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Pertuzumab e Trastuzumab-DM1.

Pertuzumab e Trastuzumab-DM1. Filippo Montemuro, M.D. Divisione di Oncologia Medica 1 Fondazione del Piemonte per l’Oncologia/Istituto per la Ricerca e la Cura del Cancro, Candiolo. HER2 targeting has changed the natural history of HER2-positive advanced breast cancer. 1991-2007.

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Pertuzumab e Trastuzumab-DM1.

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  1. Pertuzumab e Trastuzumab-DM1. Filippo Montemuro, M.D. Divisione di Oncologia Medica 1 Fondazione del Piemonte per l’Oncologia/Istituto per la Ricerca e la Cura del Cancro, Candiolo

  2. HER2 targeting has changed the natural history of HER2-positive advanced breast cancer 1991-2007 Dawood et al, J Clin Oncol 28;92, 2009

  3. Proposed Mechanisms of Action of Trastuzumab Spector, J Clin Oncol 27;5838, 2009

  4. From linear cascades to integrated networks 1 ligand 10 ligands • Evolutionary processes: • Gene Duplication • Subfunctionalization (i.e. HER2 no known ligands, HER3 no tyrosine kinase activity) Amit I, Wides R, Yarden Y, Molecular Systems Biology 2007

  5. PDGF VEGF Targeting key pathways in HER signalling…and beyond Trastuzumab/DM1 Pertuzumab MM-111 Pertuzumab Cixitumumab ADAM 17 inhibitors Bevacizumab Sorafenib Sunitinib Pazopanib Lapatinib Neratinib BIBW 2992 Canertinib Erlotinib Gefitinib PDGFR HSP90 Inhibitors VEGFR Everolimus Temsirolimus Endothelial Cell HDAC inhibitors

  6. HER2:HER3 dimers may provide an escape mechanism from trastuzumab Homodimers Heterodimers HER1:HER2 HER4:HER4 HER1:HER3 HER1:HER4 HER3:HER3 HER2:HER3 HER2:HER2 HER2:HER4 HER1:HER1 HER3:HER4 + + + + + + + + + + + + + + + Signaling activity Tzahar et al. Mol Cell Biol 1996;Sergina et al. Nature 2007 Tzahar, et al. Mol Cell Biol 1996

  7. Different mechanisms of action of trastuzumab and pertuzumab on heterodimers

  8. Activity of pertuzumab in HER2-negative breast cancer Gianni et al. J Clin Oncol, 28; 1131, 2010

  9. Toxicity profile of pertuzumab 8 patients experienced drops in LVEF ≥10% to <50%, including 1 CHF Gianni et al. J Clin Oncol, 28; 1131, 2010

  10. Pertuzumab, demonstrates synergistic activity with trastuzumab HER2 receptor Pertuzumab Trastuzumab Dimerization domain of HER2 Subdomain IV of HER2 • Preferentially inhibits ligand-independent HER2 signaling • Prevents shedding of HER2 ECD • Flags cells for destruction by the immune system • Inhibits formation of HER2 dimer pairs • Suppresses multiple HER signalling pathways, leading to a more comprehensive blockade of HER2-driven signalling • Flags cells for destruction by the immune system Junttila et al. Cancer Cell 2009

  11. Activity of trastuzumab and pertuzumab in HER2 positive xenografts Scheuer et al, Cancer Res 2009

  12. Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy Pertuzumab + trastuzumab(n=66) HER2-positive MBC Progressed on trastuzumab + chemotherapy (Cohorts 1 and 2, n=66) Cohorts 1 and 21 HER2-positive MBC Progressed on trastuzumab + chemotherapy (n=29) Pertuzumab(n=29) Pertuzumab + trastuzumab (n=15) Cohort 32 Primary objectives • Safety and efficacy Population • ≤3 prior lines cytotoxic therapy (including adjuvant treatment) 1. Baselga et al. JCO 2010; 2. Baselga et al. SABCS 2009

  13. Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone 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 Cohorts 1 and 21,2 (P + H) (n=66) Cohort 33(P)(n=27*) Cohort 33(P  P + H)(n=11†) *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); ‡at data cut-off, 21 (31.8%) patients had not experienced PD 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

  14. Toxicity, non cardiac Baselga et al, J Clin Oncol, 28;1138, 2010

  15. Cardiac toxicity Baselga et al, J Clin Oncol, 28;1138, 2010

  16. Further development of this combination Cleopatra Pherexa HER2-positive MBC No prior chemotherapy for MBC(except 1 prior hormonal regimen)(n=800*) HER2-positive MBC 2nd line, progressed on prior trastuzumab(n=450) 1:1 1:1 Trastuzumab + capecitabine + placebo Trastuzumab + capecitabine + pertuzumab Trastuzumab + docetaxel + placebo Trastuzumab + docetaxel + pertuzumab 125 centers, 20 countries Accrual completed

  17. The NEOSPHERE trial Trastuzumab + Docetaxel Surgery FEC X 3 trastuzumab q3w until week 52 Trastuzumab + Docetaxel + Pertuzumab FEC X 3 trastuzumab q3w until week 52 HER2+LABC Trastuzumab + Docetaxel FEC X 3 trastuzumab q3w until week 52 Trastuzumab + Pertuzumab 400 patients Docetaxel + Pertuzumab FEC X 3 trastuzumab q3w until week 52 • End Points: • pCR • Biomarker analysis

  18. Gianni et al. SABCS 2011

  19. Gianni et al. SABCS 2011

  20. Gianni et al. SABCS 2011

  21. Gianni et al. SABCS 2011

  22. Gianni et al. SABCS 2011

  23. Gianni et al. SABCS 2011

  24. PI3K inhibition

  25. Multiple targeting with trastuzumab, pertuzumab and GDC-0941

  26. Trastuzumab-DM1

  27. T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells • Trastuzumab-like activity by binding to HER2 • Targeted intracellular delivery of a potent antimicrotubule agent, DM1 T-DM1 binds to the HER2 protein on cancer cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

  28. Phase I study in patients with HER2-positive advanced breast cancer

  29. Phase I study in patients with HER2-positive advanced breast cancer

  30. Clinical Study Descriptions

  31. Antitumor Activity, All Treated Patients • Both Phase II studies demonstrated clinically meaningful ORR for single-agent T-DM1.

  32. Prior Chemotherapy and Anti-HER2 Therapy:TDM4258g

  33. Summary of activity as a single agent: TDM4258g

  34. Activity according to HER2 status

  35. Adverse events

  36. Patients treated with TDM1 retain sensitivity to further antiHER2-based therapy

  37. PD Study Design HER2-positive, recurrent locally advanced BC or MBC (n=137) • Randomized, phase II, international, open-label study • HER2-positive, measurable disease required • Stratification factors • World region, prior adjuvant trastuzumab therapy, disease-free interval • Primary endpoints: PFS by INV, safety • Key Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control T-DM1 3.6 mg/kg Q3W until PD 1:1 Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m2 Q3W Crossover T-DM1 Perez EA, et al. Abstr LBA3. ESMO 2010

  38. Objective Response by Investigator (ITT)Randomized Patients * Objective response = complete or partial response based on RECIST 1.0 determined on two consecutive tumor assessments at least 4 weeks apart † Clinical benefit = objective response or maintained stable disease for at least 6 months from start of study treatment ‡ 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

  39. AE SummarySafety Evaluable Patients * 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

  40. Phase Ib/II trial of T-DM1 + pertuzumab in patients with locally-advanced and MBC who were previously treated with trastuzumab Expansion phase (completed) Dose escalation phase(completed) Phase Ib/II: HER2-positive MBC in all therapeutic lines(n=67) T-DM1 + pertuzumab(n=9) T-DM1 + pertuzumab(n=58, including 22 first line) • Primary endpoints: • Safety • ORR by RECIST 1.0 • Secondary endpoints: • PFS • DoR • Phase Ib: 3+3 dose escalation • Cohort I: T-DM1 3.0 mg/kg; pertuzumab (840 mg loading dose, 420 mg maintenance dose) • Cohort II: T-DM1 3.6 mg/kg; pertuzumab (840 mg loading dose, 420 mg maintenance dose) • Phase II • Expansion at dose level established in Phase Ib • Heavily pretreated population: • Median of 6 prior therapeutic agents in the metastatic setting Miller et al. ASCO 2010

  41. T-DM1 + pertuzumab shows promising efficacy in patients pretreated with trastuzumab + lapatinib • ORR was 35.7% (10/28 patients), per investigator assessment • All responses were confirmed PRs • 1/13 patients with SD had an unconfirmed response Miller et al. ASCO 2010

  42. T-DM1 + pertuzumab has an encouraging safety and tolerability profile *One Grade 5 AE was reported (pneumonia) in a patient who died before her first tumor assessment. This AE was considered to be unrelated to study treatment †Primarily attributed to pneumonia or the disease under study (lung metastases & pleural effusions) Miller et al. ASCO 2010 AST, aspartate aminotransferase

  43. First-line T-DM1 + pertuzumab vs trastuzumab + docetaxel Primary endpoints • PFS (independent assessment) • Safety Secondary endpoints • ORR (independent assessment) • OS • 1-year survival • PFS • ORR (investigator assessment) • CBR • TTF • DoR • Safety and tolerability HER2-positive MBCNo prior chemotherapy (n=1092) Trastuzumab + taxane T-DM1 +pertuzumab T-DM1 + placebo Global study starts summer 2010332 centers in 40 countries Clinicaltrials.gov

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