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A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer

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Abstract

Purpose

There are limited data on trastuzumab–pertuzumab (HP)-based treatments beyond the first-line, HER2+ metastatic breast cancer (MBC) setting. We conducted a phase II study of eribulin mesylate, which extends survival in MBC, with HP in patients with previously treated HER2+ MBC to evaluate efficacy, toxicity, and genomic alterations driving therapeutic response.

Methods

After a run-in phase for eribulin dosing, two cohorts were enrolled (Cohort A-no prior pertuzumab; Cohort B-prior pertuzumab). All patients received eribulin 1.4 mg/m2 on days 1, 8 with standard-dose HP on day 1 (21-day cycles). The primary endpoint was objective response rate (ORR). Genomic characterization via whole exome sequencing (WES) was completed on tumor DNA and matched germline DNA from 19 patients.

Results

The six-patient run-in established a dose of eribulin 1.4 mg/m2 with HP. Cohorts A and B enrolled 17 and 7 patients, respectively. Accrual stopped early due to an evolving treatment landscape and slow enrollment. The ORR was 26.3% (95% Confidence Interval [CI] 9.2–51.2%) in Cohort A and 0% in Cohort B (95% CI 0–41.0%). WES revealed more frequent alterations in TP53 (p < 0.05, q > 0.05) in patients without clinical benefit (disease control for < 24 weeks) which was not significant after multiple hypothesis correction.

Conclusion

Eribulin–HP had manageable toxicity and modest clinical activity in patients without prior pertuzumab exposure. This study provides a preliminary landscape of somatic alterations in this patient cohort. Our data add to the literature on how genomic alterations may predict for therapy response/resistance, as we work to individualize choices in a quickly evolving HER2+ MBC treatment landscape.

Trial registration

www.clinicaltrials.gov, NCT01912963. Registered 24 July 2013.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the patients who participated in this study and who graciously provided blood and tissue samples for genomic analyses. We also thank Kaitlyn Bifolck, BA, for her assistance with manuscript formatting and journal submission.

Funding

Eisai Co. Ltd. In addition, Susan G. Komen (CCR14298143 and CCRCR18552788 to RAF) and American Cancer Society (MRSG-14-240-01-CPPB to RAF).

Author information

Author notes

  1. Jorge E. Buendia-Buendia

    Present address: Cellarity, Inc., Cambridge, MA, USA

Authors and Affiliations

  1. The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Sara M. Balch, Esha Jain, Jorge E. Buendia-Buendia, Erin Shannon & Nikhil Wagle

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1259, Boston, MA, 02215, USA

    Sara M. Balch, Ines Vaz-Luis, Esha Jain, Karla Helvie, Ian E. Krop, Nancy U. Lin, Nikhil Wagle & Rachel A. Freedman

  3. Institut Gustave Roussy, Unit INSERM 981, Villejuif, France

    Ines Vaz-Luis

  4. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA

    Tianyu Li & Nabihah Tayob

  5. Massachusetts General Hospital, Boston, MA, USA

    Steven J. Isakoff

  6. Harvard Medical School, Boston, MA, USA

    Steven J. Isakoff, Nadine M. Tung, Ian E. Krop, Nancy U. Lin, Nikhil Wagle & Rachel A. Freedman

  7. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Nadine M. Tung

Authors
  1. Sara M. Balch
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Contributions

Conceptualization—RAF, IVL, NUL, NW; data curation—RAF, IVL, SMB, EJ, KH, J B-B, NW; formal analysis—RAF, IVL, TL, NT, SMB, EJ, JB-B, NW; funding acquisition—RAF and NUL; investigation—all authors; methodology—RAF, IVL, SMB, EJ, NW, NUL; supervision—RAF and NW; writing: original draft—IVL, RAF, SMB; writing: review & editing—all authors.

Corresponding author

Correspondence to Rachel A. Freedman.

Ethics declarations

Conflict of interest

IVL reports institutional honoraria from Pfizer, Astra-Zeneca, and Amgen. IEK reports research support (paid to his institution) from Genentech/Roche and Pfizer, has received fees from Novartis and Merck for Data Monitoring Board participation, received honoraria from Celltrion, and has received consulting fees from Bristol Meyers Squibb, Daiichi/Sankyo, Macrogenics, Context Therapeutics, Taiho Oncology, Genentech/Roche, Seattle Genetics, and AstraZeneca. NU reports research support (to institution) from Genentech, Merck, Pfizer, Seattle Genetics; Consultant/ad board: Puma, Seattle Genetics, Daiichi Sankyo, AstraZeneca, Denali Therapeutics, California Institute for Regenerative Medicine, Prelude Therapeutics. RAF reports research support (to institution, no salary support): Eisai and Puma. SJI has received institutional research funding from Abbive, Astrazeneca, Genetech, Merck and OcnoPep, and fees from Seattle genetics, Novartis, Puma. N.W. reports advisory relationships and consulting with Eli Lilly and Co.; advising and stockholding interest in Relay Therapeutics; and grant support from Puma Biotechnology. JB-B is now employed by Cellarity, Inc. Cambridge, MA, USA.

Ethical approval

The study was conducted according to the current guidelines for good and sound research practice after approval from the Dana-Farber Cancer Institute Office for Human Research Studies.

Informed consent

Informed consent was obtained from all individual participants included in the study. Prior to any study procedures, all patients provided written informed consent for study participation.

Consent for publication

Included in patient consent for study.

Research involving human and animal participants

The study was conducted according to the current guidelines for good and sound research practice after approval from the Dana-Farber Cancer Institute Office for Human Research Studies.

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Publisher's Note

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

Nikhil Wagle and Rachel A. Freedman share co-senior authorship.

Prior Presentations: American Society of Clinical Oncology (ASCO) Annual Meeting, June 2–6, 2017, Chicago, IL.

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Balch, S.M., Vaz-Luis, I., Li, T. et al. A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer. Breast Cancer Res Treat 189, 411–423 (2021). https://doi.org/10.1007/s10549-021-06329-x

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