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Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis

A Publisher Correction to this article was published on 18 June 2020

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An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1,2,3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients—17 with breast cancer, two with lung cancer and one with ovarian cancer—were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2–12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39–0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.

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Data availability

Any requests for raw and analyzed data will be reviewed by the Dana-Farber/Harvard Cancer Center institutional review board. Patient-related data not included in the paper were generated as part of a clinical trial and are subject to patient confidentiality. Any data and materials (for example, tissue samples or imaging data) that can be shared will need approval from the Dana-Farber/Harvard Cancer Center institutional review board and a Material Transfer Agreement in place. All data shared will be de-identified.

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Funding was provided by the Melanoma Research Alliance, the Breast Cancer Research Foundation, Merck and the Massachusetts General Hospital. P.K.B. and S.L.C. are supported by the National Cancer Institute (1R01CA227156-01, 5R21CA220253-02 and 1R01CA244975-01). P.K.B. is also currently supported by the Damon Runyon Cancer Research Foundation and has previously received funding from the Susan G. Komen Foundation, the American Brain Tumor Association, the Terri Brodeur Breast Cancer Foundation and the Conquer Cancer Foundation. We also thank the patients and their families for contributing to research efforts.

Author information

Authors and Affiliations



P.K.B., R.J.S. and D.P.C. conceived the study. P.K.B. wrote the protocol with input from R.J.S., D.P.C., S.L.C., A.G.-H., T.T.B., E.R.G. and K.O. E.Q.L., J.V.C., S.M.T., N.U.L., N.W., U.C., M.D.W., C.A.-B., I.K., M.K.M., L.N., J.D., D.A.F., B.V.N., T.T.B., H.A.S., E.R.G., B.M., P.K.B., R.J.S., D.P.C., K.O. and D.L. supported the clinical trial, including recruitment and/or management of patients in the trial. A.G.-H. performed the statistical analysis. B.S., N.G., N.N., A.K., J.L.M., M.D.W., M.S.B. and M.S. helped collect data and samples. E.R.G. was the imaging chair of the study. P.K.B., D.P.C. and R.J.S. wrote the manuscript. All authors interpreted the data, reviewed the manuscript and approved the final version.

Corresponding author

Correspondence to Priscilla K. Brastianos.

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Competing interests

P.K.B. has consulted for Tesaro, Angiochem, Genentech-Roche, ElevateBio and Eli Lilly, has received institutional research funding (to Massachusetts General Hospital) from Merck, Eli Lilly, BMS and Pfizer and has received honoraria from Merck and Genentech-Roche. J.C. has received consulting fees from Sanofi-Genzyme and BMS. D.P.C. has consulted for Eli Lilly and Boston Pharmaceuticals and has received travel and speaking fees from Merck. S.M.T. receives institutional research funding from Novartis, Genentech, Eli Lilly, Pfizer, Merck, Exelixis, Eisai, Bristol Meyers Squibb, AstraZeneca, Cyclacel, Immunomedics, Odenate and Nektar. S.M.T. has served as an advisor and consultant to Novartis, Eli Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech, Immunomedics, Nektar, Tesaro, Daiichi Sankyo, Athenex, Sanofi, Bristol Meyers Squibb and Nanostring. N.U.L. has received institutional research funding from Seattle Genetics, Genentech, Merck and Pfizer. N.U.L. has also served on an advistory board or consulted for PUMA Biotechnology, Seattle Genetics and Daichii Sankyo. R.J.S. has received research funding from Amgen and Merck and has served as a paid consultant and/or been on an advisory board for Array BioPharma, Amgen, Asan Biosciences, BMS, Compugen, Genentech, Merck, Novartis and Replimmune. E.Q.L. has received royalties from Wolters Kluwers (UpToDate, Inc) and has consulted for Eli Lilly. B.M. has received institutional research funding from PUMA Biotechnology. D.A.F. is an Eli Lilly shareholder. I.K. has received personal fees for being a member of a Merck DSMC, has received research funding from Genentech and Pfizer and has served as a paid consultant and/or been on an advisory board for Genentech, Bristol Meyers Squibb, Daiichi/Sankyo, Macrogenics and AstraZeneca. T.T.B. is on the Scientific Advisory Board for Genomicare. M.D.W. is a consultant at Boston Pharmaceuticals. Dana-Farber Cancer Institute has a financial interest in pembrolizumab and has taken steps to manage any actual or potential conflict of interest created by this financial interest, which was described in the information sheet available to all participants in this study.

Additional information

Peer review information Saheli Sadanand was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Enrolment information.

A total of 22 patients with leptomeningeal carcinomatosis were consented and enrolled to the study between October 2016 to April 2018.

Extended Data Fig. 2 Characteristics of patients alive at three months.

Clinical characteristics of the 12 patients with leptomeningeal carcinomatosis receiving pembrolizumab who were alive at three months.

Extended Data Fig. 3 All adverse events new or worsening during study occurring in 4 or more patients.

List of all new or worsening adverse events occurring in 4 patients or more with leptomeningeal carcinomatosis receiving pembrolizumab on study.

Extended Data Fig. 4 Grade 4 and 5 adverse events with attributions.

List of Grade 4 and 5 adverse events in patients with leptomeningeal carcinomatosis receiving pembrolizumab on study.

Supplementary information

Supplementary Information

Consort Checklist Clinical Protocol Document

Reporting Summary

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Brastianos, P.K., Lee, E.Q., Cohen, J.V. et al. Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. Nat Med 26, 1280–1284 (2020).

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