BALKAN MCO 2011 - S. Beslija - Targeted therapy: trastuzumab and beyond
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BALKAN MCO 2011 - S. Beslija - Targeted therapy: trastuzumab and beyond
- 1. Targeted therapy: Trastuzumab and beyond Semir Beslija, MD, PhD Institute of oncology Clinical Center of Sarajevo University
- 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. 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.
- 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.
- 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. 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
- 19. What does this mean for clinical practice in patients with progressive disease on trastuzumab?
- 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. 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
- 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
- 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
- 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. 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
- 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
- 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
- 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. 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)
- 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
Hinweis der Redaktion
- 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 & 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 <10% of the cells, (B) 1+ when >10% of the cells present in the tumour show a barely perceptible membranous reactivity, (C) 2+ when >10% of the cells show moderate but complete membranous reactivity, and (D) 3+ when >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 <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 & 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 <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.
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