Researchers at Moffitt Cancer Center have reported encouraging results from a phase 1B clinical trial demonstrating that avelumab immunotherapy combined with whole brain radiotherapy may offer a safe and potentially effective treatment for leptomeningeal disease (LMD), one of the most aggressive complications of advanced cancer. The findings, published in Neuro-Oncology, challenge the historically grim prognosis associated with this devastating condition.
Novel Combination Shows Survival Benefit
The study enrolled 15 patients with leptomeningeal disease originating from diverse primary solid tumors including breast, lung, ovarian, and pancreatic cancers. Each participant received avelumab, a programmed death-ligand 1 (PD-L1) inhibitor, administered before, during, and after whole brain radiotherapy.
Survival outcomes exceeded historical expectations, with 67% of patients surviving at least three months post-treatment and several patients achieving survival beyond one year. This represents a significant improvement over conventional outcomes, where median survival after LMD diagnosis typically spans only several weeks to months.
"Patients with leptomeningeal disease face some of the poorest outcomes in oncology," said Dr. Yolanda Piña, neuro-oncologist at Moffitt and the study's lead author. "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."
Manageable Safety Profile
The combined treatment demonstrated a manageable safety profile, with adverse effects being generally mild to moderate and no treatment-related deaths occurring. This safety profile is particularly significant given the central nervous system involvement, where therapeutic interventions must carefully balance efficacy with the risk of neurotoxicity and other serious complications.
Immune System Activation Revealed
Beyond clinical outcomes, researchers conducted detailed molecular analyses of cerebrospinal fluid (CSF) samples collected before and after treatment. These investigations revealed pronounced immune activation characterized by a reduction of regulatory T cells—a subset that typically suppresses immune response and facilitates tumor immune escape.
The analysis also detected alterations in immune checkpoint activity within CD8+ cytotoxic T cells and macrophages, indicating enhanced immune surveillance and effector function following treatment. These immune modulations provide mechanistic support for the observed clinical benefits and offer potential biomarkers for treatment response.
"By analyzing cerebrospinal fluid before and after treatment, we gained valuable insight into how the immune system responds," said Dr. Peter Forsyth, chair of Moffitt's Neuro-Oncology Department and senior author of the study. "This work points to new therapeutic strategies, including targeting immune checkpoints like LAG3, to overcome resistance."
Addressing Critical Unmet Need
Leptomeningeal disease occurs when malignant cells infiltrate the meninges—the thin membranes enveloping the brain and spinal cord. This infiltration disrupts normal neurological function and has historically been associated with dismal prognoses due to limited effective treatment strategies and few prospective clinical trials addressing this patient population.
The combination approach explores synergistic mechanisms where avelumab reinvigorates the immune system's ability to recognize and eradicate tumor cells by preventing cancer's immune evasion tactics, while radiotherapy induces tumor cell death and potentially enhances immune visibility of the cancer.
Path Forward
While the study's modest sample size and phase 1B design primarily focused on assessing safety, the encouraging survival data and detailed immune profiling collectively justify advancing to a phase 2 clinical trial. Such a trial would enable more robust evaluation of efficacy endpoints while continuing to elucidate the complex interplay between radiotherapy, immunotherapy, and the neuroimmune microenvironment.
The study was supported by Pfizer and conducted under a collaborative alliance between the health care business of Merck KGaA and Pfizer, with additional funding from the National Cancer Institute and the Florida Department of Health Bankhead-Coley Program.
