Phase 3 trials for metastatic breast cancer, lung cancer, and melanoma do not include leptomeningeal disease-specific endpoints, according to research published in JAMA Oncology.

Researchers noted that patients with leptomeningeal disease are commonly excluded from clinical trials because of concerns about limited survival and the potential for rapid clinical deterioration. This has resulted in a lack of high-quality evidence to guide management decisions related to the presence of leptomeningeal disease. 

With this in mind, the researchers investigated whether phase 3 trials of metastatic breast cancer, lung cancer, or melanoma included patients with leptomeningeal disease and/or assessed leptomeningeal disease-specific endpoints.

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The researchers searched the database on December 22, 2020, and identified 244 eligible phase 3 randomized trials. 

Of these 244 trials, 67 specifically excluded patients with leptomeningeal disease, 169 did not specify the inclusion or exclusion of leptomeningeal disease, and 8 trials expressly allowed enrollment of patients with leptomeningeal disease. 

All 8 trials allowed enrollment of patients with asymptomatic leptomeningeal disease, and 4 allowed previously treated leptomeningeal disease. All 8 trials were lung cancer trials. 

Of the 169 trials not specifying the inclusion or exclusion of leptomeningeal disease, 90 included patients with central nervous system (CNS) metastases, 30 excluded all patients with CNS metastases, and 49 did not specify inclusion or exclusion criteria for CNS disease.

Thirteen trials included CNS disease-specific outcomes. CNS-specific response criteria were used in 2 of these trials, and 1 trial was designed to assess neurocognitive outcomes.

However, outcomes specific to leptomeningeal disease were not included in any of the 244 trials. The researchers speculated that this may be because leptomeningeal disease-specific criteria are relatively new and not validated. 

“We believe inclusion of patients with LMD [leptomeningeal disease] should be encouraged in clinical trials, either within larger trials or in separate smaller studies, with incorporation of standardized LMD-specific endpoints,” the researchers concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Sharma AE, Corbett K, Soliman H, et al. Assessment of phase 3 randomized clinical trials including patients with leptomeningeal disease: A systematic review. JAMA Oncol. Published online February 9, 2023. doi:10.1001/jamaoncol.2022.7364