Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety, and cerebrospinal fluid biomarkers.
Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety, and cerebrospinal fluid biomarkers.
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DOI：
10.1136/jitc-2021-002473
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发表时间：
2021-08
影响因子：
10.9
通讯作者：
Grossman SA
中科院分区：
文献类型：
--
作者：
Naidoo J;Schreck KC;Fu W;Hu C;Carvajal-Gonzalez A;Connolly RM;Santa-Maria CA;Lipson EJ;Holdhoff M;Forde PM;Douville C;Riemer J;Barnes A;Redmond KJ;Kleinberg L;Page B;Aygun N;Kinzler KW;Papadopoulos N;Bettegowda C;Venkatesan A;Brahmer JR;Grossman SA
The benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown. We undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0–1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines. Thirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22–79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together. Pembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study. NCT03091478
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影响因子：
82.9
作者：
Brastianos, Priscilla K.;Lee, Eudocia Quant;Sullivan, Ryan J.
通讯作者：
Sullivan, Ryan J.
影响因子：
51.1
作者：
Goldberg, Sarah B.;Schalper, Kurt A.;Kluger, Harriet M.
通讯作者：
Kluger, Harriet M.
影响因子：
15.9
作者：
Chamberlain, Marc;Junck, Larry;Jaeckle, Kurt A.
通讯作者：
Jaeckle, Kurt A.
DOI：
10.1126/science.aaz2193
发表时间：
2020-07-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chi Y;Remsik J;Kiseliovas V;Derderian C;Sener U;Alghader M;Saadeh F;Nikishina K;Bale T;Iacobuzio-Donahue C;Thomas T;Pe'er D;Mazutis L;Boire A
通讯作者：
Boire A
影响因子：
4.4
作者：
Prins, Robert M.;Vo, Dan D.;Ribas, Antoni
通讯作者：
Ribas, Antoni