e14506 Background: Leptomeningeal metastasis (LMM) from solid tumors are rare and often refractory to standard therapies. Pembrolizumab (anti-PD-1) has efficacy in patients (pts) with brain metastases from ICI-responsive tumors, however pts with LMM are often excluded from ICI trials. We hypothesized that: 1. Pembrolizumab will lead to CNS response in LMM, and 2. Genomic/immunologic analyses on CSF could identify CNS biomarkers of response. Methods: We conducted an investigator-initiated open-label phase 2 trial of Pembrolizumab in pts with LMM from any solid tumor (NCT03091478). Eligible pts had: LMM on MRI ( > 3mm lesion) or CSF cytology, ECOG PS ≤1, and were PD-naïve. Prior RT to LMM was allowed > 3 months before study start or to non-target areas. Pembrolizumab was administered IV 200mg q3W until disease progression/unacceptable toxicity. The primary endpoint was CNS response after 12 weeks, defined as radiologic (RECIST 1.1)/cytologic/clinical response to therapy. Serial CSF samples were assessed by chromosomal copy number changes using a PCR-based approach (RealSeqS) to detect tumor-derived DNA (CSF-tDNA), and 16-color flow cytometry. Results: Thirteen of a planned 18 pts were treated 04/2017-12/2019, the study was closed early for low accrual. Median age was 58 years (22-79), 53% were female. Pts had breast carcinoma (38%, n = 5), NSCLC (23%, n = 3), high-grade glioma (23%, n = 3), HNSCC (8%, n = 1) and cutaneous squamous cell carcinoma (8%, n = 1). Median no. of prior therapies was 4 (0-8), 76% of pts had prior RT to LMM. CNS response was seen in 38% of pts (5/13: 2 = complete response (NSCLC; Squamous skin); 3 = stable disease (NSCLC, Glioma, HER2+BC) by RECIST 1.1. Treatment-related adverse events were seen in 31% (4/13) of pts, 15% (2/13) G3+ (fatigue = 1, infection = 1). CSF cytology was negative at ICI start in 6 cases, but positive by CSF-tDNA in 5/6 cases. In addition, CSF-tDNA levels can correlate with disease status. CSF flow cytometry demonstrated increase in CD45R0+ activated memory T-cells, and a shift from immature to antibody-secreting B-cells in both pts with CRs in LMM. Conclusions: Pembrolizumab was well-tolerated and demonstrated anti-tumor activity in pts with LMM in ICI-responsive tumors. Correlative analyses identified CSF-tDNA can potentially be used from diagnosis to longitudinally monitor LMM; and that T and B cell populations may be enriched in the CSF of pts whose LMM regressed. These findings support inclusion of pts with LMM in ICI studies and interrogation of CSF biomarkers. Clinical trial information: NCT03091478.
