- This open-label phase 2 trial investigated the combination of ipilimumab and nivolumab in 151 patients with leptomeningeal disease
- 78% of patients had a performance status of 1 or 2
- Eight of 18 patients (44%) were alive three months after enrollment; the trial met its primary endpoint
- Median overall survival was 2.9 months and median progression-free survival for intracranial disease was 1.93 months
- There were no unexpected adverse events, treatment-related deaths, or excess neurologic or autoimmune toxicities
Up to 10% of patients with solid tumors develop leptomeningeal disease (LMD) in which cancer metastasizes to the leptomeninges and cerebrospinal fluid. This dire complication is usually rapidly fatal, with an average survival of only three to seven weeks.
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Current therapies for LMD (e.g., craniospinal radiation and intrathecal therapies) have uncertain benefits and substantial adverse effects. Researchers at the Massachusetts General Hospital Cancer Center recently reported in Nature Medicine that pembrolizumab, an immune checkpoint inhibitor (ICI), was safe and effective for LMD in a phase 2 trial.
The team has now published similarly favorable results from a phase 2 trial of combined ICI therapy in patients with diverse types of primary solid tumors. The authors of the report, which appears in Nature Communications, are Priscilla K. Brastianos, MD, director of the Central Nervous System Metastasis Program at the Mass General Cancer Center, Daniel P. Cahill, MD, PhD, neurosurgeon at Mass General and neurosurgical oncologist at the Mass General Cancer Center, Ryan J. Sullivan, MD, oncologist at the Mass General Cancer Center, and colleagues.
The open-label trial involved 18 patients with LMD who received intravenous therapy with ipilimumab and nivolumab between February 2018 and April 2019. The primary diagnosis was breast cancer in eight patients and melanoma in two; the other patients had eight different diagnoses. The average number of prior systemic therapies was 3.1.
For both drugs, the median number of doses was two. 78% of patients received corticosteroids during ICI therapy.
The prespecified criterion for a successful primary endpoint was six or more patients alive three months after enrollment. Eight patients (44%) were alive at that timepoint.
Some secondary efficacy endpoints were:
- Median survival—2.9 months
- The best response of central nervous system disease, including LMD—one patient had a complete response, seven had stable disease, four had progressive disease, and six were not evaluable
- The median progression-free survival for intracranial disease—1.93 months
- The best response of extracranial disease—one patient had a partial response, three had stable disease, three had progressive disease, and 11 were not evaluable
- The median progression-free survival for extracranial disease—1.94 months
The safety and toxicity profile was comparable to previous trials of ICIs for brain metastases. There were no unexpected adverse events, treatment-related deaths, or excess neurologic or autoimmune toxicities.
Despite their need for therapies that provide a meaningful survival benefit, patients with LMD have traditionally been excluded from clinical trials of ICIs. The results of this study suggest that combined ICI therapy is a safe and tolerable option for LMD that warrants larger trials.
Notably, all but four patients had an ECOG performance status of 1 or 2, suggesting ICIs need not be withheld from deconditioned patients with LMD.
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