Abstract
Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31–54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5–8.7 months) across both cohorts, 6.5 months (90% CI: 4.5–18.7 months) for cohort A and 8.1 months (90% CI: 5.3–9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41–64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585
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Data availability
The raw clinical and imaging data are protected due to patient privacy laws. Information is taken directly from the electronic medical record or original source generated by treating investigators (for example, email confirmations, AE logs). This is stored on a secured network drive to which only appropriately trained and delegated staff have access to. Lesion measurements are obtained from the Tumor Metrics Imaging Core online portal that uses a secure server to which only appropriately trained and delegated staff are granted access to. Any requests for raw and analyzed data should be sent in writing to P.B. and will be reviewed by the DF/HCC Institutional Review Board in an expeditious fashion (for example, approximately 6 months). 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, study protocol, clinical data or imaging data) that can be shared will require approval from the DF/HCC Institutional Review Board and a material transfer agreement. De-identified data then will be transferred to the inquiring investigator in an expeditious fashion over secure file transfer. The study protocol and statistical analysis plan are included with the submission.
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Acknowledgements
Funding for this trial was provided by Merck Sharp & Dohme, a subsidiary of Merck & Co. (to MGH), Damon Runyon Cancer Research Foundation (to P.K.B.), Ben and Catherine Ivy Foundation (to P.K.B.). P.K.B. also receives support from Breast Cancer Research Foundation, Hellenic Women’s Club Demetra Fund, Terry and Jean de Gunzburg MGH Research Scholar Fund and the National Institutes of Health (1R01CA227156-01 and 1R01CA244975-01). A.E.K. is supported by an American Brain Tumor Association Basic Research Fellowship In Honor of P. Fabbri, the William G. Kaelin, Jr., Physician-Scientist Award of the Damon Runyon Cancer Research Foundation, American Association for Cancer Research Breast Cancer Research Fellowship and the American Society of Clinical Oncology Young Investigator Award. E.R.G. is supported by the National Cancer Institute (R01CA211238 and R01CA244975). Most importantly, we thank the patients and their families for contributing to research efforts.
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P.K.B. and R.J.S. conceived the study and wrote the protocol with input from E.R.G., D.P.C., F.G.B. and A.G.-H. P.K.B., A.E.K., E.Q.L., N.U.L., B.O., P.Y.W., L.N., J.V.C., J.D., A.E., R.S.H., I.K., D.L., E.M., E.W., M.M., K.O., H.A.S., D.P.C., E.R.G., M.M. and R.J.S. supported the clinical trial, including recruitment and/or management of patients in the trial. A.G.-H. performed the statistical analysis. A.E.K., B.B., M.A.S., N.I., J.M.L., B.M., S.N., N.M., S.R. and E.J.S. helped collect data and samples. E.R.G. was the imaging chair of the study. A.E.K., P.K.B., E.R.G. and R.J.S. wrote the manuscript. All the authors interpreted the data, reviewed the manuscript and approved the final version.
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P.K.B. consulted for Tesaro, Angiochem, Genentech-Roche, ElevateBio, Eli Lilly, SK Life Sciences, Pfizer, Voyager Therapeutics, Sintetica, MPM, Advise Connect Inspire, Kazia and Dantari, received institutional research funding (to MGH) from Merck, Mirati, Eli Lilly, Kinnate, BMS and Pfizer and has received honoraria from Merck, Medscape, Pfizer, and Genentech-Roche. B.O. has received clinical trial support from Incyte and Eisai. J.D. has served as a consultant for Amgen, Blue Earth Diagnostics and Unum Therapeutics and received research support (to MGH) from Novartis and Eli Lilly. R.S.H. consulted for AbbVie, Daichii Sankyo, EMD Serono, Lilly, Novartis, Regeneron, and Sanofi; and received institutional research funding (to MGH) from Abbvie, Agios, Corvus, Daichii Sankyo, Erasca, Exelixis, Lilly, Mirati, Novartis and Turning Point. P.Y.W. received institutional research funding (to DF/HCC) from AstraZeneca/Medimmune, Beigene, Celgene, Chimerix, Eli Lilly, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Puma, Servier, Vascular Biogenics and VBI Vaccines, and has served on the scientific advisory board for AstraZeneca, Bayer, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics and VBI Vaccines. H.A.S. has served on the scientific advisory board for Advanced Accelerator Applications, and received institutional research funding (to MGH) from AbbVie. R.J.S. consulted for Novartis, BMS and Pfizer, and received institutional research funding (to MGH) from Merck. The remaining authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Kaplan-Meier Estimate for Intracranial Progression-free Survival, by Cohort.
The median intracranial PFS was 1.6 months for cohort A (blue line - 90% CI: 1.2-4.5 months) and 2.2 months for cohort B (red line - 90% CI: 1.4-3.1 months).
Extended Data Fig. 2 Kaplan-Meier Estimate for Extracranial Progression-Free Survival.
The median extracranial PFS was 4.5 months (90% CI: 2.7-8.0 months). Extracranial PFS was defined as the time of enrollment until the earlier of RECIST-defined disease progression or death. Patients who neither progressed nor died have follow-up that is censored at the date of last visit. CNS progression events are ignored. 53 of 57 patients (93%) experienced an extracranial PFS event. 18 patients experienced systemic progression and 35 additional died without systemic progression.
Extended Data Fig. 3 Kaplan-Meier Estimate for Extracranial Progression-Free Survival, by Cohort.
The median time to extracranial progression was 4.5 months (blue line - 90% CI: 1.2-6.7 months) for cohort A and 4.6 months (red line - 90% CI: 2.7-8.1 months) for cohort B.
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Clinical trial protocol.
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Brastianos, P.K., Kim, A.E., Giobbie-Hurder, A. et al. Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results. Nat Med 29, 1728–1737 (2023). https://doi.org/10.1038/s41591-023-02392-7
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DOI: https://doi.org/10.1038/s41591-023-02392-7
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