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Palbociclib demonstrates intracranial activity in progressive brain metastases harboring cyclin-dependent kinase pathway alterations


Recent studies suggest that the cyclin-dependent kinase (CDK) pathway may be a therapeutic target for brain metastases (BM). Here, we present interim analysis of a basket trial evaluating the intracranial efficacy of the CDK inhibitor palbociclib in patients with progressive BM and CDK alterations. Our study met its primary endpoint and provides evidence for performing molecular testing of archival BM tissue, if available, to inform the choice of CNS-penetrant targeted therapy.

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Fig. 1: Kaplan–Meier curve for overall survival.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary Information. Any requests for additional data (e.g., clinical outcomes, tissue samples) should be sent to P.K.B. and will be reviewed by the DF/HCC IRB. Patient-related data not included in the paper were generated as part of a clinical trial and are subject to patient confidentiality. Any data that can be shared will need approval from the DF/HCC IRB and a Material Transfer Agreement in place. All data shared will be deidentified. Source data are provided with this paper. All other data supporting the findings of this study are available from the corresponding author upon request. Please note that any materials (for example, tissue samples or imaging data) that can be shared will need approval from the DF/HCC IRB and a Material Transfer Agreement in place. All materials shared will be deidentified.


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We thank the patients and their families for contributing to research efforts. Funding was provided by the Damon Runyon Cancer Research Foundation, the Ben and Catherine Ivy Foundation, the Breast Cancer Research Foundation, Pfizer and the Massachusetts General Hospital. P.K.B. and S.L.C. are supported by the NCI (1R01CA227156–01, 5R21CA220253–02 and 1R01CA244975–01). A.E.K. is supported by an American Brain Tumor Association Basic Research Fellowship In Honor of Paul Fabbri (BRF1900017).

Author information

Authors and Affiliations



P.K.B., R.J.S., S.L.C. and D.P.C. conceived of the study idea. P.K.B. wrote the protocol with input from R.J.S., D.P.C., S.L.C., S.S., T.T.B., A.G.-H., E.R.G. and K.O. A.E.K., N.W., E.Q.L., J.L., J.V.C., U.N.C., D.F., M.D.W., H.A.S., J.F.G., R.S.H., M.M., E.R.G., K.O., D.L., D.P.R., D.P.C. and R.J.S. supported the clinical trial, including recruitment and/or management of patients on the trial. A.J.I. assisted with the genetic profiling analysis. A.G.-H. performed the statistical analysis. E.R.G. was the imaging chair of the study. P.K.B., A.E.K., 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, Voyager Therapeutics, AngioChem, Genentech/Roche, ElevateBio, SK Life Science, Dantari, Pfizer and Lilly; has received research funding (to Massachusetts General Hospital) from Merck, Mirati, Lilly, BMS and Pfizer; and has received honoraria from Merck and Genentech/Roche. N.W. has received compensation from Seattle Genetics and Wolters Kluwer; and has research funding (to institution, not self) from Merck. E.Q.L. has received royalties from Wolters Kluwer (UpToDate) and has consulted for Lilly. J.V.C. has received consulting fees from Sanofi/Genzyme and BMS. H.A.S. serves on the Board of Directors for the Radiosurgery Society and has received compensation from Wolters Kluwer (UpToDate). D.F. has stock ownership (<$10,000) in Eli Lilly. J.F.G. has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Novartis, Merck, and GlydeBio; research support from Novartis, Genentech/Roche, and Ariad/Takeda; institutional research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. R.S.H. has received consulting honoraria from Novartis, Daichii Sankyo, EMD Serono, Boehringer Ingelheim, Tarveda, Apollomics; and has research funding (to institution, not to self) from Agios, Abbvie, Daichii Sankyo, Novartis, Lilly, Mirati, Corvus, Genentech Roche, Exelixis, Turning Point. D.P.R. holds equity in MPM Capital and Acworth Pharmaceuticals; has served as a paid consultant and/or on an advisory board for MPM Capital, Oncorus, Gritstone Oncology, Maverick Therapeutics, and Boehringer Ingelheim; and has received compensation from Johns Hopkins University Press, Wolters Kluwer (UpToDate), and McGraw Hill. A.J.I. holds equity in Invitae, and has consulted for Paige.AI, Kinnate, Repare, and Oncoclinicas Brasil. S.S. has consulted for RareCyte, Inc. D.P.C. has consulted for Lilly, GSK, and Boston Pharmaceuticals and has received travel/speaking fees from Merck. R.J.S. has received research funding from Amgen and Merck and served as a paid consultant and/or on an advisory board for Array BioPharma, Amgen, Asana BioSciences, AstraZeneca, BMS, Compugen, Eisai, Genentech, Merck, Novartis, OncoSec, Pfizer and Replimune.

Additional information

Peer review information Nature Cancer thanks Frédéric Dhermain, Priya U. Kumthekar and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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

Extended data

Extended Data Fig. 1 Cummulative Incidence of Intracranial Progression-Free Survival, with Extracranial Progression as a Competing Risk.

Competing risk analysis was performed for all 15 patients enrolled on trial. At 6 months, the proportion of patients who were intracranial progression free was 0.60 (90% CI: 0.34-0.79).

Source data

Extended Data Fig. 2 Cummulative Incidence of Extracranial Progression-free Survival, with Intracranial Progression as a Competing Risk.

Competing risk analysis was performed for the 10 patients with evaluable systemic imaging. At 6 months, the proportion of patients extracranial progression free was 0.33 (90% CI: 0.14-0.54).

Source data

Supplementary information

Supplementary Information

Clinical trial protocol.

Reporting Summary

Supplementary Tables

Supplementary Table 1: Demographics at enrollment and baseline disease characteristics for the eight patients with intracranial benefit. Supplementary Table 2: Predicted and actual survival for patients on trial. Patients labeled in red had intracranial benefit (as defined by complete response, partial response or stable disease by RANO). Five patients had improvement in neurologic symptom burden. An additional four patients had neurologic stability while on palbociclib. Supplementary Table 3: New or worsening adverse events/toxicities relative to enrollment. Shown are the treatment-related adverse events of any grade that were deemed by the investigator to be possibly, probably or definitely related to palbociclib.

Source data

Source Data Fig. 1

Statistical and numerical data for the Kaplan–Meier survival curve included in Fig. 1.

Source Data Extended Data Fig. 1

Statistical and numerical data for the Kaplan–Meier survival curve included in Extended Data Fig. 1.

Source Data Extended Data Fig. 2

Statistical and numerical data for the Kaplan–Meier survival curve included in Extended Data Fig. 2.

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Brastianos, P.K., Kim, A.E., Wang, N. et al. Palbociclib demonstrates intracranial activity in progressive brain metastases harboring cyclin-dependent kinase pathway alterations. Nat Cancer 2, 498–502 (2021).

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