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References:
1. Rowinsky EK. The ErbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med. 2004;55:433-457.
2. Gullick WJ. The type 1 growth factor receptors and their ligands considered as a complex system.
Endocr Relat Cancer. 2001;8:75-82.
3. Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159-3167.
4. Hynes NE, Lane HA. ErbB receptors and cancer: the complexity of targeted inhibitors. Nature Rev. 2005;5:341-354.
5. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127-137.
6. Burgess AW, Cho HS, Eigenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12:541-552.
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Ligand-mediated dimerization of the ErbB receptors and subsequent autophosphorylation or transphosphorylation leads to their association with a variety of cytoplasmic phosphotyrosine binding proteins. This results in the initiation of a phosphorylation cascade and activation of several downstream pathways involved in cell growth and survival, including the Ras/Raf/MAPK and PI3K/Akt pathways.1 Stimulation of these pathways transmits a signal to the nucleus resulting in modification of gene transcription patterns that ultimately affects processes such as cell division, apoptosis, adhesion, migration, and/or differentiation.
Although the various dimer combinations activate overlapping downstream pathways, each receptor exhibits a unique phosphorylation pattern. The profile of the adaptor proteins that interact with each family member, and thus the quality and potency of the output signal, is distinct. For example, Erb-B-3 contains 6 binding sites for a PI3K subunit, leading to particularly potent activation of the Akt survival pathway through dimers containing this receptor.2 In addition, the same receptor can also exhibit a different phosphorylation pattern and bind a unique subset of adaptor proteins dependent on ligand and dimerization partner. To illustrate, while EGF-activated ErbB1 homodimers recruit Shc and Grb2 and display rapid internalization, ErbB1 and ErbB4 heterodimers activated by NRG-1 recruit Shc but not Grb2 and internalize more slowly.3 This combinatorial diversity allows for exquisite control and fine tuning of signal transmission and cellular responses through the ErbB family of receptors.
1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127-37.
2. Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites for phosphatidylinositol 3′-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J 1994; 13:2831-41.
3. Olayioye MA, Graus-Porta D, Beerli RR, et al. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol 1998; 18:5042-51.
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There are currently several different agents on the market or being tested in clinical trials that target the ErbB signaling pathway.1 The full or partial humanized monoclonal antibodies targeting ErbB1 (cetuximab) and ErbB2 (trastuzumab) bind to the extracellular domain of the respective receptors. The small molecule inhibitors gefitinib and erlotinib, which target ErbB1, work inside the cell and block receptor kinase activity. However, as single-target agents, all of these agents work primarily against a single family member. As a small molecule, lapatinib exerts its effect by blocking the ATP binding site at the intracellular domain. Theoretically, lapatinib may exhibit potent activity against both ErbB1 and ErbB2 receptors.
1. Normanno N, Bianco C, De Luca A, et al. Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr Relat Cancer 2003; 10:1-21.
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Dans l’AMM, la pososlogie à 2 mg/kg peut être perfusée en 30 mn.
Le schéma 1fs/15 jours n’est pas développé.
 
Dans l’AMM, la pososlogie à 2 mg/kg peut être perfusée en 30 mn.
Le schéma 1fs/15 jours n’est pas développé.
 
Dans l’AMM, la pososlogie à 2 mg/kg peut être perfusée en 30 mn.
Le schéma 1fs/15 jours n’est pas développé.
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      Agents targeting ErbB receptors have also been tested in conjunction with more
traditional chemotherapeutic compounds.1-6 Trastuzumab has been paired
with a variety of agents for the treatment of MBC, and all have demonstrated
activity.1-4 In the BOND trial, the combination of cetuximab/irinotecan in
patients with irinotecan-refractory metastatic CRC induced a higher RR than
cetuximab alone, though both approaches showed activity.5
1. 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; 344:783-92.
2. Seidman AD, Fornier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19:2587-95.
3.Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20:1800-8.
4.Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21:2889-95.
5.Cunningham D, Humblet Y, Siena S. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth-factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Proc. Am. Soc. Clin. Oncol. 2003; 22:252 (Abstract 1012).
6.Fisher GA, Kuo T, Cho CD, et al. A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. Proc Am Soc Oncol 2004:Abstract 3514.
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The study was originally designed with 90% power and Type I error of 0.05 to detect a 50% increase in median TTP in subjects who received lapatinib+capecitabine assuming a median time to progression of 3 and 4.5 months in the capecitabine and lapatinib plus capecitabine arms, respectively. The study was subsequently amended so it was also powered to detect a difference in overall survival (a secondary study endpoint). A maximum of 457 deaths were required for the analysis of overall survival to have an 80% chance of successfully detecting a 30% increase in median survival time in subjects who received lapatinib plus capecitabine, based on median survival times of 8 and 10.4 months in the capecitabine and lapatinib plus capecitabine arms, respectively, i.e. a hazard ratio of 0.769. To achieve the 80% power an estimated total of 528 subjects would have been required.
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TAnDEM trial serves as proof of concept in HER2+
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ALTTO study design: use of lapatinib in adjuvant setting1 
Design 1 of this randomised, multicentre, Phase III study will compare the efficacy of lapatinib alone, versus trastuzumab alone, versus trastuzumab followed by lapatinib, or versus lapatinib plus trastuzumab, as adjuvant treatment. Design 2 is similar except that all patients will also receive concurrent paclitaxel for the first 12 weeks after randomisation. This pioneering collaborative group study is one of the largest adjuvant breast cancers studies to date (planned enrolment of 8000 patients) and the first truly global collaborative study. ALTTO will also provide the most comprehensive translational research to date, aimed towards identifying those patients most likely to respond to lapatinib treatment.
1. ALTTO (EGF106708) study design outline
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AVADO was a randomized, double-blind, placebo-controlled phase III study.
Patients with locally recurrent or metastatic breast cancer were randomized to one of three treatment arms; patients were stratified by: region, presence or absence of measurable disease, hormone receptor status, disease-free interval and prior taxane therapy.
Patients were randomized to receive docetaxel 100mg/m2 every 3 weeks, for a maximum of nine cycles, with either placebo or bevacizumab. Dose reduction of docetaxel to 75mg/m2 and/or 60mg/m2 was permitted in the event of toxicity.
Bevacizumab was given at either 7.5 or 15mg/kg every
3 weeks. Patients continued to receive placebo or bevacizumab until disease progression.
All patients were given the option to receive bevacizumab in combination with their second-line chemotherapy regimen.
The primary endpoint of the trial was progression-free survival. Secondary endpoints were overall response rate, duration of response, time to treatment failure, overall survival, safety and quality of life.
For patients randomized to bevacizumab 7.5mg/kg, the unstratified hazard ratio for progression-free survival was 0.79, p=0.0318. Median progression-free survival was 8.0 months in the placebo arm and 8.7 months in this bevacizumab arm.
The unstratified hazard ratio for progression-free survival in the bevacizumab 15mg/kg trial arm versus placebo was 0.72, p=0.0099. Median progression-free survival was 8.8 months in this bevacizumab arm.
Here, median PFS is not entirely reflective of treatment effect as it is based on only one point on the curve, whereas hazard ratio is representative of the whole study period.
In the analysis for FDA purposes, which is the stratified analysis with data censored for non-protocol therapy before disease progression (patients with NPT before PD: 3% in placebo arm, 4% in 7.5mg/kg bevacizumab arm and 3% in 15mg/kg bevacizumab arm), the hazard ratios for PFS were 0.69 for the lower and 0.61 for the higher bevacizumab dose.
Response was analysed in the subset of the ITT population who had measurable disease at baseline.
Response rates were significantly higher in both bevacizumab arms than the placebo arm, with 44% in the placebo arm, 55% in the bevacizumab 7.5mg/kg arm and 63% in the bevacizumab 15mg/kg arm.
Although there is a numerical difference between the two bevacizumab arms, this is not statistically significant.
These are a selection of the adverse events that were reported with a ≥2% difference in incidence between study arms. Other adverse events that would qualify for this table are not present because they are known toxicities of special interest with bevacizumab and are covered on the next slide.
While most toxicities listed here occurred more frequently in the bevacizumab arms, anemia and infection were more common in the control arm than either bevacizumab arm.
This is also true for grade ≥3 peripheral edema, which does not qualify for inclusion in the table, but was also reported at a higher incidence in the control arm (2.1%) than the bevacizumab arms (1.2% [7.5mg/kg], 0.4% [15mg/kg]).
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