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Targeting the HER2 network: what’s new?

Targeting the HER2 network: what’s new?. P Pronzato, Genova. Increased cell proliferation Increased cell migration Resistance to apoptosis. HER2 Overexpression Leads to Increased Signaling. Yarden et al. Nat Rev Mol Cell Biol 2001. HER2 testing.

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Targeting the HER2 network: what’s new?

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  1. Targeting the HER2 network:what’s new? P Pronzato, Genova

  2. Increased cell proliferation Increased cell migration Resistance to apoptosis HER2 Overexpression Leads to Increased Signaling Yarden et al. Nat Rev Mol Cell Biol 2001

  3. HER2 testing

  4. In a randomized trial, benefit confined to HER2/neu amplified/overexpressors (Seidman, CALGB 9840) Subset analysis of CALGB 9840 suggests benefit in FISH-negative patients with Chr 17 2.2 (polysomy) (Kaufman, ASCO 2007) Trastuzumab and HER2 Status in Advanced Breast Cancer: Prior Observations R Livingston, ASCO 2008

  5. Kaplan-Meier Estimates of PFS: HER2-Negative Subjects 1.0 Polysomy 17 ≤ 2.2, L+P (n = 178) Polysomy 17 > 2.2, L+P (n = 23) 0.8 Polysomy 17 ≤ 2.2, P (n = 183) Polysomy 17 > 2.2, P (n = 21) 0.6 Cumulative progression-free survival 0.4 0.2 0 0 20 40 60 80 100 120 Time, weeks

  6. Discordance

  7. Benefit from adjuvant trastuzumab may not be confined to patients with IHC3+ and/or FISH positive tumors Paik et. Al, ASCO 2007, abstr. 511

  8. Benefit from adjuvant trastuzumab may not be confined to patients with IHC3+ and/or FISH positive tumors Paik et. Al, ASCO 2007, abstr. 511

  9. Benefit from adjuvant trastuzumab may not be confined to patients with IHC3+ and/or FISH positive tumors Paik et. Al, ASCO 2007, abstr. 511

  10. Discordance primary/relapse

  11. ECD JC Thery

  12. EGF30001 Study Design N = 579 • Key Inclusion • Incurable stage III/IV • No prior treatment for M+ • HER2-negative or untested RANDOMIZATION Paclitaxel 175 mg/m2 q3wLapatinib 1,500 mg PO QD (N = 291) • Stratification • Disease sites • Stage of disease Paclitaxel 175 mg/m2 q3w Placebo PO QD(N = 288) • Endpoints • Primary: TTP • Secondary: PFS, OS, safety Serum ECD measured by ELISA (Oncogene Science) pretreatment, week 9, and q12 weeks. Di Leo et al. J Clin Oncol. 2008. In press.

  13. Poor Correlation of Baseline ECD With HER2 Status by FISH or IHC R = 0.34 (P< 0.001; n = 461) R = 0.28 overall (P < 0.001;n = 402)* *FISH+: R = 0.34 (P = 0.003; n = 75) FISH–: R = 0.03 (P = 0.596; n = 327) Correlation with IHC3+ 47/64 = 73%

  14. Conversion From ECD-negative to -positive Is Associated With Worse PFS in HER2-negative Patients 1.0 1.0 0.8 0.8 P + Lapatinib P + Placebo 0.6 0.6 Converting Converting PFS PFS Non-converting (remain negative) Non-converting (remain negative) 0.4 0.4 0.2 0.2 0.0 0.0 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Time, weeks Time, weeks HR = Hazard of converting.

  15. Conversion From ECD-positive to -negative Is Associated With Improved PFS 1.0 1.0 0.8 0.8 P + Lapatinib P + Placebo 0.6 0.6 Converting Converting PFS PFS Non-converting (remain positive) Non-converting (remain positive) 0.4 0.4 0.2 0.2 0.0 0.0 0 20 40 60 80 100 120 0 20 40 60 80 100 120 Time, weeks Time, weeks HR = Hazard of converting. 30 patients seroconvertered: 17 PR, 12 SD, 1 PD

  16. Trastuzumab for metastatic breast cancer

  17. Study Design • arm A: trastuzumab (T) + docetaxel (D) (100mg/m2, q3wks), • with continuation of T after D until PD • R • arm B: trastuzumab docetaxel (100mg/m2, q3wks) • at PD • loading dose trastuzumab 4 mg/kg, thereafter weekly 2 mg/kg • docetaxel: at least 6 cycles • no routine use of haematological growth factor support

  18. Best Overall Response during treatment (RECIST criteria) Combination Sequential T + D T  H p = 0.03

  19. Median time to first progression p=0.0001 Combination therapy T + D: 9.4 mo Monotherapy T : 3.9 mo

  20. Progression Free SurvivalCombination versus Sequential therapy p=0.42 Combination T + D: 9.4 mo Sequential T  D: 10.8 mo

  21. Overall Survival Combination T + D: 30.5 mo Sequential T  D: 20.2 mo p=0.15

  22. Herceptin prolongs survival in women with 1st-line MBC H0648g (IHC 3+) M77001 BCIRG 007 US Oncology (IHC 3+) Median survival (months) IHC, immunohistochemistry; P, paclitaxel H, Herceptin; D, docetaxel; Carbo, carboplatin Smith et al 2001; Marty et al 2005 Robert et al 2006; Pegram et al 2007

  23. HTX Herceptin 8mg/kg (loading dose), d1followed by 6mg/kg, d1, q21d Docetaxel 75mg/m2, d1 Xeloda 950mg/m2 bid, d1–14 R A N D O M I S A T I O N HT Herceptin 8mg/kg (loading dose), d1 followed by 6mg/kg, d1, q21d Docetaxel 100mg/m2, d1 CHAT: a large randomised phase II trial No prior Herceptin, docetaxel or Xeloda • Stratification: • prior paclitaxel • prior anthracycline • liver metastases • KPS KPS = Karnofsky performance status Wardley A et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S33(Abst 309)

  24. HTX significantly increases progression-free survival Events HR 95% CI p-value HTX 75 0.725 0.529, 0.99 0.0402 HT 85 1.0 0.8 0.6 0.4 0.2 0 Estimated probability 12.8 17.9 0 5 10 15 20 25 30 35 40 45 50 Months Wardley A et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S33(Abst 309)

  25. Phase III Study to Test if Total HER2 Blockade Improves Clinical Outcome RANDOMIZATION • Key Inclusion • HER2+(FISH+/ IHC3+) MBC • Progression on • Anthracycline • Taxane • Trastuzumab • Progression on most recent trastuzumab regimen Lapatinib 1500 mg/day PO N=148 Crossover if PD after 4wk therapy (N=73) • Stratification Factors • Visceral Disease • Hormone Receptor Lapatinib 1000 mg/day PO Trastuzumab 4 2 mg/kg IV qw N=148 J O Shaughnessy, ASCO 2008 Study conducted and funded by GlaxoSmithKline

  26. Treatment Efficacy *Confirmed CR+PR †CR+PR+SD ≥ 6 mo

  27. Progression-Free Survival 100 80 60 Cumulative % Alive without Progression 40 28% 6 Mo PFS 20 13% 0 0 10 20 30 40 50 60 Time from Randomization (wks) Subjects At Risk L L+T 148 148 53 73 21 42 13 27 5 8 0 2

  28. Adjuvant Trastuzumab

  29. Adjuvant Herceptin has an extensive evidence base with >13,000 patients treated in 4 major trials Docetaxel + carboplatin Docetaxel Herceptin Paclitaxel Standard CTx HERA (ex-USA) BCIRG 006 (global) Observation IHC / FISH (n=5,090) FISH(n=3,222) 1 year 1 year 2 years 1 year NCCTG N9831 (USA) NSABP B-31 (USA) IHC / FISH (n=2,030) IHC / FISH (n=3,505) 1 year 1 year 1 year Doxorubicin + cyclophosphamide IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006

  30. HERA HERA update Lancet 2007

  31. Trastuzumab sequenziale

  32. 1 In favor of Obs. Trastuzumab Adjuvant Trials 0 2 In favor of T

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