Targeted therapy: Trastuzumab and beyond Semir Beslija, MD, PhD Institute of oncology Clinical Center of Sarajevo University
Prevalence and clinical relevance of HER2 overexpression <ul><li>~430,000 new cases of breast cancer per year in Europe 1 ...
The HER receptor tyrosine kinases as  targets in breast cancer therapy <ul><li>Family of four type  HER  receptor tyrosine...
Homodimers and Heterodimers <ul><li>Ligand binding causes HER receptors to associate in pairs in a process called dimeriza...
HER2 receptors signal through two main pathways: MAPK and PI3K Ligands HER2 Other HER Proliferation Cell cycle, Survival P...
Histopathology. 2010 Apr HER2 status, either gene copy number or the protein expression level , is the best predictive mar...
J Clin Oncol. 2009 Mar Histopathology. 2010 Apr <ul><li>FISH+ and IHC 3+ testing correlated best with improved clinical be...
Trastuzumab binds to the extracellular domain of HER2 to induce anti-tumour effect <ul><li>Effect of trastuzumab on cell s...
Pivotal Concurrent Trial of 1st-Line Chemotherapy    Trastuzumab in MBC: Efficacy  ORR P <0.001 Median TTP P <0.001 Media...
Trastuzumab in MBC: Safety <ul><li>Most adverse events mild to moderate in severity </li></ul><ul><ul><li>Infusion-associa...
Trastuzumab provides proven OS benefit in first-line HER2-positive MBC Median survival (months) IHC, immunohistochemistry;...
Adjuvant Trastuzumab Trials Disease-free Survival Study FU,  yrs Pts HERA 1 3,387 2 3,401 NSABP B-31/ NCCTG 9831 2 3,351 4...
Adjuvant Trastuzumab Should Be Added for HER2+ Breast Cancer Implications <ul><li>Reliable HER2 testing for all patients <...
Pivotal trials of first-line trastuzumab–taxane combinations showed that a proportion of patients do not respond <ul><li>M...
Majority of patients with HER2-positive MBC responding to trastuzumab plus taxane or vinorelbine 1 st -line progress withi...
Studies with trastuzumab in HER2-positive EBC <ul><li>More than 17,000 patients, including four registration trials, nearl...
Trastuzumab resistance <ul><li>Possible mechanisms include: 1,2 </li></ul><ul><ul><li>Altered binding to ErbB2 receptor 1,...
Current anti-ErbB2 molecules <ul><li>Trastuzumab binds to extracellular domain of ErbB2  –  mAb </li></ul><ul><li>Trastuzu...
What does this mean for clinical practice in patients with progressive disease on trastuzumab?
GBG26; Trastuzumab beyond progression Capecitabine 2500 mg/m 2 /day  po  Days 1–14  q3wk + continuation of trastuzumab 6 m...
GBG26; Kaplan-Meier estimates of  time to progression 0.8 1.0 0.6 0.4 0.2 0 Progression-free survival (probability) 0 10 2...
L apatinib   —   A Dual Receptor Tyrosine Kinase Inhibitor <ul><li>Potent, oral, reversible dual tyrosine kinase inhibitor...
Lapatinib + capecitabine versus capecitabine Patients with ErbB2-positive locally advanced or metastatic breast cancer who...
EGF100151 patient population: pre-treatment <ul><li>>75% patients were third line or later </li></ul><ul><ul><li>Patients ...
EGF100151: Kaplan-Meier estimates of  time to progression <ul><li>These data led to the EMEA registration of lapatinib in ...
EGF100151: safety profile <ul><li>The safety profile of lapatinib + capecitabine was generally predictable and manageable ...
Brain Metastases as  Site of First Progression  *P -value (Fisher’s exact, 2-sided)   = 0.045 <ul><li>Lin Clin Cancer Res ...
Rationale for combining lapatinib with trastuzumab <ul><li>Combining lapatinib with trastuzumab may provide total blockade...
EGF104900: study design Crossover if PD after 4 weeks of therapy (n=77) Primary endpoint: PFS Secondary endpoints: OS, ORR...
Lapatinib in combination with trastuzumab provides an  OS  benefit in this heavily pre-treated patient population 6-month ...
Rationale for combined targeted therapy <ul><li>Dual targeting of oestrogen and growth factor signalling (EGFR/HER2) is on...
Phase III, Randomized, Double-Blind Controlled Trial: Study Design Letrozole 2.5 mg daily + Lapatinib 1500 mg daily  <ul><...
Progression free survival :  EGF30008 ErbB2+ population (N=219) Let + lap Let + plac 33 26 69 43 20 18 12 12 111 108 1 2 4...
Response rate :  EGF30008 ErbB2+ population (N=219) p=0.003 p=0.021 % of patients Response rates were compared using strat...
EGF30008 safety: most common adverse events <ul><li>60 patients with Grade 3/4 diarrhoea </li></ul><ul><li>15% discontinue...
EGF30008: summary <ul><li>In postmenopausal women with HR+, ErbB2+ MBC lapatinib plus letrozole showed </li></ul><ul><ul><...
HER2:HER3 dimers may provide an escape mechanism from trastuzumab + + + + + + + + + + + Signaling activity + + + + Homodim...
Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity <ul><li>Preferentially inhibits...
BO17929: a Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based t...
Pertuzumab / trastuzumab combination therapy  more active than treatment with either agent alone Cohorts 1 and 2 1,2  (P +...
T-DM1: the first-in-class HER2-targeted  antibody-drug conjugate  Monoclonal antibody: trastuzumab <ul><ul><li>Target expr...
T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells Receptor-T-DM1 complex is internalized into...
Single-agent T-DM1 shows promising efficacy in  pretreated HER2-positive MBC patients DLT, dose-limiting toxicity  q3w, ev...
Single-agent T-DM1 shows promising efficacy in  pretreated HER2-positive MBC patients DLT, dose-limiting toxicity  q3w, ev...
Single-agent T-DM1 shows promising efficacy in  pretreated HER2-positive MBC patients DLT, dose-limiting toxicity  q3w, ev...
TDM4450g: Study Design <ul><li>Randomized, phase II, international, open-label study </li></ul><ul><li>Stratification:  re...
TDM4450g: Overall Response (ITT) ‡  Stable disease includes 11 patients with unconfirmed partial response (5 in T-DM1 arm ...
TDM4450g: Adverse Event Summary   *  AEs that result in death, are life-threatening, require inpatient hospitalization or ...
The PI3K/AKT/mTOR Pathway <ul><li>mTOR (mammalian target of rapamycin) signaling plays a key role in </li></ul><ul><ul><li...
Everolimus Overcomes Trastuzumab  Resistance Mechanisms 1.  Widakowich C, et al .   Anticancer Agents Med Chem.  2008,8(5)...
Everolimus + Trastuzumab:  Phase Ib/II Data Abbreviations: mBC, metastatic breast cancer; SD, stable disease. 1. Dalenc F,...
Everolimus + Trastuzumab:  Safety Data <ul><li>Dalenc F, et al. Presented at: ASCO 2010. Abstract 1013; 2. Morrow PH, et a...
<ul><li>There is efficacy data of trastuzumab in combination with paclitaxel, docetaxel, and vinorelbine in the first-line...
Conclusions   <ul><li>Lapatinib trials are on the go to provide  </li></ul><ul><ul><li>Comprehensive understanding of the ...
<ul><li>Discordances in HER2 assessment can influence clinical decision making with anti-HER2 therapies.  </li></ul><ul><l...
Targeted treatments of HER2 positive breast cancers: 2010 news <ul><ul><li>Active as monotherapy </li></ul></ul><ul><ul><l...
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BALKAN MCO 2011 - S. Beslija - Targeted therapy: trastuzumab and beyond

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  • Prevalence and clinical relevance of ErbB2 overexpression The burden of breast cancer is considerable in Europe, 1 and indeed worldwide, being associated with significant mortality. Within breast cancer, ErbB2-positive disease is particularly burdensome. ErbB2 is overexpressed in up to 30% of breast tumours, 2 where it is an independent marker of poor prognosis, 3,4 predicting significantly reduced survival. 2   1. Ferlay et al. Ann Oncol 2007; 18 :581–92 2. Slamon et al. Science 1987; 235 :177–82 3. Goldhirsch et al. Ann Oncol 2005 ;16 :1569–83 4. Thuerlimann et al. Eur J Cancer 2007; 43 :46–52
  • Focus on ErbB receptor tyrosine kinases as a target in breast cancer therapy The human ErbB receptors belong to the type I receptor tyrosine kinase family. The ErbB family is comprised of four evolutionarily related receptor tyrosine kinases; ErbB1 (also known as the epidermal growth factor receptor [EGFR] or HER1), ErbB2 (also known as HER2/neu), ErbB3 (HER3) and ErbB4 (HER4). The four members of this family share a similar conserved structure – an extracellular domain (ECD), a single transmembrane-spanning domain, and an intracellular tyrosine kinase domain 1,2 . ErbB receptor activation induced by ligand binding regulates multiple intracellular signal transduction pathways that are involved in the growth and development of cells 3 . These receptors are overexpressed in certain malignancies. ErbB1 (EGFR), ErbB2 and ErbB3 all predict poor prognosis in breast cancer (ErbB4 has not been shown to be a risk factor in breast cancer) 4,5 , although ErbB1 has not been shown to be a major therapeutic target to date (however, it may be a valid target in other tumours, such as bladder, and head and neck). Holbro &amp; Hynes. Annu Rev Pharmacol Toxicol 2004; 44 :195-217. Marmor et al. Int J Radiat Oncol Biol Phys 2004; 58 :903-13. Rowinsky. Annu Rev Med 2004; 55 :433-57. Wiseman et al. Cancer 2005; 103 (9):1770–7 Sundvall et al. J Mammary Gland Biol Neoplasia 2008; 13 :259–68
  • Interaction with a ligand induces the ErbB receptor to dimerize, or pair up, which is critical to the initiation of an intracellular signal. Dimerized receptors are then activated through either autophosphorylation or intermolecular transphosphorylation of key tyrosine residues within the cytoplasmic domains. 1 These phosphotyrosine residues then serve as binding sites for other downstream signaling molecules, which in turn are linked to additional kinases. This multiprotein complex thereby initiates a signaling cascade that transmits a message to the nucleus, where it can influence diverse processes such as cell proliferation, survival, and/or migration. 1,2 Pairs of identical receptors are called homodimers, while pairs composed of different receptors are called heterodimers. Within the ErbB family, both types of combinations can occur. However, there seems to be a definite hierarchy in the propensity of each possible dimer to form. 3 Interestingly, ErbB2, which doesn’t appear to have its own ligand, is the favored dimerization partner with the other ErbB receptors. 3 Heterodimers containing ErbB2 exhibit certain characteristics such as slower ligand dissociation, relaxed ligand specificity, slower endocytosis, rapid recycling and prolonged firing, resulting in increased dimer stability and producing longer-lasting, more potent downstream signals, potentially leading to greater cell proliferation. 1,4 1. Rowinsky EK. Targeting signal transduction. Horiz Cancer Ther 2001; 2:3-35. 2. Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000; 19:3159-67. 3. Graus-Porta D, Beerli RR, Daly JM, et al. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997; 16:1647-55. 4. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127-37.
  • ErbB2 receptors signal through two main pathways: MAPK and PI3K Activation of the ErbB family occurs on ligand binding followed by dimerisation, which then leads to intracellular signalling; the exception is ErbB2, which is unable to bind ligand, but is held in a so-called ‘pre-primed configuration’ similar to that of an activated ligand-bound receptor 1 . Consequently, ErbB2 can form homodimers (i.e. with another ErbB2 monomer, as happens in ErbB2-overexpressing breast tumours) or heterodimers with ligand-bound ErbB1 or ErbB3 monomers 1 . Indeed, ErbB2 is a preferred partner for other ErbB family monomers. Unlike other ErbB family members, the ErbB3 receptor lacks a functional intracellular tyrosine kinase domain and must dimerise with another ErbB receptor monomer (generally ErbB2) to become activated and stimulate downstream intracellular signalling 2 . The composition of the heterodimer or homodimer determines the signal transduction pathway that is activated, and the cellular process that is affected 2 . Citri and Yarden. Nature Rev Molecular Cell Biol 2006; 7 :505–516 Wiseman et al. Cancer 2005; 103 (9):1770–7
  • Figure 4. Immunohistochemistry analysis. Detection of HER2 protein expression in breast cancer cores by immunohistochemistry (Herceptest) and scoring according to American Society of Clinical Oncologyguidelines. The cells were labelled with a specific antibody against HER2 to detect the intensity of expression of this protein present in the cell membrane. The cells are scored in four different classes of protein expression: (A) 0 when a faint membranous immunoreactivity is observed in &lt;10% of the cells, (B) 1+ when &gt;10% of the cells present in the tumour show a barely perceptible membranous reactivity, (C) 2+ when &gt;10% of the cells show moderate but complete membranous reactivity, and (D) 3+ when &gt;10% of the cells show strong complete membranous reactivity.
  • Fig 3. Patterns of human epidermal growth factor receptor 2 ( HER2) gene copy alterations as detected by fluorescent in situ hybridization. Red dots indicate the HER2 gene probe, and green signals represent the CEP17 reference probe. (A) Classical amplification with clusters of red HER2 signals. (B) Normal HER2/CEP17 copy numbers. (C) Low-level increase of HER2 relative to CEP17. (D) Coamplification of HER2 and CEP17. More than 95% of breast cancers correspond to categories A and B, either clearly HER2 amplified or clearly not amplified. Figure 5. Chromogenic in situ hybridization (CISH) analysis. Detection of HER2 gene amplification in breast cancer cells by CISH. A, Example of breast cancer cells revealing a HER2 ⁄ CEN17 ratio &lt;2. B, Example of breast cancer cells revealing HER2 gene amplification, i.e. HER2 ⁄ CEN17 ratio ‡2.
  • NOTE: animated slide Trastuzumab binds to the extracellular domain of ErbB2 to induce anti-tumour effect Trastuzumab binds to the extracellular domain of ErbB2, [click 1] but its effect on cell signalling is not well understood. [click 2] The major mechanism of action appears to be activation of the body ’s own immune response, resulting in apoptosis of the tumour cell via antibody-dependent cellular cytotoxicity (ADCC) 1 : When trastuzumab binds to the ErbB2 molecules on the surface of tumour cells, lymphocytes called natural killer (NK) cells, which express receptors that recognize the Fc domain of trastuzumab, are recruited 2 Once bound to trastuzumab, the NK cells release substances that perforate the tumour cell membrane and promote cell death 3 This mechanism of action has been demonstrated in a preclinical model, where mice without the Fc gamma receptor expressed on NK cells only showed 29% tumour growth inhibition with trastuzumab versus 96% in control mice expressing the Fc receptor with intact NK cell function 2 . In addition, two studies in breast cancer patients have suggested a role for ADCC in trastuzumab action 3,4 . Nahta &amp; Esteva. Breast Cancer Res 2006; 8 :215 Clynes et al. Nat Med 2000; 6 :443–6 Gennari et al. Clin Cancer Res 2004; 10 :5650–5 Arnould et al. Br J Cancer 2006; 94 :259–67
  • Efficacy data for the combination trial H0648g reveal that 1,2 Significant improvements in ORR, median TTP, and median survival resulted from the addition of trastuzumab to CT (combined analysis of AC and paclitaxel). Median duration of response, trastuzumab + CT: 9.1 months; CT: 6.1 months ( P &lt;0.001) 1. Slamon et al. N Engl J Med . 2001;344:783. 2. Herceptin ® (trastuzumab) PI.
  • References Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783–792. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005; 23:4265–4274. Pegram et al. BCIRG 007: First overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC). JCO 2007; 2 5:18s (June 20 Supplement): LBA1008. Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2006; 24:2786–2792.
  • Pivotal trials of first-line trastuzumab–taxane combinations showed that a proportion of patients do not respond Despite the clinical successes seen with trastuzumab, there are several important limitations associated with trastuzumab treatment of ErbB2-overexpressing breast cancer. Firstly, up to 60% of patients simply do not respond; for example, as shown here for pivotal trials of trastuzumab–taxane regimens. 1–3 Notes for presenter: Marty 2005 study (M77001) 1 : 1 st -line treatment with trastuzumab + docetaxel vs docetaxel alone (N=92) Slamon/Smith study (H0648g) 2,3 : 1 st -line treatment with trastuzumab + paclitaxel vs paclitaxel alone (N=68) [183/188 patients had received prior adjuvant chemotherapy according to the baseline patient characteristics (presumably anthracyclines as all patients in the T+P or P arms had received prior anthracyclines), therefore, only five patients must have received prior anthracycline as 1 st -line MBC – these must have been the only true second-line MBC patients] ORR = overall response rate (complete or partial response) 1. Marty et al. J Clin Oncol 2005; 23 :4265–74 2. Slamon et al. N Engl J Med 2001; 344 :783–92 3. Smith et al. Anticancer Drugs 2001; 12(Suppl 4) :S3–10
  • Majority of patients with ErbB2-positive MBC responding to trastuzumab plus taxane or vinorelbine 1 st -line progress within 1 year Another limitation of current therapy for ErbB2-positive metastatic breast cancer is that, even among those patients who do respond to first-line trastuzumab (in combination with taxanes or vinorelbine), the majority progress within one year. Burstein 2007 (N=40); P or D qwk 1 Slamon/Smith (H0648g; N=68) 2,3 : P [183/188 patients had received prior adjuvant chemotherapy according to the baseline patient characteristics (presumably anthracyclines as all patients in the T+P or P arms had received prior anthracyclines), therefore, only five patients must have received prior anthracycline as 1 st -line MBC – these must have been the only true second-line MBC patients] Burstein 2001 (N=40); vinorelbine 4 Gasparini 2007 (N=60); P qwk 5 Pegram 2007 (N=131); D q3wk 6 Marty 2005 (M77001; N=92); D q3wk 7 Tedesco 2004 (N=26); D qwk 8 Burstein et al. Cancer 2007; 110 (5):965–72 Slamon et al. N Engl J Med 2001; 344 :783–92 Smith et al. Anticancer Drugs 2001; 12 (Suppl 4):S3–10 Burstein et al. J Clin Oncol 2001; 19 :2722–30 Gasparini et al. Breast Cancer Res Treat 2007; 110 (5):965–72 Pegram et al. J Clin Oncol ASCO Annual Meeting Proceedings 2007; 25 (18S): Abstract #LBA1008 Marty et al. J Clin Oncol 2005; 23 :4265–74 Tedesco et al. J Clin Oncol 2004; 22 (6):1071–7
  • Trastuzumab resistance Possible mechanisms involved in the development of resistance to trastuzumab include: 1,2 Mutated or truncated (p95) ErbB2 receptors – trastuzumab neither binds to nor inhibits growth in breast cancer cell lines transfected with p95 ErbB2. 1,3,4 Binding of other proteins (e.g. MUC4) to the ErbB2 receptor to prevent binding of trastuzumab – MUC4 has been shown to bind and hinder ErbB2 from binding to trastuzumab. 1,5,6 Loss of PTEN / reduced PTEN expression in breast cancer cells leading to constitutive activation of the PI3K pathway – PTEN activation is associated with sensitivity to trastuzumab whereas PTEN deficient tumours have a poorer response. 1,7,8 Increased signalling from alternate growth regulatory pathways such as the insulin-like growth factor-1 receptor (IGF-1R), due to increased IGF-1R expression or cross-talk between the ErbB2 and IGF-1R pathways. 1,9   Nahta R, Esteva FJ. HER2 therapy: Molecular mechanisms of trastuzumab resistance. Breast Cancer Res 2006;8:215-23. Meric-Bernstam F, Hung M-C. Advances in targeting human epidermal growth factor receptor-2 signalling for cancer therapy. Clin Cancer Res 2006;12(21):6326-30. Scaltriti M, Rojo F, Ocana A et al. Expression of p95HER2, a truncate form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 2007;899:628-38. Moy B, Goss PE. Lapatinib: Current Status and Future Directions in Breast Cancer. Oncologist 2006;11:1047-57. Price-Schiavi SA, Jepson S, Li P, et al. Rat Muc4 (sialomucin complex) reduces binding of anti-ErB2 antibodies to tumor cell surfaces, a potential mechanism of herceptin resistance. Int J Cancer 2002;99:783-91. Nagy P, Friedlander E, Tanner M, et al. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin resistant, MUC4-expressing breast cancer cell line. Cancer Res 2005;65:473-82. Nagata Y, Lan K-H, Zhou X, et al. PTEN activation contributes to tumour inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117-27. Fujita T, Doilara H, Kawasaki et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 2006;94:247-52. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-1 receptor signalling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001; 93:1852-7.
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  • Tykerb is a potent, oral, reversible dual tyrosine kinase inhibitor that competitively binds to the ATP binding sites of both erbB-1 and erbB-2 receptor tyrosine kinases. It inhibits ATP binding to the kinase, thereby blocking the ability of the enzyme to phosphorylate receptor tyrosine residues. By this mechanism it may inhibit downstream cell signaling pathways, inducing growth arrest and apoptosis. It also may partially reverse tumor resistance to chemotherapy, radiation, and hormonal therapies. Unlike monoclonal antibodies, it has been shown to inhibit the enzymatic activity of truncated erbB-2, and it is not inhibited by the presence of high levels of ligand. (Blackwell et al, 2004; Burris, 2004; Rusnak et al, 2001; Wood et al, 2004; Xia et al, 2002; Xia et al, 2004; Zhou et al, 2004)
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  • The development of brain metastases are an increasing clinical problem in patients with ErbB2-positive MBC, with about a third of women treated with trastuzumab for metastatic disease reported to relapse in the brain, 1,2 often as the first site of progression. 3,4 The prognosis for patients with brain metastases is poor and there are very few treatment options available. 2 In the ‘151 study, a retrospective analysis found that fewer patients receiving lapatinib plus capecitabine relapsed with brain metastases as first site of progression than those on single-agent capecitabine (4 vs. 13 patients, p=0.045). 5 Whilst this was an exploratory analysis carried out post-hoc and the patient numbers are small, the data provide an interesting signal that lapatinib may reduce the risk of disease progression to the brain. Note: p-value not in SmPC – SmPC is a summary of the data and is not comprehensive. One of the conditions of the conditional marketing authorisation is a requirement to conduct a further study to evaluate the effect of lapatinib + capecitabine on reducing the incidence of relapse in the CNS. Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003; 97(12):2972-7. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol 2004; 22: 3608-3617. Yau T, Swanton C, Chua S, et al. Incidence, pattern and timing of brain m etastases among patients with advanced cancer treated with trastuzumab. Acta Oncologica 2006; 45: 196-201. Burstein HJ, Lieberman G, Slamon DJ, et al. Isolated central nervous system metastases in patients with HEr2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy. Ann Oncol 2005; 16: 1772-1777. Cameron D, Casey M, Press M, et al. A phase III randomised comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on tratsuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008; epub ahead of print publication.
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  • Inhibition of HER2:HER2 dimerization may provide a more comprehensive blockade of HER2-driven signaling References Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 1996;16:5276–5287. Sergina NV, Rausch M, Wang D, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 2007; 445:437–441.
  • Reference Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 2009; 15:353–355.
  • References Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010:28;1138–44. Baselga J, Cortés J, Fumoleau P, et al. Pertuzumab and trastuzumab: re-responses to 2 biological agents in patients with HER2-positive breast cancer which had previously progressed during therapy with each agent given separately – a new biological and clinical observation. Poster 5114 presented at SABCS, 9–13 December, 2009.
  • References Gelmon K, Fumoleau P, Verma S, et al. Results of a Phase III trial of trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy. JCO 2008; 26: Abstract 1026. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 2010:28;1138–44. Baselga J, Cortés J, Fumoleau P, et al. Pertuzumab and trastuzumab: re-responses to 2 biological agents in patients with HER2-positive breast cancer which had previously progressed during therapy with each agent given separately – a new biological and clinical observation. Poster 5114 presented at SABCS, 9–13 December, 2009.
  • References : Krop E, Beeram M, Modi S, et al. Phase I study of trastuzumab-Dm1, a HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. JCO 2010; 28 [Epub]. Burris H III, Vukelja S, Krop I, et al. Pharmacokinetics, safety and efficacy of trastuzumab (T)-DM1, a HER2 antibody-drug conjugate (ADC) in patients with HER2+ metastatic breast cancer (MBC): phase I and phase II trial results. Eur J Cancer Suppl. 2009; 7:266 (Abstract PD-0520). Vogel, CL, Burris HA, Limentani S, et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC) in patients (pts) with HER2+ metastatic breast cancer (MBC). J Clin Oncol 2009;27:15s (Suppl; abstr 1017). Krop IE, Burris HA, Rugo H, et al. Quantitative assessment of HER2 status and correlation with efficacy for patients (pts) with metastatic breast cancer (MBC) in a phase II study of trastuzumab-DM1 (T-DM1). J Clin Oncol 27:15s, 2009 (suppl; abstr 1003). LoRusso P, Krop IE, Burris HA, et al. Quantitative assessment of diagnostic markers and correlations with efficacy in two phase II studies of trastuzumab-DM1 (T-DM1) for patients (pts) with metastatic breast cancer (MBC) who had progressed on prior HER2-directed therapy. Poster 1016 presented at ASCO, 4–8 June, 2010.
  • References : Krop E, Beeram M, Modi S, et al. Phase I study of trastuzumab-Dm1, a HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. JCO 2010; 28 [Epub]. Burris H III, Vukelja S, Krop I, et al. Pharmacokinetics, safety and efficacy of trastuzumab (T)-DM1, a HER2 antibody-drug conjugate (ADC) in patients with HER2+ metastatic breast cancer (MBC): phase I and phase II trial results. Eur J Cancer Suppl. 2009; 7:266 (Abstract PD-0520). Vogel, CL, Burris HA, Limentani S, et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC) in patients (pts) with HER2+ metastatic breast cancer (MBC). J Clin Oncol 2009;27:15s (Suppl; abstr 1017). Krop IE, Burris HA, Rugo H, et al. Quantitative assessment of HER2 status and correlation with efficacy for patients (pts) with metastatic breast cancer (MBC) in a phase II study of trastuzumab-DM1 (T-DM1). J Clin Oncol 27:15s, 2009 (suppl; abstr 1003). LoRusso P, Krop IE, Burris HA, et al. Quantitative assessment of diagnostic markers and correlations with efficacy in two phase II studies of trastuzumab-DM1 (T-DM1) for patients (pts) with metastatic breast cancer (MBC) who had progressed on prior HER2-directed therapy. Poster 1016 presented at ASCO, 4–8 June, 2010.
  • References : Krop E, Beeram M, Modi S, et al. Phase I study of trastuzumab-Dm1, a HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. JCO 2010; 28 [Epub]. Burris H III, Vukelja S, Krop I, et al. Pharmacokinetics, safety and efficacy of trastuzumab (T)-DM1, a HER2 antibody-drug conjugate (ADC) in patients with HER2+ metastatic breast cancer (MBC): phase I and phase II trial results. Eur J Cancer Suppl. 2009; 7:266 (Abstract PD-0520). Vogel, CL, Burris HA, Limentani S, et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC) in patients (pts) with HER2+ metastatic breast cancer (MBC). J Clin Oncol 2009;27:15s (Suppl; abstr 1017). Krop IE, Burris HA, Rugo H, et al. Quantitative assessment of HER2 status and correlation with efficacy for patients (pts) with metastatic breast cancer (MBC) in a phase II study of trastuzumab-DM1 (T-DM1). J Clin Oncol 27:15s, 2009 (suppl; abstr 1003). LoRusso P, Krop IE, Burris HA, et al. Quantitative assessment of diagnostic markers and correlations with efficacy in two phase II studies of trastuzumab-DM1 (T-DM1) for patients (pts) with metastatic breast cancer (MBC) who had progressed on prior HER2-directed therapy. Poster 1016 presented at ASCO, 4–8 June, 2010.
  • 06/06/11
  • BALKAN MCO 2011 - S. Beslija - Targeted therapy: trastuzumab and beyond

    1. 1. Targeted therapy: Trastuzumab and beyond Semir Beslija, MD, PhD Institute of oncology Clinical Center of Sarajevo University
    2. 2. Prevalence and clinical relevance of HER2 overexpression <ul><li>~430,000 new cases of breast cancer per year in Europe 1 </li></ul><ul><li>In 2006, breast cancer represented 13.5% of all cancers diagnosed, and 29% of all female cancers, with 131,900 deaths due to breast cancer 1 </li></ul><ul><li>HER2 is overexpressed in up to 30% of breast tumours 2 , and recognised as independent marker for poor prognosis 3,4 </li></ul><ul><li>Ferlay et al. Ann Oncol 2007; 18 :581–92; 2. Slamon et al. Science 1987; 235 :177–82; </li></ul><ul><li>3. Goldhirsch et al. Ann Oncol 2005 ;16 :1569–83 ; 4. Thuerlimann et al. Eur J Cancer 2007; 43 :46–52 </li></ul>
    3. 3. The HER receptor tyrosine kinases as targets in breast cancer therapy <ul><li>Family of four type HER receptor tyrosine kinases </li></ul><ul><li>Important in human growth and development </li></ul><ul><li>Similar structure, but: </li></ul><ul><ul><li>HER2 lacks ligand-binding domain </li></ul></ul><ul><ul><li>HER3 lacks functional intracellular tyrosine kinase domain </li></ul></ul><ul><li>Holbro & Hynes. Annu Rev Pharmacol Toxicol 2004; 44 :195 - 217; </li></ul><ul><li>2. Marmor et al. Int J Radiat Oncol Biol Phys 2004; 58 :903-13; 3. Rowinsky. Annu Rev Med 2004; 55 :433-57; </li></ul><ul><li>4. Wiseman et al. Cancer 2005; 103 (9):1770-7; 5. Sundvall et al. J Mammary Gland Biol Neoplasia 2008; 13 :259-68 </li></ul>HER1 (EGFR) HER2 (HER2) HER3 HER4
    4. 4. Homodimers and Heterodimers <ul><li>Ligand binding causes HER receptors to associate in pairs in a process called dimerization. </li></ul><ul><li>Dimerization and autophosphorylation must occur for downstream signal transmission. </li></ul><ul><li>Pairs can be formed between 2 identical receptors (homodimers) or between 2 different family members (heterodimers). </li></ul><ul><li>HER2 is the preferred dimerization partner with other HER receptors. </li></ul>B + B A + B
    5. 5. HER2 receptors signal through two main pathways: MAPK and PI3K Ligands HER2 Other HER Proliferation Cell cycle, Survival PI3K/Akt pathway MAPK pathway (Ras/Raf/ MEK/ERK) 1. Citri & Yarden. Nature Rev Molecular Cell Biol 2006; 7 :505-16; 2. Wiseman et al. Cancer 2005; 103 (9):1770-7
    6. 6. Histopathology. 2010 Apr HER2 status, either gene copy number or the protein expression level , is the best predictive marker available for assessing response to HER2 targeted therapy.
    7. 7. J Clin Oncol. 2009 Mar Histopathology. 2010 Apr <ul><li>FISH+ and IHC 3+ testing correlated best with improved clinical benefit (response and/or survival) </li></ul><ul><ul><li>A survival advantage with trastuzumab was seen in patients with FISH+ or IHC 3+ tumors </li></ul></ul>
    8. 8. Trastuzumab binds to the extracellular domain of HER2 to induce anti-tumour effect <ul><li>Effect of trastuzumab on cell signalling not well understood </li></ul><ul><li>Activity has been attributed to antibody-dependent cellular cytotoxicity (ADCC) 1 – 4 </li></ul><ul><li>Nahta & Esteva. Breast Cancer Res 2006; 8 :215; 2. Clynes et al. Nat Med 2000; 6 :443 – 6; 3. Gennari et al. Clin Cancer Res 2004; 10 :5650–5; </li></ul><ul><li>4. Arnould et al. Br J Cancer 2006; 94 :259–67 </li></ul>Trastuzumab binds to ErbB2 on tumour cells Immune cells bind to trastuzumab and release substances that promote tumour cell death
    9. 9. Pivotal Concurrent Trial of 1st-Line Chemotherapy  Trastuzumab in MBC: Efficacy ORR P <0.001 Median TTP P <0.001 Median Survival P =0.046 Months (TTP, survival) ORR (%) Trastuzumab + chemotherapy (N=235 ) Chemotherapy (N=234) Slamon. N Engl J Med . 2001;344:783; He rceptin (trastuzumab) PI.
    10. 10. Trastuzumab in MBC: Safety <ul><li>Most adverse events mild to moderate in severity </li></ul><ul><ul><li>Infusion-associated symptoms, including fever and chills, primarily with first dose </li></ul></ul><ul><li>Serious adverse events infrequent </li></ul><ul><li>Increased incidence of cardiac dysfunction, particularly when administered with anthracycline-based therapy </li></ul>Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
    11. 11. Trastuzumab provides proven OS benefit in first-line HER2-positive MBC Median survival (months) IHC, immunohistochemistry; P, paclitaxel (Taxol); H, trastuzumab (Herceptin); T, docetaxel (Taxotere); C, carboplatin H0648g (IHC 3+) 1 M77001 2 BCIRG 007 3 US Oncology (IHC 3+) 4 1. Slamon et al. NEJM 2001; 2. Marty et al. JCO 2005; 3. Pegram et al. JCO 2007; 4. Robert et al. JCO 2006 0 10 20 30 40 50 P + H P + C + H T + H T + C + H T + H T P + H P p=0.046 p=0.033 p=0.65 p=0.5
    12. 12. Adjuvant Trastuzumab Trials Disease-free Survival Study FU, yrs Pts HERA 1 3,387 2 3,401 NSABP B-31/ NCCTG 9831 2 3,351 4 3,968 NCCTG 9831 seq BCIRG 006 1.5 3 1,964 3,222 FinHer 3 231 PACS 04 4 528 0 1 2 In favor of T In favor of Obs. HR 0.54 0.64 0.48 0.48 0.87 0.61 0.42 0.86
    13. 13. Adjuvant Trastuzumab Should Be Added for HER2+ Breast Cancer Implications <ul><li>Reliable HER2 testing for all patients </li></ul><ul><ul><li>IHC or FISH </li></ul></ul><ul><li>Timing of starting trastuzumab to be further investigated, but concurrent Rx with chemotherapy appears better </li></ul><ul><li>Several chemotherapy options </li></ul><ul><li>Duration of treatment : 1 year </li></ul><ul><li>Careful cardiac monitoring required </li></ul><ul><li>Translational studies </li></ul><ul><li>Platform for new HER2 + adjuvant studies </li></ul>
    14. 14. Pivotal trials of first-line trastuzumab–taxane combinations showed that a proportion of patients do not respond <ul><li>Marty et al. J Clin Oncol 2005; 23 :4265–74; </li></ul><ul><li>2. Slamon et al. N Engl J Med 2001; 344 :783–92; 3. Smith et al. Anticancer Drugs 2001; 12 (Suppl 4):S3–10 </li></ul>* ErbB2 IHC 3+ subgroup Trial N ORR M77001 (Marty 2005) 1 92 61% H0648g (Slamon/Smith 2001) 2,3 68* 49%
    15. 15. Majority of patients with HER2-positive MBC responding to trastuzumab plus taxane or vinorelbine 1 st -line progress within 1 year <ul><li>Burstein et al. Cancer 2007; 110 (5):965–72 ; 2. Slamon et al. N Engl J Med 2001; 344 :783–92; 3. Smith et al. Anticancer Drugs 2001; 12 (Suppl </li></ul><ul><li>4):S3–10 ; 4. Burstein et al. J Clin Oncol 2001; 19 :2722–30; 5. Gasparini et al. Breast Cancer Res Treat 2007; 110 (5):965–72; </li></ul><ul><li>6. Pegram et al. J Clin Oncol ASCO Annual Meeting Proceedings 2007; 25 (18S): Abstract #LBA1008; </li></ul><ul><li>7. Marty et al. J Clin Oncol 2005; 23 :4265–74; 8. Tedesco et al. J Clin Oncol 2004; 22 (6):1071–7 </li></ul>0 2 4 6 8 10 12 months * ErbB2 IHC 3+ subgroup 7.1 2,3* 7.8 4 11.7 7 6 1 9.9 5 12.4 8 11.1 6 Median TTP 74%!
    16. 16. Studies with trastuzumab in HER2-positive EBC <ul><li>More than 17,000 patients, including four registration trials, nearly all with central labs for ErbB2 testing. But… </li></ul><ul><li>Not a single effort to identify mechanisms of resistance </li></ul>Smith et al. Lancet 2007; 369 : 29–36 100 80 60 40 20 0 218 316 Events HR 95% CI p value 0.63 0.53, 0.75 <0.0001 3-year DFS 80.6 74.0 0 6 12 18 24 30 36 Resistant Already cured Sensitive HERA Trial 8% 19%
    17. 17. Trastuzumab resistance <ul><li>Possible mechanisms include: 1,2 </li></ul><ul><ul><li>Altered binding to ErbB2 receptor 1,3,4–6 </li></ul></ul><ul><ul><ul><li>Truncated ECD (p95 ErbB2) </li></ul></ul></ul><ul><ul><ul><li>Receptor mutations </li></ul></ul></ul><ul><ul><ul><li>Binding of other proteins (MUC 4) </li></ul></ul></ul><ul><ul><li>Loss of PTEN function leading to constitutive activation of the PI3K / AKT pathway 1,7,8 </li></ul></ul><ul><ul><li>Switching to alternate growth regulatory pathways e.g. IGFR pathway 1,9 </li></ul></ul><ul><li>Nahta R et al. Breast Cancer Res 2006; 2. Meric-Bernstam F, Hung M-C. Clin Cancer Res 2006; </li></ul><ul><li>3. Scaltriti M et al. J Natl Cancer Inst 2007; 4. Moy B, Goss PE. Oncologist 2006; 5. Price-Schiavi SA et al. Int J Cancer 2002; </li></ul><ul><li>6. Nagy P et al. Cancer Res 2005; 7. Nagata Y et al. Cancer Cell 2004; 8. Fujita T et al. Br J Cancer 2006; 9. Lu Y et al. J Natl Cancer Inst 2001 </li></ul>
    18. 18. Current anti-ErbB2 molecules <ul><li>Trastuzumab binds to extracellular domain of ErbB2 – mAb </li></ul><ul><li>Trastuzumab-DM1 is trastuzumab linked to a an timicrotubule drug – Investigational mAb </li></ul><ul><li>Pertuzumab inhibits ErbB2-HER3 dimerization – Investigational </li></ul>-Trastuzumab -Trastuzumab DM1 Other HER HER2 Ligands Only lapatinib and trastuzumab are approved anti-ErbB2 therapies Lapatinib <ul><li>Lapatinib is directed toward intracellular kinase domain – TKI </li></ul>Pertuzumab
    19. 19. What does this mean for clinical practice in patients with progressive disease on trastuzumab?
    20. 20. GBG26; Trastuzumab beyond progression Capecitabine 2500 mg/m 2 /day po Days 1–14 q3wk + continuation of trastuzumab 6 mg/kg q3wk Patients with ErbB2-positive locally advanced or metastatic breast cancer who progressed on one line of trastuzumab (N=156) RANDOMIZATION Capecitabine 2500 mg/m 2 /day po Days 1–14 q3wk Trial stopped early due to slow accrual and introduction of lapatinib – analysed with 156 out of planned 482 patients Von Minckwitz et al. J Clin Oncol 2009; 27 : 1999–2006
    21. 21. GBG26; Kaplan-Meier estimates of time to progression 0.8 1.0 0.6 0.4 0.2 0 Progression-free survival (probability) 0 10 20 30 40 Capecitabine Trastuzumab + capecitabine 74 77 40 55 15 29 15 29 8 12 5 4 3 3 2 1 1 1 1 1 No. at risk Time (months) Von Minckwitz et al. J Clin Oncol 2009; 27 : 1999–2006 Capecitabine (n=78) Trastuzumab + capecitabine (n=78) p<0.0467 Censored HR=0.69 (two-sided p=0.0338; one-sided p=0.017) 5.6 (4.2–6.3) months 8.2 (7.3–11.2) months
    22. 22. L apatinib — A Dual Receptor Tyrosine Kinase Inhibitor <ul><li>Potent, oral, reversible dual tyrosine kinase inhibitor </li></ul><ul><li>Binds to ATP site of erbB-1 and erbB-2 receptor kinases, blocking kinase activity and downstream signaling </li></ul>
    23. 23. Lapatinib + capecitabine versus capecitabine Patients with ErbB2-positive locally advanced or metastatic breast cancer who progressed after prior anthracycline, taxane and trastuzumab (N=399) RANDOMIZATION Capecitabine 2500 mg/m 2 /day po Days 1–14 q3wk Lapatinib 1250 mg po qd continuously + capecitabine 2000 mg/m 2 /day po Days 1–14 q3wk EGF100151 1,2 Trial stopped early due to achievement of primary endpoint (TTP) at planned interim analysis – analysed with 399 patients out of planned 528 patients 1. Cameron et al. Breast Cancer Res Treat 2008; 112 : 533–43; 2. Geyer et al. N Engl J Med 2006; 355 : 2733–43
    24. 24. EGF100151 patient population: pre-treatment <ul><li>>75% patients were third line or later </li></ul><ul><ul><li>Patients enrolled had progressed after prior treatment with an anthracycline, a taxane and trastuzumab in metastatic setting 1,2 </li></ul></ul><ul><li>EGF100151 trial halted early due to achievement of study endpoint (superior efficacy in lapatinib + capecitabine arm) 1 </li></ul><ul><ul><li>399 of planned 528 patients enrolled between March 2004 and April 2006 </li></ul></ul><ul><ul><li>Cross-over allowed in April 2006 2 </li></ul></ul>1. Geyer et al. N Engl J Med 2006; 355 : 2733–43; 2. Cameron et al. Breast Cancer Res Treat 2008; 112 : 533–43
    25. 25. EGF100151: Kaplan-Meier estimates of time to progression <ul><li>These data led to the EMEA registration of lapatinib in June 2008 </li></ul>Cumulative progression-free (%) Time (weeks) Lapatinib + capecitabine (n=198) Capecitabine (n=201) HR: 0.57 (95% CI: 0.43, 0.77) Log-rank p=0.00013 27.1 weeks (6.2 months) 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 Cameron et al. Breast Cancer Res Treat 2008; 112 : 533–43 18.6 weeks (4.3 months)
    26. 26. EGF100151: safety profile <ul><li>The safety profile of lapatinib + capecitabine was generally predictable and manageable </li></ul>Diarrhoea PPE Vomiting Nausea Fatigue Rash Patients (%) 0 10 20 30 40 50 60 70 L+C L+C L+C L+C L+C L+C C C C C C C 1 <1 3 10 11 12 9 3 1 4 9 2 7 20 2 7 13 2 6 2 15 27 2 13 29 14 25 12 12 29 13 13 20 31 10 14 16 18 Cameron et al. Breast Cancer Res Treat 2008; 112 : 533–43 Grade 1 Grade 2 Grade 3 Grade 4
    27. 27. Brain Metastases as Site of First Progression *P -value (Fisher’s exact, 2-sided) = 0.045 <ul><li>Lin Clin Cancer Res 2007 </li></ul><ul><li>Patients with ErbB2+ breast cancer are at increased risk of developing brain metastases 1 </li></ul>EGF100151: Post hoc analysis (April 2006 dataset) 2 EGF100151: Cameron et al . Breast Cancer Res Treat 2008 Lapatinib + Capecitabine (n=198) Capecitabine (n=201) Patients with CNS relapse as site of first progression* 4 (2%) 13 (6%)
    28. 28. Rationale for combining lapatinib with trastuzumab <ul><li>Combining lapatinib with trastuzumab may provide total blockade of HER2 resulting in greater anti-tumour activity versus either agent alone, and potential to overcome trastuzumab resistance </li></ul>ErbB1 – ErbB1 ErbB1–p95 ErbB1 – ErbB3 ErbB2 –ErbB2 ErbB2–ErbB4 ErbB1 –ErbB4 PTEN PTEN Cell proliferation Cell survival Cell mobility and invasiveness PI3K Akt MUC4 PI3K Akt SOS RAS RAF MEK MAPK Transcription ErbB2–ErbB3
    29. 29. EGF104900: study design Crossover if PD after 4 weeks of therapy (n=77) Primary endpoint: PFS Secondary endpoints: OS, ORR and CBR <ul><li>Key inclusion criteria </li></ul><ul><li>ErbB2-positive MBC (FISH+/ IHC3+) </li></ul><ul><li>Progression on </li></ul><ul><ul><ul><li>Anthracycline </li></ul></ul></ul><ul><ul><ul><li>Taxane </li></ul></ul></ul><ul><ul><ul><li>Trastuzumab </li></ul></ul></ul><ul><li>Progression on most recent trastuzumab regimen </li></ul>Blackwell et al. J Clin Oncol 2010; DOI:1200/JCO.2008.21.4437 Lapatinib 1000 mg po od Trastuzumab 4  2 mg/kg IV qw n=148 Lapatinib 1500 mg po od n=148
    30. 30. Lapatinib in combination with trastuzumab provides an OS benefit in this heavily pre-treated patient population 6-month OS 80% 70% 12-month OS 56% 41% Cumulative % alive without progression Patients at risk 148 148 L L+T 121 102 88 65 64 47 43 28 25 13 0 20 40 60 80 100 0 5 10 15 20 25 Time from randomization (months) 30 35 1 Blackwell et al. Cancer Res 2009; 69 (Suppl): 9157, abstract 61 and oral presentation
    31. 31. Rationale for combined targeted therapy <ul><li>Dual targeting of oestrogen and growth factor signalling (EGFR/HER2) is one rational approach to overcome endocrine resistance 1–4 </li></ul><ul><li>Agents that target both EGFR and HER2 may be more efficacious at overcoming endocrine resistance than those that target HER2 alone 1,5 </li></ul>1. Johnston. Breast Cancer Res 2008; 10 (Suppl 4): S20; 2. Xia et al. Proc Natl Acad Sci U S A 2006; 103 : 7795–800; 3. Chu et al. Cancer Res 2005; 65 : 18–25: 4. Leary et al. Clin Cancer Res; 2010; 16 (5): 1486–97; 5. Prat and Baselga. Nat Clin Pract Oncol 2008; 5 : 531–42
    32. 32. Phase III, Randomized, Double-Blind Controlled Trial: Study Design Letrozole 2.5 mg daily + Lapatinib 1500 mg daily <ul><li>Patient Population </li></ul><ul><li>ER+ and/or PgR+ </li></ul><ul><li>Postmenopausal </li></ul><ul><li>HER2+ , HER2-ve / Unknown </li></ul><ul><li>Stage IIIb/IIIc/IV </li></ul><ul><li>No prior treatment for MBC </li></ul><ul><li>Stratification </li></ul><ul><li>Disease sites </li></ul><ul><ul><li>Bone only / visceral or soft tissue </li></ul></ul><ul><li>Interval since adjuvant tamoxifen therapy </li></ul><ul><ul><li>< 6 mo / ≥ 6 mo or none </li></ul></ul>R A N D O M I Z E N=1286 (including n=219 HER2+) Letrozole 2.5 mg daily + Placebo
    33. 33. Progression free survival : EGF30008 ErbB2+ population (N=219) Let + lap Let + plac 33 26 69 43 20 18 12 12 111 108 1 2 4 5 1 2 8 7 Pts at risk: Time from randomization (months) % Alive without progression 3.0 8.2 Johnston et al. J Clin Oncol 2009; 27 (33): 5538–46 0 60 40 20 80 100 Letrozole + placebo (N=108) Letrozole + lapatinib (N=111) Progressed or died 89 (82%) 88 (79%) Median PFS, mo 3.0 8.2 Hazard ratio (95% CI) 0.71 (0.53, 0.96) p value 0.019 0 5 10 15 30 35 20 40 45 50 25
    34. 34. Response rate : EGF30008 ErbB2+ population (N=219) p=0.003 p=0.021 % of patients Response rates were compared using stratified Fisher’s exact test 15% 28% 29% 48% Johnston et al. J Clin Oncol 2009; 27 (33): 5538–46 Letrozole + placebo Letrozole + lapatinib
    35. 35. EGF30008 safety: most common adverse events <ul><li>60 patients with Grade 3/4 diarrhoea </li></ul><ul><li>15% discontinued drug </li></ul><ul><li>19% dose reduction </li></ul><ul><li>36% dose interruption </li></ul><ul><li>31% supportive measures </li></ul>15 32 11 28 14 22 16 12 10 12 4 22 15 6 8 6 6 7 7 9 2 <1 <1 <1 <1 1 1 2 1 <1 0 10 20 30 40 50 60 70 Patients (%) 1. Johnston et al. J Clin Oncol 2009; 27 (33): 5538–46; 2. Schwarzberg et al. Oncologist 2010; 15 (2): 122–129; 3. Ro et al. Cancer Res 2009; 69 (Suppl): 9157 abstract 5094 8 38 30 15 20 12 10 23 16 2 7 6 6 7 <1 <1 4 0 10 20 30 40 50 60 70 Patients (%) 8 <1 8 4 15 4 4 ITT population 1 ErbB2+ population 2 <ul><li>Updated safety data for the overall study population, obtained 8 months beyond trial reporting, are consistent with the findings reported initially 3 </li></ul>L+P L+L L+P L+L L+P L+L L+P L+L L+P L+L L+P L+L L+P L+L L+P L+L L+P L+L L+P L+L Diarrhoea Rash Nausea Arthralgia Fatigue Grade 4 Grade 3 Grade 2 Grade 1 Grade 4 Grade 3 Grade 2 Grade 1 Diarrhoea Rash Nausea Arthralgia Fatigue
    36. 36. EGF30008: summary <ul><li>In postmenopausal women with HR+, ErbB2+ MBC lapatinib plus letrozole showed </li></ul><ul><ul><li>Significant reduction in risk of disease progression (29%) </li></ul></ul><ul><ul><li>Improvement in median PFS from 3.0 to 8.2 months </li></ul></ul><ul><ul><li>Significant improvement in CBR </li></ul></ul><ul><li>The safety profile of lapatinib and letrozole was predictable and manageable </li></ul>Johnston et al. J Clin Oncol 2009; 27 (33): 5538–46
    37. 37. HER2:HER3 dimers may provide an escape mechanism from trastuzumab + + + + + + + + + + + Signaling activity + + + + Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 Tzahar, et al. Mol Cell Biol 1996 Tzahar et al. Mol Cell Biol 1996; Sergina et al. Nature 2007 Inhibition of HER2:HER 3 dimerization may provide a more comprehensive blockade of HER2-driven signaling
    38. 38. Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity <ul><li>Preferentially inhibits ligand-independent HER2 signaling </li></ul><ul><li>Prevents shedding of HER2 ECD </li></ul><ul><li>Flags cells for destruction by the immune system </li></ul><ul><li>Inhibits formation of HER2 dimer pairs </li></ul><ul><li>Suppresses multiple HER signalling pathways, leading to a more comprehensive blockade of HER2-driven signalling </li></ul><ul><li>Flags cells for destruction by the immune system </li></ul>HER2 receptor Trastuzumab Pertuzumab Subdomain IV of HER2 Dimerization domain of HER2 Junttila et al. Cancer Cell 2009
    39. 39. BO17929: a Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy Pertuzumab + trastuzumab (n=66) Cohorts 1 and 2 1 HER2-positive MBC Progressed on trastuzumab + chemotherapy (Cohorts 1 and 2, n=66) <ul><li>Primary objectives </li></ul><ul><li>Safety and efficacy </li></ul><ul><li>Population </li></ul><ul><li>≤ 3 prior lines cytotoxic therapy (including adjuvant treatment) </li></ul>1. Baselga et al. JCO 2010; 2. Baselga et al. SABCS 2009 HER2-positive MBC Progressed on trastuzumab + chemotherapy (n=29) Pertuzumab (n=29) Pertuzumab + trastuzumab (n=15) Cohort 3 2
    40. 40. Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone Cohorts 1 and 2 1,2 (P + H) (n=66) Cohort 3 3 (P) (n=27*) Cohort 3 3 (P  P + H) (n=11 † ) 1. Gelmon et al. ASCO 2008; 2. Baselga et al. JCO 2010; 3. Baselga et al. SABCS 2009 CR, complete response; PR, partial response; SD, stable disease *n=27, as at data cut-off 2/29 patients had not reached overall best response endpoint (8 cycles of assessment during this phase); † n=11, as at data cut-off 4/15 patients had not reached overall best response endpoint (8 cycles of assessment during this phase); ‡ a t data cut-off, 21 (31.8%) patients had not experienced PD CR, % 7.6 0.0 0.0 PR, % 16.7 3.4 21.4 ORR, % 24.2 3.4 21.4 SD  6 months, % 25.8 6.9 21.4 CBR, % (CR + PR + SD  6 months) 50.0 ‡ 10.3 37.5 PD, % 50.0 82.8 57.1
    41. 41. T-DM1: the first-in-class HER2-targeted antibody-drug conjugate Monoclonal antibody: trastuzumab <ul><ul><li>Target expression: HER2 </li></ul></ul>Highly potent chemotherapy (maytansine derivative) <ul><ul><li>Cytotoxic agent: DM1 </li></ul></ul>Systemically stable Breaks down in target cancer cell <ul><ul><li>Linker </li></ul></ul>T-DM1
    42. 42. T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell T-DM1 binds to the HER2 protein on cancer cells <ul><li>Trastuzumab-like activity by binding to HER2 </li></ul><ul><li>Targeted intracellular delivery of a potent antimicrotubule agent, DM1 </li></ul>
    43. 43. Single-agent T-DM1 shows promising efficacy in pretreated HER2-positive MBC patients DLT, dose-limiting toxicity q3w, every 3 weeks 1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 Phase I TDM3569g 1, 2 (n=52) <ul><li>Dose escalation, q1w and q3w </li></ul><ul><li>DLT: grade 4 thrombocytopenia </li></ul><ul><li>T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended </li></ul>
    44. 44. Single-agent T-DM1 shows promising efficacy in pretreated HER2-positive MBC patients DLT, dose-limiting toxicity q3w, every 3 weeks 1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 Phase I TDM3569g 1, 2 (n=52) <ul><li>Dose escalation, q1w and q3w </li></ul><ul><li>DLT: grade 4 thrombocytopenia </li></ul><ul><li>T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended </li></ul>Phase II TDM4258g 2–5 (n=112) <ul><li>Proof-of-concept study of T-DM1 (3.6 mg/kg i.v. q3w) in trastuzumab pretreated (60% lapatinib) and ≥1 line of chemotherapy for MBC </li></ul><ul><li>ORR: 34% (centrally confirmed HER2-positive patients) 5 </li></ul><ul><li>No new safety signals identified </li></ul>
    45. 45. Single-agent T-DM1 shows promising efficacy in pretreated HER2-positive MBC patients DLT, dose-limiting toxicity q3w, every 3 weeks 1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 Phase I TDM3569g 1, 2 (n=52) <ul><li>Dose escalation, q1w and q3w </li></ul><ul><li>DLT: grade 4 thrombocytopenia </li></ul><ul><li>T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended </li></ul>Phase II TDM4258g 2–5 (n=112) <ul><li>Proof-of-concept study of T-DM1 (3.6 mg/kg i.v. q3w) in trastuzumab pretreated (60% lapatinib) and ≥1 line of chemotherapy for MBC </li></ul><ul><li>ORR: 34% (centrally confirmed HER2-positive patients) 5 </li></ul><ul><li>No new safety signals identified </li></ul>Phase II TDM4374g 2–5 (n=112) <ul><li>Pivotal study of T-DM1 (3.6 mg/kg i.v. q3w) in patients pretreated with anthracyclines, taxanes, capecitabine, trastuzumab and lapatinib </li></ul><ul><li>ORR: 41% (centrally confirmed HER2-positive patients) 5 </li></ul><ul><li>No new safety signals identified </li></ul>
    46. 46. TDM4450g: Study Design <ul><li>Randomized, phase II, international, open-label study </li></ul><ul><li>Stratification: region, prior adjuvant trastuzumab, disease-free interval </li></ul><ul><li>Primary endpoints: PFS by INV, safety </li></ul><ul><li>Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control </li></ul>1:1 Perez EA, et al. Abstr LBA3. ESMO 2010 T-DM1 3.6 mg/kg Q3W until PD Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m 2 Q3W HER2-positive MBC (n=137) PD Crossover T-DM1
    47. 47. TDM4450g: Overall Response (ITT) ‡ Stable disease includes 11 patients with unconfirmed partial response (5 in T-DM1 arm and 6 in the trastuzumab + docetaxel arm) Perez EA, et al. Abstr LBA3. ESMO 2010 T-DM1 (n=67) Trastuzumab + Docetaxel (n=70) Patients with an Objective Response,* n (%) 32 (47.8) 29 (41.4) 95% CI (35.4, 60.3) (30.2, 53.8) Patients with Clinical Benefit, † n (%) 37 (55.2) 40 (57.1) 95% CI (43.1, 67.2) (44.8, 68.9) Objective Responses, n (%) Complete Response 3 (4.5) 1 (1.4) Partial Response 29 (43.3) 28 (40.0) Stable Disease ‡ 22 (32.8) 29 (41.4) Progressive Disease 8 (11.9) 4 (5.7) Unable to Evaluate 4 (6.0) 4 (5.7)
    48. 48. TDM4450g: Adverse Event Summary * AEs that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies/birth defects Perez EA, et al. Abstr LBA3. ESMO 2010 T-DM1 (n=67) Trastuzumab + Docetaxel (n=68) Any AE, n (%) 63 (94.0) 68 (100.0) Grade ≥3 AE 25 (37.3) 51 (75.0) Serious AE* 13 (19.4) 15 (22.1) Three most common AEs (any grade) in T-DM1 arm Nausea Fatigue Pyrexia 32 (47.8) 31 (46.3) 24 (35.8) 27 (39.7) 29 (46.2) 14 (20.6) Three most common AEs (any grade) in trastuzumab + docetaxel arm Alopecia Neutropenia Diarrhea 1 (1.5) 5 (7.5) 7 (10.4) 45 (66.2) 39 (57.4) 31 (45.6)
    49. 49. The PI3K/AKT/mTOR Pathway <ul><li>mTOR (mammalian target of rapamycin) signaling plays a key role in </li></ul><ul><ul><li>C ell growth </li></ul></ul><ul><ul><li>C ell proliferation </li></ul></ul><ul><ul><li>Regulation of </li></ul></ul><ul><ul><ul><li>Apoptosis </li></ul></ul></ul><ul><ul><ul><li>Angiogenesis </li></ul></ul></ul><ul><ul><ul><li>Lymphocytes </li></ul></ul></ul><ul><ul><ul><li>Homeostasis </li></ul></ul></ul><ul><ul><ul><li>Metabolism </li></ul></ul></ul>Protein production AKT 4E-BP1 PI3K PTEN S6 S6K1 elF-4E Cell growth and proliferation Angiogenesis mTOR Oxygen, energy, and nutrients TSC2 TSC1 Growth factors including IGF-1, VEGF, ErbB Estrogen receptor Ras/Raf pathway kinases Nutrient uptake and metabolism 1. Bjornsti MA, et al. Nat Rev Cancer . 2004;34(5):335-348; 2. Crespo JL, et al. Microbiol Mol Biol Rev . 2002;66(4):579-591; 3. Huang S, et al. Cancer Biol Ther . 2003;2(3):222-232; 4. Mita MM, et al. Clin Breast Cancer. 2003;4(2):126-137; 5. Wullschleger S, et al. Cell. 2006;124(3):471-484; 6. Johnston SR. Clin Cancer Res . 2005;11(2 Pt 2):889S-899S.
    50. 50. Everolimus Overcomes Trastuzumab Resistance Mechanisms 1. Widakowich C, et al . Anticancer Agents Med Chem. 2008,8(5):488-496; 2. Johnston SR. Clin Cancer Res . 2005;11(2 Pt 2):889S-899S. Receptor signaling Constitutive activation of downstream pathways Increased signaling through IGF-1R Constitutive PI3K/AKT activation Elevated AKT or pAKT Absent or low PTEN Truncated HER-2 Downstream inhibition with everolimus counters resistance mechanisms Angiogenesis AMPK TSC1 TSC2 LKB1 Cell growth and proliferation Cell metabolism IGF-1R EGFR/HER2 Nutrients mTOR AKT PTEN PI3K RHEB Everolimus
    51. 51. Everolimus + Trastuzumab: Phase Ib/II Data Abbreviations: mBC, metastatic breast cancer; SD, stable disease. 1. Dalenc F, et al. J Clin Oncol. 2010.; 2. Morrow PH, et al. Presented at: ASCO 2010. Abstract 1014. Study/Patient population Treatments N Outcome <ul><li>NCT00426556 </li></ul><ul><li>HER-2 + mBC </li></ul><ul><li>Refractory to trastuzumab AND taxanes </li></ul><ul><li>Previous chemotherapy for mBC </li></ul><ul><li>≤ 6 lines </li></ul>Everolimus, trastuzumab, paclitaxel 55 Clinical benefit (≥ SD for ≥ 24 wk) in 40% of patients 1 <ul><li>NCT00317720 </li></ul><ul><li>HER-2 + mBC </li></ul><ul><li>Disease progression on/after trastuzumab </li></ul><ul><li>Prior lapatinib OK </li></ul>Everolimus, trastuzumab (without chemotherapy) 47 Clinical benefit (≥ SD for ≥ 24 wk) in 34% of patients 2
    52. 52. Everolimus + Trastuzumab: Safety Data <ul><li>Dalenc F, et al. Presented at: ASCO 2010. Abstract 1013; 2. Morrow PH, et al. Presented at: ASCO 2010. Abstract 1014; </li></ul><ul><li>3. Jerusalem G, et al. Presented at: ASCO 2010. Abstract 1041. </li></ul>Grade 3/4 AE >5% of pts Dalenc et al 1 (N = 55) Morrow et al 2 (N = 47) Jerusalem et al 3 (N = 31; Chemo phase) Jerusalem et al 3 (N = 31; Maintenance phase) n (%) (%) n (%) n (%) Leukopenia 5 (9) 12 (43) 2 (7) Lymphopenia 8 (14) (13) 5 (18) 2 (7) Neutropenia 15 (28) 21(75) 2 (7) Anemia 3 (5) 3 (10) — Metabolic disorders (Na/K/triglycerides) 4 (7) 2 (7) 2 (7) Hyperglycemia (13) Mucositis (11) Stomatitis 11 (20) 4 (14) 1 (4) Diarrhea 3 (5) 2 (7) — Weight loss — 2 (7) Asthenia/fatigue 4 (7) Skin disorders & alopecia 4 (7) 3 (10) — Others 6 (11) 4 (14) 2 (7)
    53. 53. <ul><li>There is efficacy data of trastuzumab in combination with paclitaxel, docetaxel, and vinorelbine in the first-line metastatic setting, suggesting that trastuzumab is a therapeutic equalizer that renders the choice of partnering chemotherapy secondary, allowing for the selection of a treatment regimen that will be best tolerated. </li></ul><ul><li>Five adjuvant trials with trastuzumab in HER 2 over-expressing EBC have shown its strengths and weaknesses . Major DFS and OS gain were obtained when: </li></ul><ul><ul><ul><li>Trastuzumab was given concomitantly with taxanes </li></ul></ul></ul><ul><ul><ul><li>Anthracyclines were included in the schema </li></ul></ul></ul><ul><li>The risk of myocardial damage formally contraindicate concurrent administration of anthracyclines and trastuzumab 1 </li></ul><ul><li>Little knowledge in the mechanism of HER 2 resistance in EBC orv MBC </li></ul>Conclusions
    54. 54. Conclusions <ul><li>Lapatinib trials are on the go to provide </li></ul><ul><ul><li>Comprehensive understanding of the HER 2 machinery </li></ul></ul><ul><ul><li>Explore the potential synergism with anthracyclines </li></ul></ul><ul><ul><li>Confirm the effectiveness of the dual blockage of HER 2 by the trastuzumab and lapatinib combination </li></ul></ul><ul><li>The most promising systemic therapies for HER2- positive central nervous system (CNS) metastases following cranial irradiation are lapatinib and capecitabine, after progression during treatment with trastuzumab. </li></ul><ul><li>There is an urgent need to increase therapeutic options in this subgroup of patients with novel agents and multimodality treatment through trials with specific CNS end points. </li></ul>
    55. 55. <ul><li>Discordances in HER2 assessment can influence clinical decision making with anti-HER2 therapies. </li></ul><ul><li>Reassessment of tumor phenotype at relapse is </li></ul><ul><li>rec-ommended, particularly after a substantial interval period has passed since the last pathologic assessment. </li></ul><ul><li>Pertuzumab, TDM-1 and everolimus new exciting molecules </li></ul><ul><li>Total HER2 blockade by combining molecules without CT </li></ul>Conclusions
    56. 56. Targeted treatments of HER2 positive breast cancers: 2010 news <ul><ul><li>Active as monotherapy </li></ul></ul><ul><ul><li>Maybe better In combination with Pertuzumab </li></ul></ul><ul><ul><li>In combination with Trastuzumab </li></ul></ul><ul><ul><li>In combination with Trastuzumab </li></ul></ul><ul><ul><li>In combination with Trastuzumab </li></ul></ul>Lapatinib Pertuzumab TDM-1 RAD001

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