safer and more effective option for leptomeningeal disease (LMD). The findings, published in Neuro-Oncology, come from a tightly regulated trial that addresses one of the most aggressive and treatment-refractory complications of advanced cancer: cancer cells spreading to the membranes surrounding the brain and spinal cord.
Leptomeningeal disease is notoriously difficult to treat. Patients typically face rapid neurological decline and limited survival. In this study, 15 patients with LMD from breast, lung, ovarian, pancreatic and other solid tumors were enrolled and treated with avelumab both before and after undergoing whole-brain radiotherapy, aiming to harness the immune system to attack cancer cells in the central nervous system.
What the trial looked at
The trial was designed primarily to assess safety and feasibility, while also exploring early signals of clinical benefit. Participants received avelumab on a schedule aligned with their radiotherapy, reflecting a treatment strategy that combines immune activation with radiation-induced tumor antigen release. Although small, the cohort provides a window into how the brain’s immune environment responds to this combination therapy.
Key findings
Survival signals
Among the most striking observations, about two-thirds (67%) of patients were alive three months after treatment, and several remained alive for more than a year. While these numbers must be interpreted with caution given the small sample size, they suggest potential disease control or stabilized progression in a subset of patients with otherwise dismal prognoses.
Safety profile
Safety findings were notable for being manageable with no treatment-related deaths reported. The absence of severe, treatment-limiting toxicities supports the feasibility of this combined approach and provides a rationale for testing the regimen in larger studies challenging the leptomeningeal disease space.
Immune activity in the CSF
A key part of the translational work involved analyzing cerebrospinal fluid (CSF) before and after treatment. Researchers observed an adaptive immune response marked by a reduction in regulatory T cells and notable alterations in immune-checkpoint activity among CD8+ T cells and macrophages. This immune modulation aligns with the therapeutic hypothesis: that immunotherapy and radiation can synergistically stimulate immune cells to recognize and attack cancer cells within the meninges.
Translational insights and future directions
Peter Forsyth, M.D., chair of Moffitt’s Neuro-Oncology Department and senior author, emphasized the value of the translational data. “By analyzing cerebrospinal fluid before and after treatment, we gained valuable insight into how the immune system responds,” Forsyth said. “This work points to new therapeutic strategies, including targeting immune checkpoints like LAG3, to overcome resistance.”
Yolanda Piña, M.D., the study’s lead author, highlighted the practical implications. “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.”
Limitations and the path forward
As a small, early-phase trial, the study’s primary aim was to establish safety and feasibility. Nevertheless, the observed survival signals and the CSF immune findings provide a compelling rationale for advancing to a phase 2 trial. The field is watching closely for larger studies that can more definitively determine whether this approach translates into meaningful, long-term benefits for patients with LMD.
Context, funding, and ongoing research
The study was supported by Pfizer and linked to an alliance between Merck KGaA’s healthcare business and Pfizer. Additional backing came from the National Cancer Institute and the Florida Department of Health Bankhead-Coley Program. These partnerships underscore the collaborative effort to push forward innovative strategies for a disease that has traditionally had limited treatment options.
In the broader scientific arena, the findings underscore the importance of integrating translational science with clinical trials. As researchers continue to explore combinations such as immune checkpoint inhibitors and radiotherapy, the hope is to refine patient selection, optimize dosing, and identify biomarkers that predict who will benefit most. The next generation of trials will determine whether this early promise can become a new standard of care for leptomeningeal disease.
