Conference Coverage

Immunotherapy could fill unmet need in leptomeningeal metastases


 

FROM SITC 2020

Immunotherapy with pembrolizumab holds promise for improving the generally dismal outlook in patients with leptomeningeal metastases, a phase 2 trial suggests.

Jarushka Naidoo, MBBCH, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin, Ireland

Dr. Jarushka Naidoo

Results from the trial were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks,” commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.

“While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types,” Dr. Naidoo added.

With this in mind, Dr. Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.

The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.

Response, safety, and biomarkers

Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Dr. Naidoo reported.

Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.

For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.

“This is consistent with published prospective studies of systemic agents for leptomeningeal disease,” Dr. Naidoo pointed out. “Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies.”

The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.

The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.

The trial’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).

A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.

Given the trial’s 38% CNS response rate, pembrolizumab “needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors,” Dr. Naidoo concluded. “Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity.”

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