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  • 1. Targeted therapy:Trastuzumab and beyond Semir Beslija, MD, PhD Institute of oncology Clinical Center of Sarajevo University ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 2. Prevalence and clinical relevance of HER2 overexpression • ~430,000 new cases of breast cancer per year in Europe1 • In 2006, breast cancer represented 13.5% of all cancers diagnosed, and 29% of all female cancers, with 131,900 deaths due to breast cancer1 • HER2 is overexpressed in up to 30% of breast tumours2, and recognised as independent marker for poor prognosis3,4 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.20111. Ferlay et al. Ann Oncol 2007;18:581–92; 2. Slamon et al. Science 1987;235:177–82; Dubrovnik, Croatia2. 3. Goldhirsch et al. Ann Oncol 2005;16:1569–83; 4. Thuerlimann et al. Eur J Cancer 2007;43:46–52
  • 3. The HER receptor tyrosine kinases as targets in breast cancer therapy • Family of four type HER receptor tyrosine kinases • Important in human growth and development • Similar structure, but: – HER2 lacks ligand- binding domain – HER3 lacks functional HER1 (EGFR) HER2 (HER2) HER3 HER4 intracellular tyrosine kinase domain1. Holbro & Hynes. Annu Rev Pharmacol Toxicol 2004;44:195-217; ESO Balkan Masterclass in Clinical Oncology2. Marmor et al. Int J Radiat Oncol Biol Phys 2004;58:903-13; 3. Rowinsky. Annu Rev Med 2004;55:433-57; 11.5.2011- 15.5.20114. Wiseman et al. Cancer 2005;103(9):1770-7; 5. Sundvall et al. J Mammary Gland Biol Neoplasia 2008;13:259-68 Dubrovnik, Croatia
  • 4. Homodimers and Heterodimers A+B B+B• Ligand binding causes HER receptors to associate in pairs in a process called dimerization.• Dimerization and autophosphorylation must occur for downstream signal transmission.• Pairs can be formed between 2 identical receptors (homodimers) or between 2 different family members (heterodimers).• HER2 is the preferred dimerization partner with other HER receptors. ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 5. HER2 receptors signal through two main pathways: MAPK and PI3K Ligands Other HER HER2 MAPK pathway (Ras/Raf/ PI3K/Akt pathway MEK/ERK) Proliferation Cell cycle, ESO Balkan15.5.2011 in Clinical Oncology Survival 11.5.2011- Masterclass Dubrovnik, Croatia1. Citri & Yarden. Nature Rev Molecular Cell Biol 2006;7:505-16; 2. Wiseman et al. Cancer 2005;103(9):1770-7
  • 6. HER2 detection by IHC HER2 status, either gene copy number or the protein expression level , is the best predictive marker available for assessing response to HER2 targeted therapy. ESO Balkan Masterclass in Clinical OncologyHistopathology. 2010 Apr 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 7. HER2 by FISH and CISHHistopathology. 2010 Apr FISH+ and IHC 3+ testing correlated best with improved clinicalJ Clin Oncol. 2009 Mar benefit (response and/or survival) ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 A survival advantage with trastuzumab was seen in Dubrovnik, Croatia patients with FISH+ or IHC 3+ tumors
  • 8. Trastuzumab binds to the extracellular domain of HER2 to induce anti-tumour effect Trastuzumab binds to ErbB2 on tumour cells Immune cells bind to trastuzumab and release substances that promote tumour cell death • Effect of trastuzumab on cell signalling not well understood • Activity has been attributed to antibody-dependent cellular cytotoxicity (ADCC)1–4 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.20111. 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; Dubrovnik, Croatia2. 4. Arnould et al. Br J Cancer 2006;94:259–67
  • 9. Pivotal Concurrent Trial of 1st-Line Chemotherapy Trastuzumab in MBC: Efficacy Trastuzumab + chemotherapy (N=235) Months (TTP, survival) Chemotherapy (N=234)ORR (%) ORR Median Median P<0.001 TTP Survival P<0.001 P=0.046 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Slamon. N Engl J Med. 2001;344:783; Herceptin (trastuzumab) PI. Dubrovnik, Croatia
  • 10. Trastuzumab in MBC: Safety • Most adverse events mild to moderate in severity – Infusion-associated symptoms, including fever and chills, primarily with first dose • Serious adverse events infrequent • Increased incidence of cardiac dysfunction, particularly when administered with anthracycline-based therapy ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011Slamon DJ, et al. N Engl J Med. 2001;344:783-792. Dubrovnik, Croatia
  • 11. Trastuzumab provides proven OS benefit in first-line HER2-positive MBC P H0648g p=0.046 (IHC 3+)1 P+H T p=0.033M770012 T+H T+C+HBCIRG 0073 p=0.65 T+HUS Oncology P + C + H(IHC 3+)4 p=0.5 P+H 0 10 20 30 40 50 Median survival (months)IHC, immunohistochemistry;P, paclitaxel (Taxol); H, trastuzumab (Herceptin); ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 1. Slamon et al. NEJM 2001; 2. Marty et al. JCO 2005;T, docetaxel (Taxotere); C, carboplatin 3. Pegram et al. JCO 2007; 4. Robert et al. JCO 2006 Dubrovnik, Croatia
  • 12. Adjuvant Trastuzumab Trials Disease-free Survival Study FU, yrs Pts HR 1 3,387 0.54HERA 2 3,401 0.64NSABP B-31/ 2 3,351 0.48NCCTG 9831 4 3,968 0.48 1.5 1,964 0.87NCCTG 9831 seq 3 3,222 0.61BCIRG 006 0.42FinHer 3 231PACS 04 4 528 0.86 0 1 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 2 In favor of T In favor of Obs. Dubrovnik, Croatia
  • 13. Adjuvant Trastuzumab Should Be Added for HER2+ Breast Cancer Implications• Reliable HER2 testing for all patients – IHC or FISH• Timing of starting trastuzumab to be further investigated, but concurrent Rx with chemotherapy appears better• Several chemotherapy options• D at i on of t r eat m ur ent : 1 year• Careful cardiac monitoring required• Translational studies• Platform for new HER2 + adjuvant studies ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 14. Pivotal trials of first-line trastuzumab–taxane combinations showed that a proportion of patients do not respond Trial N ORR M77001 (Marty 2005)1 92 61% H0648g (Slamon/Smith 68* 49% 2001)2,3 *ErbB2 IHC 3+ subgroup ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.20111. Marty et al. J Clin Oncol 2005;23:4265–74; Dubrovnik, Croatia2. 2. Slamon et al. N Engl J Med 2001;344:783–92; 3.Smith et al. Anticancer Drugs 2001;12(Suppl 4):S3–10
  • 15. Majority of patients with HER2-positive MBC responding to trastuzumab plus taxane or vinorelbine 1st-line progress within 1 year 0 2 4 6 8 10 12 months 61 7.12,3* Median TTP 7.84 9.95 11.16 11.77 12.48*ErbB2 IHC 3+ subgroup1. 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(Suppl4):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; ESO Balkan Masterclass in Clinical Oncology6. Pegram et al. J Clin Oncol ASCO Annual Meeting Proceedings 2007;25(18S): Abstract #LBA1008; 11.5.2011- 15.5.20117. Marty et al. J Clin Oncol 2005;23:4265–74; 8. Tedesco et al. J Clin Oncol 2004;22(6):1071–7 Dubrovnik, Croatia
  • 16. Studies with trastuzumab in HER2- positive EBC 100 Resistant 80 Sensitive Disease-free survival (%) 60 HERA Trial 40 3-year Events DFS HR 95% CI p value Already 20 218 80.6 0.63 0.53, 0.75 <0.0001 cured 316 74.0 0 0 6 12 18 24 30 36• More than 17,000 patients, including four registration trials, nearly all with central labs for ErbB2 testing. But…• Not a single effort to identify mechanisms of resistance ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaSmith et al. Lancet 2007; 369: 29–36
  • 17. Trastuzumab resistance• Possible mechanisms include:1,2 – Altered binding to ErbB2 receptor1,3,4–6 • Truncated ECD (p95 ErbB2) • Receptor mutations • Binding of other proteins (MUC 4) – Loss of PTEN function leading to constitutive activation of the PI3K / AKT pathway1,7,8 – Switching to alternate growth regulatory pathways e.g. IGFR pathway1,9 ESO Balkan Masterclass in Clinical Oncology 1. Nahta R et al. Breast Cancer Res 2006; 2. Meric-Bernstam F, Hung M-C. Clin Cancer Res 2006; 11.5.2011- 15.5.2011 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; Dubrovnik, Croatia 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
  • 18. Current anti-ErbB2 molecules Ligands • Trastuzumab binds toOther HER HER2 extracellular domain of ErbB2 – mAb -Trastuzumab • Trastuzumab-DM1 is Pertuzumab DM1 trastuzumab linked to a antimicrotubule drug – Investigational mAb • Pertuzumab inhibits ErbB2- HER3 dimerization – Investigational  Lapatinib is directed toward Lapatinib intracellular kinase domain – TKIOnly lapatinib and trastuzumab are approved anti-ErbB2 therapies ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 19. What does this mean for clinical practice in patients with progressive disease on trastuzumab? ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 20. GBG26; Trastuzumab beyond progression Patients with ErbB2-positive locally advanced or metastatic breast cancer who progressed on one line of trastuzumab (N=156) RANDOMIZATION Capecitabine 2500 mg/m2/day Capecitabine 2500 po Days 1–14 mg/m2/day q3wk po Days 1–14 + continuation of q3wk trastuzumab 6 mg/kg q3wk Trial stopped early due to slow accrual and introduction of lapatinib – analysed with 156 out of planned 482 patients ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaVon Minckwitz et al. J Clin Oncol 2009; 27: 1999–2006
  • 21. GBG26; Kaplan-Meier estimates of time to progression 1.0 Progression-free survival (probability) Capecitabine (n=78) 5.6 (4.2–6.3) months Trastuzumab 8.2 (7.3–11.2) months 0.8 + capecitabine (n=78) p<0.0467 Censored 0.6 HR=0.69 (two-sided p=0.0338; one-sided p=0.017) 0.4 0.2 0 0 10 20 30 40 No. at risk Time (months) Capecitabine 74 40 15 8 5 3 2 1 1 Trastuzumab + capecitabine 77 55 29 12 4 3 1 1 1 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaVon Minckwitz et al. J Clin Oncol 2009; 27: 1999–2006
  • 22. Lapatinib — A Dual Receptor Tyrosine Kinase Inhibitor• Potent, oral, reversible dual tyrosine kinase inhibitor• Binds to ATP site of erbB-1 and erbB-2 receptor kinases, blocking kinase activity and downstream signaling ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 23. Lapatinib + capecitabine versus capecitabine EGF1001511,2 Patients with ErbB2-positive locally advanced or metastatic breast cancer who progressed after prior anthracycline, taxane and trastuzumab (N=399) RANDOMIZATION Lapatinib 1250 mg po Capecitabine 2500 qd continuously + mg/m2/day capecitabine 2000 po Days 1–14 mg/m2/day q3wk po Days 1–14 q3wk Trial stopped early due to achievement of primary endpoint (TTP) at planned interim analysis – analysed with 399 patients out of planned 528 patients ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia1. Cameron et al. Breast Cancer Res Treat 2008; 112: 533–43; 2. Geyer et al. N Engl J Med 2006; 355: 2733–43
  • 24. EGF100151 patient population: pre-treatment• >75% patients were third line or later – Patients enrolled had progressed after prior treatment with an anthracycline, a taxane and trastuzumab in metastatic setting1,2• EGF100151 trial halted early due to achievement of study endpoint (superior efficacy in lapatinib + capecitabine arm)1 – 399 of planned 528 patients enrolled between March 2004 and April 2006 – Cross-over allowed in April 20062 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia1. Geyer et al. N Engl J Med 2006; 355: 2733–43; 2. Cameron et al. Breast Cancer Res Treat 2008; 112: 533–43
  • 25. EGF100151: Kaplan-Meier estimates of time to progression 100 Cumulative progression-free (%) 90 Lapatinib + capecitabine (n=198) 80 Capecitabine (n=201) 70 HR: 0.57 (95% CI: 0.43, 0.77) 60 Log-rank p=0.00013 50 40 30 20 18.6 weeks 27.1 weeks 10 (4.3 months) (6.2 months) 0 0 10 20 30 40 50 60 70 80 90 Time (weeks)• These data led to the EMEA registration of lapatinib in June 2008 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaCameron et al. Breast Cancer Res Treat 2008; 112: 533–43
  • 26. EGF100151: safety profile• The safety profile of lapatinib + capecitabine was generally predictable and manageable 70 1 Grade 1 60 13 Grade 2 50 Grade 3 12 Patients (%) 2 2 Grade 4 14 40 20 10 13 15 30 2 2 <1 14 29 25 2 7 20 6 3 3 29 27 7 9 10 1 10 31 20 4 16 13 12 18 13 12 11 9 0 L+C C L+C C L+C C L+C C L+C C L+C C Diarrhoea PPE Nausea Vomiting Fatigue Balkan Masterclass in Clinical Oncology ESO Rash 11.5.2011- 15.5.2011 Dubrovnik, CroatiaCameron et al. Breast Cancer Res Treat 2008; 112: 533–43
  • 27. Brain Metastases as Site of First Progression• Patients with ErbB2+ breast cancer are at increased risk ofdeveloping brain metastases1 EGF100151: Post hoc analysis (April 2006 dataset)2 Lapatinib + Capecitabine Capecitabine (n=198) (n=201)Patients with CNS relapseas site of first 4 (2%) 13 (6%)progression* *P-value (Fisher’s exact, 2-sided) = 0.0451. Lin Clin Cancer Res 2007 ESO Balkan Masterclass in Clinical Oncology2. EGF100151: Cameron et al. Breast Cancer Res Treat 2008 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 28. Rationale for combining lapatinib with trastuzumab• 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 MUC4 ErbB1–ErbB3 ErbB2–ErbB2 PTEN ErbB2–ErbB3 ErbB1–p95 ErbB1–ErbB1 SOS PI3K RAS Akt RAF MAPK MEK Cell proliferation Cell survival Cell mobility and invasiveness ESO Balkan Masterclass in Clinical Oncology Transcription 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 29. EGF104900: study design Lapatinib 1500 mg po od Key inclusion criteria n=148 •ErbB2-positive MBC (FISH+/ IHC3+) •Progression on • Anthracycline Crossover if PD after • Taxane 4 weeks of therapy • Trastuzumab (n=77) •Progression on most recent trastuzumab regimen Lapatinib 1000 mg po od Trastuzumab 4  2 mg/kg IV qw n=148 Primary endpoint: PFS Secondary endpoints: OS, ORR and CBR Oncology ESO Balkan Masterclass in Clinical 11.5.2011- 15.5.2011 Dubrovnik, CroatiaBlackwell et al. J Clin Oncol 2010; DOI:1200/JCO.2008.21.4437
  • 30. Lapatinib in combination with trastuzumab provides an OS benefit in this heavily pre- treated patient population 100 Lapatinib Cumulative % alive without progression Lapatinib + 80% n=145 trastuzumab 80 n=146 113 (78) 105 (72) Median, months 9.5 14 60 70% Hazard ratio (95% CI) 0.74 (0.57, 0.97) 56% Log-rank p value 0.026 40 6-month OS 41% 20 12-month OS 0 0 5 10 15 20 25 30 35Patients at risk Time from randomization (months) L 148 121 88 64 43 25 1 ESO Balkan Masterclass in Clinical Oncology L+T 148 102 65 47 28 13 11.5.2011- 15.5.2011 Dubrovnik, CroatiaBlackwell et al. Cancer Res 2009; 69(Suppl): 9157, abstract 61 and oral presentation
  • 31. Rationale for combined targeted therapy • Dual targeting of oestrogen and growth factor signalling (EGFR/HER2) is one rational approach to overcome endocrine resistance1–4 • Agents that target both EGFR and HER2 may be more efficacious at overcoming endocrine resistance than those that target HER2 alone1,51. Johnston. Breast Cancer Res 2008; 10(Suppl 4): S20; 2. Xia et al. Proc Natl Acad Sci U S A 2006; 103: 7795–800;Clinical Oncology ESO Balkan Masterclass in 3. Chu et al. 11.5.2011- 15.5.2011Cancer Res 2005; 65: 18–25: 4. Leary et al. Clin Cancer Res; 2010; 16(5): 1486–97; Dubrovnik, Croatia5. Prat and Baselga. Nat Clin Pract Oncol 2008; 5: 531–42
  • 32. Phase III, Randomized, Double-Blind Controlled Trial: Study DesignPatient Population• ER+ and/or PgR+ R• Postmenopausal• HER2+ , HER2-ve / Unknown A Letrozole 2.5 mg daily +• Stage IIIb/IIIc/IV N Placebo• No prior treatment for MBC D OStratification M• Disease sites I Letrozole 2.5 mg daily + • Bone only / visceral or soft tissue Z Lapatinib 1500 mg daily• Interval since adjuvant E tamoxifen therapy • < 6 mo / ≥ 6 mo or none N=1286 (including n=219 HER2+) ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 33. Progression free survival: EGF30008 ErbB2+ population 100 (N=219) Letrozole Letrozole + + % Alive without progression 80 placebo lapatinib (N=108) (N=111) Progressed or died 89 (82%) 88 (79%) 60 Median PFS, mo 3.0 8.2 Hazard ratio (95% CI) 0.71 (0.53, 0.96) p value 0.019 40 20 0 3.0 8.2 0 5 10 15 20 25 30 35 40 45 50 Time from randomization (months) Pts at risk: Let + lap 111 69 33 20 12 8 4 1 1 Let + plac 108 43 26 18 12 7 5 2 2 Balkan Masterclass in Clinical Oncology ESO 11.5.2011- 15.5.2011 Dubrovnik, CroatiaJohnston et al. J Clin Oncol 2009; 27(33): 5538–46
  • 34. Response rate: EGF30008 ErbB2+ population (N=219) 60 50 p=0.003 % of patients 40 48% p=0.021 30 28% 29% 20 10 15% 0 CR PR SD ≥ 6 mo ORR CBR Letrozole + placebo Letrozole + lapatinib Response rates were compared using stratified Fisher’s exact test ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaJohnston et al. J Clin Oncol 2009; 27(33): 5538–46
  • 35. EGF30008 safety: most common adverse events ITT population1 ErbB2+ population2 60 patients with Grade 3/4 diarrhoea Grade 4 Grade 4 • 15% discontinued drug Grade 3 Grade 3 70 <1 • 19% dose reduction Grade 2 70 Grade 2 • 36% dose interruption Grade 1 7 Grade 1 60 9 60 • 31% supportive measures 50 50 23 Patients (%) 1 Patients (%) 22 40 40 15 <1 16 30 30 <1 <1 8 1 2 1 <1 2 7 <1 20 6 20 38 4 4 32 2 6 6 7 4 4 28 7 <1 <1 30 6 4 10 22 10 20 6 15 11 14 16 12 12 15 12 15 10 10 8 8 8 0 0 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 Diarrhoea Rash Nausea Arthralgia Fatigue Updated safety data for the overall study population, obtained 8 months beyond trial reporting, are consistent with the findings reported initially3 ESO Balkan Masterclass in Clinical Oncology1. Johnston et al. J Clin Oncol 2009; 27(33): 5538–46; 2. Schwarzberg et al. Oncologist 2010; 15(2): 122–129; 11.5.2011- 15.5.20113. Ro et al. Cancer Res 2009; 69(Suppl): 9157 abstract 5094 Dubrovnik, Croatia
  • 36. EGF30008: summary • In postmenopausal women with HR+, ErbB2+ MBC lapatinib plus letrozole showed – Significant reduction in risk of disease progression (29%) – Improvement in median PFS from 3.0 to 8.2 months – Significant improvement in CBR • The safety profile of lapatinib and letrozole was predictable and manageable ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaJohnston et al. J Clin Oncol 2009; 27(33): 5538–46
  • 37. HER2:HER3 dimers may provide an escape mechanism from trastuzumab Homodimers Heterodimers HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER3:HER3 HER2:HER3 HER2:HER2 HER2:HER4HER1:HER1 HER3:HER4 + + + + + + + + + + + + + + Inhibition of HER2:HER dimerization may provide a more comprehensive blockade of + HER2-driven signaling Signaling activity Tzahar et al. Mol Cell Biol 1996; ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Sergina et al. Nature 2007 Tzahar, et al. Mol Cell Biol 1996 Dubrovnik, Croatia
  • 38. Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity HER2 receptor Pertuzumab Trastuzumab Dimerization domain of HER2 Subdomain IV of HER2 ● Preferentially inhibits ligand-independent ● Inhibits formation of HER2 dimer pairs HER2 signaling ● Suppresses multiple HER signalling ● Prevents shedding of HER2 ECD pathways, leading to a more comprehensive ● Flags cells for destruction by the blockade of HER2-driven signalling immune system ● Flags cells for destruction by the immune system ESO Balkan Masterclass in Clinical OncologyJunttila et al. Cancer Cell 2009 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 39. BO17929: a Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy HER2-positive MBC Pertuzumab + Cohorts Progressed on trastuzumab + 1 and 21 trastuzumab chemotherapy (Cohorts 1 and 2, n=66) (n=66) HER2-positive MBC Pertuzumab + Pertuzumab Cohort 32 Progressed on trastuzumab + trastuzumab (n=29) chemotherapy (n=29) (n=15) Primary objectives ● Safety and efficacy Population ● ≤3 prior lines cytotoxic therapy (including adjuvant treatment) ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.20111. Baselga et al. JCO 2010; 2. Baselga et al. SABCS 2009 Dubrovnik, Croatia
  • 40. Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone Cohorts 1 and 21,2 Cohort 33 Cohort 33 (P + H) (P) (P P + H) (n=66) (n=27*) (n=11†)CR, % 7.6 0.0 0.0PR, % 16.7 3.4 21.4ORR, % 24.2 3.4 21.4SD 6 months, % 25.8 6.9 21.4CBR, %(CR + PR + SD 6 months) 50.0‡ 10.3 37.5PD, % 50.0 82.8 57.1*n=27, as at data cut-off 2/29 patients had not reached overall best response endpoint (8 cycles of assessmentduring 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); ‡at data cut-off, 21 (31.8%) patients had not experienced PD 1. Gelmon et al. ASCO 2008; 2. Baselga et al. JCO 2010; ESO Balkan Masterclass in Clinical Oncology 3. Baselga et al. SABCS 2009 11.5.2011- 15.5.2011CR, complete response; PR, partial response; SD, stable disease Dubrovnik, Croatia
  • 41. T-DM1: the first-in-class HER2-targeted antibody-drug conjugate Target expression: HER2 Monoclonal antibody: trastuzumab Cytotoxic agent: DM1 Highly potent chemotherapy (maytansine derivative) T-DM1 Linker Systemically stable Breaks down in target cancer cell ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 42. T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells • Trastuzumab-like activity by binding to HER2 to the HER2 protein T-DM1 binds on cancer cells • Targeted intracellular delivery of a potent antimicrotubule agent, DM1Receptor-T-DM1 complex is Potent antimicrotubuleinternalized into HER2-positive agent is released once insidecancer cell the HER2-positive tumor cell ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 43. Single-agent T-DM1 shows promising efficacy in pretreated HER2-positive MBC patients Phase I • Dose escalation, q1w and q3w TDM3569g1, 2 • DLT: grade 4 thrombocytopenia (n=52) • T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended 1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; ESO Balkan Masterclass in Clinical OncologyDLT, dose-limiting toxicity 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 11.5.2011- 15.5.2011q3w, every 3 weeks Dubrovnik, Croatia
  • 44. Single-agent T-DM1 shows promising efficacy in pretreated HER2-positive MBC patients Phase I • Dose escalation, q1w and q3w TDM3569g1, 2 • DLT: grade 4 thrombocytopenia (n=52) • T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended • Proof-of-concept study of T-DM1 (3.6 mg/kg i.v. q3w) in trastuzumab Phase II pretreated (60% lapatinib) and ≥1 line of chemotherapy for MBC TDM4258g2–5 • ORR: 34% (centrally confirmed HER2-positive patients)5 (n=112) • No new safety signals identified 1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; ESO Balkan Masterclass in Clinical OncologyDLT, dose-limiting toxicity 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 11.5.2011- 15.5.2011q3w, every 3 weeks Dubrovnik, Croatia
  • 45. Single-agent T-DM1 shows promising efficacy in pretreated HER2-positive MBC patients Phase I • Dose escalation, q1w and q3w TDM3569g1, 2 • DLT: grade 4 thrombocytopenia (n=52) • T-DM1 3.6 mg/kg, 30-min infusion, q3w recommended • Proof-of-concept study of T-DM1 (3.6 mg/kg i.v. q3w) in trastuzumab Phase II pretreated (60% lapatinib) and ≥1 line of chemotherapy for MBC TDM4258g2–5 • ORR: 34% (centrally confirmed HER2-positive patients)5 (n=112) • No new safety signals identified • Pivotal study of T-DM1 (3.6 mg/kg i.v. q3w) in patients pretreated with Phase II anthracyclines, taxanes, capecitabine, trastuzumab and lapatinib TDM4374g2–5 (n=112) • ORR: 41% (centrally confirmed HER2-positive patients)5 • No new safety signals identified 1. Krop et al. JCO 2010; 2. Burris et al. ECCO ESMO 2009; ESO Balkan Masterclass in Clinical OncologyDLT, dose-limiting toxicity 3. Vogel et al. JCO 2009; 4. Krop et al. JCO 2009; 5. LoRusso et al. ASCO 2010 11.5.2011- 15.5.2011q3w, every 3 weeks Dubrovnik, Croatia
  • 46. TDM4450g: Study Design T-DM1 3.6 mg/kg Q3W until PD 1:1 HER2-positive Trastuzumab MBC (n=137) 8 mg/kg dose; 6 mg/kg Q3W PD Crossover + Docetaxel T-DM1 75 or 100 mg/m2 Q3W • Randomized, phase II, international, open-label study • Stratification: region, prior adjuvant trastuzumab, disease-free interval • Primary endpoints: PFS by INV, safety • Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaPerez EA, et al. Abstr LBA3. ESMO 2010
  • 47. TDM4450g: Overall Response (ITT) Trastuzumab + T-DM1 Docetaxel (n=67) (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) ‡ Stabledisease includes 11 patients with unconfirmed partial response (5 in T-DM1 arm and 6 in the trastuzumab + docetaxel arm) ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaPerez EA, et al. Abstr LBA3. ESMO 2010
  • 48. TDM4450g: Adverse Event Summary Trastuzumab + T-DM1 Docetaxel (n=67) (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 32 (47.8) 27 (39.7) Fatigue 31 (46.3) 29 (46.2) Pyrexia 24 (35.8) 14 (20.6) Three most common AEs (any grade) in trastuzumab + docetaxel arm 1 (1.5) 45 (66.2) Alopecia 5 (7.5) 39 (57.4) Neutropenia 7 (10.4) 31 (45.6) Diarrhea * 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 ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, CroatiaPerez EA, et al. Abstr LBA3. ESMO 2010
  • 49. The PI3K/AKT/mTOR Pathway Growth factors including IGF-1, VEGF, ErbB • mTOR (mammalian target of rapamycin) signaling plays a key PI3K Oxygen, ener gy, and PTEN role in – Cell growth Estrogen nutrients AKT receptor TSC2 TSC1 – Cell proliferation Ras/Raf – Regulation of pathway kinases mTOR • Apoptosis • Angiogenesis • Lymphocytes S6K1 4E-BP1 Protein production elF-4E S6 • Homeostasis Angiogenesis Cell growth and proliferation Nutrient uptake and metabolism • Metabolism ESO Balkan Masterclass in Clinical Oncology1. 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; 11.5.2011- 15.5.20113. 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; Dubrovnik, Croatia5. Wullschleger S, et al. Cell. 2006;124(3):471-484; 6. Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.
  • 50. Everolimus Overcomes Trastuzumab Resistance Mechanisms Nutrients IGF-1R EGFR/HER2 Increased signaling through IGF-1R PI3K Truncated HER-2 PTEN LKB1 Constitutive PI3K/AKT activation AKT Absent or low PTEN AMPK TSC1 TSC2 Elevated AKT or pAKT RHEB Downstream inhibition with mTOR Everolimus everolimus counters Cell growth and proliferation resistance mechanisms Receptor Constitutive activation of Angiogenesis Cell metabolism signaling downstream pathways ESO Balkan Masterclass in Clinical Oncology1. 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. 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 51. Everolimus + Trastuzumab: Phase Ib/II Data Study/Patient population Treatments N Outcome NCT00426556 Everolimus, trastuzumab, 55 Clinical benefit paclitaxel (≥ SD for ≥ 24 wk) in •HER-2+ mBC 40% of patients1 •Refractory to trastuzumab AND taxanes •Previous chemotherapy for mBC ≤ 6 lines NCT00317720 Everolimus, trastuzumab 47 Clinical benefit (without chemotherapy) (≥ SD for ≥ 24 wk) in •HER-2+ mBC 34% of patients2 •Disease progression on/after trastuzumab •Prior lapatinib OK ESO Balkan Masterclass in Clinical OncologyAbbreviations: mBC, metastatic breast cancer; SD, stable disease. 11.5.2011- 15.5.2011 Dubrovnik, Croatia1. Dalenc F, et al. J Clin Oncol. 2010.; 2. Morrow PH, et al. Presented at: ASCO 2010. Abstract 1014.
  • 52. Everolimus + Trastuzumab: Safety Data Jerusalem et al3 Jerusalem et al3 Dalenc et al1 Morrow et al2 (N = 31; Chemo (N = 31; Maintenance Grade 3/4 AE (N = 55) (N = 47) phase) phase) >5% of pts 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 4 (7) 2 (7) 2 (7) (Na/K/triglycerides) 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 & 4 (7) 3 (10) — alopecia Others 6 (11) 4 (14) 2 (7) ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.20111. Dalenc F, et al. Presented at: ASCO 2010. Abstract 1013; 2. Morrow PH, et al. Presented at: ASCO 2010. Abstract 1014; Dubrovnik, Croatia2. 3. Jerusalem G, et al. Presented at: ASCO 2010. Abstract 1041.
  • 53. Conclusions•There is efficacy data of trastuzumab in combination withpaclitaxel, docetaxel, and vinorelbine in the first-line metastaticsetting, suggesting that trastuzumab is a therapeutic equalizerthat renders the choice of partnering chemotherapy secondary,allowing for the selection of a treatment regimen that will bebest tolerated.•Five adjuvant trials with trastuzumab in HER2 over-expressingEBC have shown its strengths and weaknesses Major DFS andOS gain were obtained when: Trastuzumab was given concomitantly with taxanes Anthracyclines were included in the schema•The risk of myocardial damage formally contraindicateconcurrent administration of anthracyclines and trastuzumab1•Little knowledge in the mechanism of HER2 resistance in EBCorv MBC ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 54. Conclusions• Lapatinib trials are on the go to provide – Comprehensive understanding of the HER2 machinery – Explore the potential synergism with anthracyclines – Confirm the effectiveness of the dual blockage of HER2 by the trastuzumab and lapatinib combination• 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.• 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. ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 55. Conclusions•Discordances in HER2 assessment can influence clinicaldecision making with anti-HER2 therapies.•Reassessment of tumor phenotype at relapse isrec-ommended, particularly after a substantial intervalperiod has passed since the last pathologic assessment.•Pertuzumab, TDM-1 and everolimus new excitingmolecules•Total HER2 blockade by combining molecules without CT ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia
  • 56. Targeted treatments of HER2positive breast cancers: 2010 news• In combination • In combination with Trastuzumab with Trastuzumab Lapatinib Pertuzumab RAD001 TDM-1• In combination • Active as with monotherapy Trastuzumab • Maybe better In combination with Pertuzumab ESO Balkan Masterclass in Clinical Oncology 11.5.2011- 15.5.2011 Dubrovnik, Croatia