NE Oncology Issue – February 2014

Jerusalem G, et al. ECC 2013:LBA16

Background

In BOLERO-3 (NCT01007942), a randomized, double-blind, placebo-controlled, phase III trial, everolimus 5 mg daily combined with weekly trastuzumab and vinorelbine significantly prolonged progression-free survival (PFS) versus placebo in patients with trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer previously treated with a taxane (HR = 0.78 [95% CI: 0.65–0.95]).1 At ECC 2013, Jerusalem and colleagues explored correlations between key members of the phosphatidylinositol 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway and everolimus efficacy in a subset of patients from this study for the identification of potential predictive biomarkers.1

Study design

  • Patients (N = 569) with locally advanced or metastatic HER2-positive breast cancer that was trastuzumab resistant were randomized 1:1 to receive vinorelbine (25 mg/m2 weekly) plus trastuzumab (2 mg/kg weekly; 4 mg/kg loading dose on day 1, cycle 1) in combination with either everolimus (5 mg orally (po) daily) or a placebo (po daily), until progressive disease or intolerable toxicity.
  • The biomarker hypothesis states that patients with tumours harbouring activated PI3K/mTOR pathway are resistant to trastuzumab and are more likely to benefit from blockade of the signaling pathway by everolimus.
    • Therefore, correlations between the biomarker data and PFS, the primary end point, were evaluated by univariate and multivariate Cox models.
  • Levels of phosphorylated ribosomal protein S6 (pS6) and phosphatase and tensin homolog (PTEN) were assessed in archival tumour samples by immunohistochemistry and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene mutations in exons 9 and 20 were identified by DNA sequencing.

131209-breast-2-study-lrg

Key findings

  • Archival tumour samples were available for biomarker analysis from 283/569 patients. Of 283 available patients, 262 had evaluable data for one or more of the measured biomarkers.
  • This biomarker population was representative of the trial population in terms of demographics, clinical characteristics, and efficacy outcomes.
  • None of the known prognostic factors were significantly imbalanced between the arms.
  • Patients with high pS6 level (optimal histology (H)-score cut-point: ≥75th percentile) derived more benefit with everolimus (HR = 0.48 [95% CI: 0.24–0.96]). (Figure 1 and Table 1)
  • Similarly, patients with low PTEN level (optimal H-score cut-point: <20th percentile) derived more benefit with everolimus (HR = 0.41[95% CI: 0.20–0.82]), with a median PFS gain of 18 to 19 weeks (41.9 weeks vs. 23.1 weeks). (Figure 2 and Table 2)
  • In contrast, patients with low pS6 or normal to high PTEN did not appear to derive any benefit from addition of everolimus (HR = 1.14 [95% CI: 0.77–1.68] and HR = 1.05 [95% CI: 0.75–1.45], respectively). (Tables 1 and 2)
  • A trend of enhanced everolimus treatment benefit was observed in patients with PIK3CA mutations (~20% of the population) and in those with activated PI3K pathway, defined as harbouring either PIK3CA mutation or low PTEN level. (Table 3)
  • Significant treatment-marker interactions were detected for PTEN and pS6 (p = 0.01 and p = 0.038, respectively), but not for PIK3CA (p = 0.32).

Key conclusions

  • Patients in BOLERO-3 with biomarkers indicative of PI3K/mTOR pathway activation may derive greater benefit from addition of everolimus to trastuzumab and vinorelbine.
  • These observations are consistent with the hypothesis that mTOR inhibition attenuates trastuzumab resistance resulting from PI3K/mTOR pathway activation.
  • The results and clinical implications of this exploratory analysis need further validation and investigation.

Reference: 1. Jerusalem G, André F, Chen D, et al. Evaluation of everolimus (EVE) in HER2+ advanced breast cancer (BC) with activated PI3K/mTOR pathway: Exploratory biomarker observations from the BOLERO-3 trial. ECC 2013:LBA16.

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Spotlight Article

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Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

 

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Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

Canadian Perspective

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Matthew Seftel, MBChB, MPH, MRCP(U.K.), FRCPC

Dr. Seftel is a hematologist/oncologist based at Princess Margaret Hospital in Toronto. He is a member of the Leukemia Group and leads the Allogeneic Blood and Marrow Transplantation Program. He is an Associate Professor at the University of Toronto in the Division of Internal Medicine. He is actively involved in clinical trials and outcomes-based research related to hematological malignancies and blood and marrow transplantation.

Investigator Commentary

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Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal investigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, Lancet Oncology, Lancet, and The New England Journal of Medicine.