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Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy

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Abstract

Purpose

A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion.

Methods

Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine.

Results

In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined.

Conclusion

Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.

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Acknowledgements

The authors would like to thank the patients who took part in this study, and their families. We thank Shaun Su, Shanthy Nuti and Tong Zhu (Novartis Pharmaceuticals Corporation) for their significant contributions towards the conduct of the study and data analyses. Editorial assistance was provided by Sarah Amir PhD and Maria Alfaradhi PhD of Articulate Science, and was funded by Novartis Pharmaceuticals Corporation.

Disclosure

Timothy Pluard reports personal fees from Novartis outside the submitted work. Thomas Bachelot reports grants, personal fees and non-financial support from Roche and Novartis and grant and personal fees from Astra Zeneca and Pfizer, outside the submitted work. Hyo Han reports research funding support from Novartis during the conduct of the study. Guy Jerusalem reports grants, personal fees and non-financial support from Novartis, Roche and BMS; grant and personal fees from Amgen; personal fees and non-financial support from Lilly; grant from MSD and personal fees from Celgene, Pfizer, Puma and Daiichi Sankyo, outside the submitted work. Emmanuelle di Tomaso reports employment with Novartis during the conduct of the study. Cristina Saura has received personal fees from Puma Biotechnology, Pfizer and Roche, outside the submitted work. Douglas Robinson and Patrick Urban report employment with Novartis.

Funding

This work was supported by Novartis Pharmaceuticals. Anthony Kong was supported by a Breakthrough Breast Cancer Clinician Scientist Fellowship (CSF 07/08) through the Holbeck Charitable Trust when this study was conducted. Stephen Chan is supported by the Nottingham Charitable Research Fund. No financial support was declared by the other authors.

Author information

Author notes

  1. B. Pistilli

    Present address: Breast Cancer Unit, Institut Gustave Roussy, 114 Rue Edouard-Vaillant, 94800, Villejuif, France

  2. A. Urruticoechea

    Present address: Onkologikoa Foundation, San Sebastian, Spain

  3. A. Kong

    Present address: University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

  4. E. D. Tomaso

    Present address: Syros Pharmaceuticals, Watertown, MA, USA

Authors and Affiliations

  1. Macerata Hospital, Macerata, Italy

    B. Pistilli

  2. Saint Luke’s Health System, Kansas City, MO, USA

    T. Pluard

  3. Catalan Institute of Oncology, Barcelona, Spain

    A. Urruticoechea

  4. Ospedale Oncologico, Cagliari, Italy

    D. Farci

  5. University of Oxford and Oxford University Hospitals NHS Trust, Oxford, UK

    A. Kong

  6. Centre Léon Bérard et Inserm U1052, Lyon, France

    T. Bachelot

  7. Nottingham University Hospitals NHS Trust, Nottingham, UK

    S. Chan

  8. Moffitt Cancer Center, Tampa, FL, USA

    H. S. Han

  9. CHU Sart Tilman Liège and University of Liège, Liège, Belgium

    G. Jerusalem

  10. Novartis Pharma AG, Basel, Switzerland

    P. Urban

  11. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    D. Robinson & E. D. Tomaso

  12. Novartis Pharmaceuticals Corporation, Rueil-Malmaison, France

    S. L. Mouhaër & C. Massacesi

  13. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    C. Saura

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Contributions

All authors were involved in the conception, design and conduct of the study, as well as in data collection and interpretation. All authors were responsible for writing, critically reviewing and revising the manuscript, with assistance from a medical writer, and approved the final version prior to submission.

Corresponding author

Correspondence to B. Pistilli.

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Pistilli, B., Pluard, T., Urruticoechea, A. et al. Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy. Breast Cancer Res Treat 168, 357–364 (2018). https://doi.org/10.1007/s10549-017-4596-7

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