NE Oncology Issue – April 2013

Baselga J, et al. SABCS 2012:S5-1

Background

The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibodies trastuzumab and pertuzumab have complementary mechanisms of action. The CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study showed that pertuzumab plus trastuzumab and docetaxel significantly improved progressionfree survival (PFS) compared with placebo plus trastuzumab and docetaxel (HR = 0.62 [95% CI: 0.51–0.75], p <0.001) in the first-line treatment of HER2-positive metastatic breast cancer (MBC), while maintaining a similar safety profile.1 At SABCS 2012, Baselga et al. examined the potential predictive and prognostic value of a panel of biomarkers that were assessed in tumour tissue and serum samples collected at baseline from patients of the CLEOPATRA study.2

Study design

  • The CLEOPATRA study enrolled patients with HER2- positive MBC who were randomized to receive one of two first-line treatment regimens:
    • Pertuzumab plus trastuzumab and docetaxel (pertuzumab arm); or
    • Placebo plus trastuzumab and docetaxel (control arm).
  • For more details on the CLEOPATRA study design and its clinical outcomes, see p. 16.
  • Samples (N = 808) were collected at baseline prior to the first dose of study drug, of which only 58% to 99% were assessable for biomarkers due to tissue availability or technical reasons.
  • HER2, HER3, insulin-like growth factor 1 receptor (IGFR1), phosphatase and tensin homolog (PTEN), and phosphorylated v-akt murine thymoma viral oncogene homolog (pAKT) were assessed by immunohistochemistry and a modified H-score was derived for each.
  • HER1, HER2, HER3, amphiregulin (AREG), and betacellulin tumour messenger ribonucleic acid (mRNA) levels were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and v-myc myelocytomatosis viral oncogene homolog (avian) (c-myc) by fluorescence in situ hybridization.
  • PCR-based methods were used for mutational analyses of eight different mutations at four hotspots within exons 7, 9, and 20 of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PI3KCA) on tumour DNA extracted from whole blood.
  • Serum concentrations of HER2 extracellular domain, AREG, epidermal growth factor (EGF), and transforming growth factor-alpha (TGFα) were detected by enzyme-linked immunosorbent assay.
  • Median values were used as cut-offs for high vs. low levels of biomarkers, except for PTEN, PIK3CA mutation, and c-myc amplification where cut-offs were applied following a biological rationale.
  • Exploratory subgroup analyses (no adjustment for multiple testing) were performed of PFS by level of each biomarker.
  • Two types of correlations between biomarkers and PFS were investigated:
    • Predictive effects:
      • Qualitative association of each biomarker (high vs. low levels) with treatment benefit.
    • Prognostic effects independent of treatment arm:
      • Relationship of each biomarker to clinical outcome of PFS.

Key findings

  • Analyses exploring the predictive value of biomarkers showed that all patients benefited from treatment with pertuzumab compared with placebo regardless of the expression levels of any assessed candidate biomarker, as hazard ratio point estimates were <1.0 for all biomarker subgroups assessed.
  • Samples with high levels of HER2 protein (p = 0.0502), HER2 mRNA (p = 0.0080), HER3 mRNA (p = 0.0348), or wild type (WT) PIK3CA (p = 0.0001) were significantly correlated with a better prognosis for these patients. (Figure 1)
  • Samples from patients who had a better prognosis also had significantly lower levels of serum HER2 (p = 0.0433). (Figure 1)
  • Irrespective of prognostic impact, the benefit of pertuzumab on PFS observed in the overall study population was maintained following individual adjustment for each biomarker.
  • PIK3CA mutation was associated with poorer prognosis for PFS but response to pertuzumab was maintained in these patients, demonstrated by the treatment differences in time to median PFS and hazard ratios:
    • PIK3CA WT (pertuzumab vs. control): 21.8 vs. 13.8 months; HR = 0.67;
    • PIK3CA mutated (pertuzumab vs. control): 12.5 vs. 8.6 months; HR = 0.64. (Figure 2 & Table 1)
  • The prognostic impact of PIK3CA mutations cannot be attributed to a specific mutation, nor to mutation(s) in a specific exon, based on the available data set showing 182 (32%) mutations detected overall (exon 7: n = 12; exon 9: n = 39; exon 20: n = 131).
  • Analyses of serum marker levels over time showed no correlation with disease progression.

Key conclusions

  • Analyses of patient samples from the CLEOPATRA study confirm HER2 as the only marker for selecting patients for HER2- targeted therapy despite comprehensive exploration of a broad panel of candidate biomarkers.
  • The PIK3CA mutational status may identify a poor prognostic group within the HER2-positive population that could be appropriate for clinical trials of HER2-targeted molecules in combination with PI3K pathway-targeted agents.

Reference 1. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109–19. 2. Baselga J, Cortés J, Im S-A, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC). SABCS Annual Meeting Abstracts 2012:S5-1.

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Canadian Perspectives

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Jean-Francois Larouche, MD

Dr. Jean-Francois Larouche obtained his medical degree in 2000. Upon graduation, he trained in internal medicine, hematology, and oncology at Laval University, Quebec City. Pursuing his interest in oncology, Dr. Larouche completed a postdoctoral fellowship in 2008 in Lyon, France, on lymphoma management. His interests include lymphomas and clinical research.

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Stephen Couban, MD, FRCPC

Dr. Stephen Couban is a professor of medicine at Dalhousie University and Director of the Blood and Marrow Transplant Program at Capital District Health Authority in Halifax, Nova Scotia. He is Co-Chair of the NCIC CTG Hematology Site Group and is also active with the Canadian Blood and Marrow Transplant Group. Dr. Couban is Vice President of the Canadian Hematology Society and a past-president of the Canadian Blood and Marrow Transplant Group. His research interests have focused on allografting and in particular on exploration of different types of grafts, including GCSF-stimulated allogeneic peripheral blood allografts and GCSF-stimulated bone marrow allografts. He is actively involved in a number of clinical trials for patients with leukemia and lymphoma, as well as those undergoing 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.

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Véronique Leblond, MD

Dr. Véronique Leblond is the Head of the Department of Haematology at Pitié- Salpêtrière Hospital, Paris, France. She has a long-standing research interest in the treatment of chronic lymphocytic leukemia (CLL) and Waldenström’s macroglobulinemia (WM). Dr. Leblond has been the Principal Investigator of several multicentre trials investigating immunological therapies and novel chemotherapies. Currently, she is Chair of the French cooperative groups on CLL and WM, and is a member of the French Society of Haematology and the American Society of Haematology. Dr. Leblond has authored over 250 research articles, books, and book chapters.

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Francesco Lo-Coco, MD

Dr. Francesco Lo-Coco is a full Professor of Hematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases at the Department of Biopathology, University of Rome Tor Vergata, Rome, Italy. His main research activities include genetic characterization, monitoring, and treatment of hematologic tumours, particularly acute myeloid leukemia and acute promyelocytic leukemia (APL). He has served as President of the Italian Society of Experimental Hematology, been a board member of the Italian Foundation for Cancer Research, and a member of the Committee on Health Research at the Italian Ministry of Health. He is presently chairman of the APL subcommittee of the Italian National Cooperative Group GIMEMA, chairman of the Education Committee of the European Hematology Association, and a member of the editorial board for the journals Leukemia and Haematologica.