DATEN - FAKTEN: KONSEQUENZEN?

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1 Therapie des fortgeschrittenen Mammakarzinoms 2012 Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I DATEN - FAKTEN: KONSEQUENZEN? New Drugs New Hopes? 25. April 2012 Palais Schönborn Wien

2 Therapie des fortgeschrittenen Mammakarzinoms Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I

3 Therapie des fortgeschrittenen Mammakarzinoms Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I

4 Therapie des fortgeschrittenen Mammakarzinoms 2012 New Drugs New Hopes? DENOSUMAB EVEROLIMUS Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I

5 Denosumab - Hintergrund fortgeschrittenes Mammakarzinom: 65-75% Knochenmetastasen Osteoklasten-vermittelter Knochenabbau Klinische Konsequenzen: Skelettkomplikationen (SRE) Bestrahlung der Knochen Pathologische Fraktur Spinale Kompression Operation am Knochen

6 Skelettkomplikationen erhöhen das Mortalitätsrisiko mediane OS: 16 Mo median OS: 7 Mo Yong M et al. Breast Cancer Res Treat Apr 2. [Epub ahead of print]

7 Denosumab Voll humaner monoklonaler Antikörper- IgG 2 Isotyp Hohe Affinität zu humanem RANK Ligand Hohe Spezifität für RANK Ligand Keine Bindung an TNF-α, TNF-β, TRAIL und CD40L Keine neutralisierenden Antikörper bisher nachweisbar

8 RANKL: zentrale Rolle im Circulus vitiosus des Knochenabbaus bei Knochenmetastasen PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Tumor Zelle RANKL RANK PDGF, BMPs TGF-β, IGFs FGFs Aktivierter Osteoklast Osteoblasten Adapted from Roodman D. N Engl J Med. 2004;350:1655.

9 Denosumab Unterbrechung des Circulus vitiosus Tumor Zelle Verhinderte Reifung RANKL RANK Denosumab PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs Osteoblasten Apoptotischer Osteoklast Adapted from Roodman D. N Engl J Med. 2004;350:1655.

10 Denosumab: 6 positive, abgeschlossene Studien in der Onkologie Behandlungsinduzierter Knochenverlust Verzögertes Auftreten von Knochenmetastasen Behandlung von Knochenmetastasen HALT Mamma (n = 252) HALT Prostata (n = 1.468) ABCSG-18 (n = 3.400) BM Prevention Prostata (n = 1.400) BM Prevention Mamma (n = 4.500) Mamma SRE (n = 2.046) Prostata SRE (n = 1.901) Solide Tumoren/MM SRE (n = 1.776) ZIEL: Reduktion von Frakturen ZIEL: Verzögerung von Knochenmetastasen ZIEL: Verzögerung von Skelettkomplikationen 60 mg alle 6 Monate 120 mg alle 4 Wochen 120 mg alle 4 Wochen ~ Patienten Patienten ~ Patienten BM = bone metastasis SRE = skeletal related events HALT = Hormone Ablation Bone Loss Trial MM = multiple myeloma Available at: Accessed April Abgeschlosse Studie Laufende Studie

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12 Phase III pivotal trial of denosumab vs zoledronic acid in breast cancer patients with bone metastases Study 136 Enrolled N = 2049 R A N D O M I S A T I O N Denosumab 120 mg SC Q4W + Placebo IV Q4W* (n = 1026) Daily supplementation with calcium ( 500 mg) and vitamin D ( 400 IU) Zoledronic acid 4 mg IV Q4W* + Placebo SC Q4W (n = 1020) Inclusion criteria Breast cancer patients aged 18 years Evidence of bone metastasis Exclusion criteria Oral bisphosphonates for the treatment of bone metastases Prior IV bisphosphonates Stopeck AT et al. J Clin Oncol 2010;28: *Per protocol and Zometa label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine IV, intravenous; Q4W, every 4 weeks

13 Sequential testing of endpoints to demonstrate superiority Primary Secondary Time to first on-study SRE (non-inferiority) Time to first on-study SRE (superiority) Time to first and subsequent SRE(s) (superiority) Safety and tolerability If the primary endpoint of noninferiority was met, the superiority test for secondary endpoints was conducted SREs were defined as any of the following: Pathological fracture Surgery to bone Radiation to bone Spinal cord compression Stopeck AT et al. J Clin Oncol 2010;28:

14 Baseline characteristics were well balanced between groups Characteristic Zoledronic acid (n = 1020) Denosumab (n = 1026) Women, n (%) 1011 (99) 1018 (99) Post-menopausal, n (%) 831 (82) 839 (82) Median (Q1, Q3) age, years 56 (49, 65) 57.0 (49, 65) 65 years, n (%) 266 (26) 275 (27) ECOG status, n (%) (48) 504 (49) (44) 451 (44) Prior SRE, n (%) 373 (37) 378 (37) Prior chemotherapy, n (%) 825 (81) 831 (81) Prior hormonal therapy, n (%) 728 (71) 755 (74) Hormone receptor positive, n (%) 726 (71) 740 (72) Stopeck AT et al. J Clin Oncol 2010;28: ECOG, Eastern Cooperative Oncology Group

15 Significantly longer time without an SRE with denosumab vs zoledronic acid % of patients without SRE Time to first SRE (primary endpoint) (n = 2046) months Not reached HR = 0.82 (95% CI, ) P = (non-inferiority) P = 0.01 (superiority) 18% Risk Reduction 10 0 No. at risk Zoledronic acid Denosumab Denosumab Zoledronic acid Study month Stopeck AT et al. J Clin Oncol 2010;28: HR, hazard ratio

16 Significantly fewer SREs with denosumab vs zoledronic acid Cumulative mean number of SREs per patient Total SREs: Denosumab: 474 Time to first and subsequent SRE* (n = 2046) Zoledronic acid: RR = 0.77 (95% CI, ) P = (superiority) 23% Risk Reduction Study month Stopeck AT et al. J Clin Oncol 2010;28: *Events occurring at least 21 days apart (multiple event analysis) RR, rate ratio

17 Significantly reduced mean skeletal morbidity rate with denosumab vs zoledronic acid 0.7 SREs per patient per year* % P = Zoledronic acid Denosumab For every 100 patients treated per year, 58 treated with zoledronic acid will experience an SRE compared with 45 treated with denosumab Stopeck AT et al. J Clin Oncol 2010;28: *Ratio of the number of SREs per patient divided by the patient s time at risk

18 Adverse events were well balanced and as expected for this patient population Adverse event (any grade), % Zoledronic acid (n = 1013) Denosumab (n = 1020) Nausea Fatigue Arthralgia Back pain Pyrexia Bone pain Vomiting Anaemia Diarrhoea Dyspnoea Pain extremity Headache Constipation Any AE Stopeck AT et al. J Clin Oncol 2010;28: AEs occurring in 20% in either group

19 Safety results of interest Adverse event (AE), % Zoledronic acid (n = 1013) Denosumab (n = 1020) Osteonecrosis of the jaw* Acute phase reactions (first 3 days) Hypocalcaemia AEs potentially associated with renal toxicity Increased blood creatinine Renal failure CTCAE grade Serious *P = 0.39 between groups. Flu-like syndrome including pyrexia, chills, flushing, bone pain, arthralgias and myalgias. Includes increased blood creatinine, hypercreatininaemia, oligouria, renal impaiment, protinuria, renal failure, decreased urine output, decreased creatinine renal clearance, acute renal failure, abnormal renal function test, anuria, increased blood urea, chronic renal failure. Stopeck AT et al. J Clin Oncol 2010;28: CTCAE, common terminology criteria of adverse events

20 NNT Denosumab vs. Zoledronsäure Zoledronsäure Denosumab SRE* Anzahl Patientenjahre unter Behandlung SRE* Anzahl Patientenjahre unter Behandlung Mammakarzinom NNT Prostatakarzinom Andere solide ,5 Tumore 3 *Erstes und nachfolgendes SRE SRE = skeletal related event; Skelettkomplikation NNT = nuber needed to treat = Anzahl notwendiger Behandlungen 1 Martin M, et al.: St. Gallen International Breast Cancer Conference P347; 2 Miller K, et al.: AUA Congress Abstract No: 648; 3 Richardson G, et al.: ASCO Congress Abstract + Poster No: 9115

21 Denosumab provides meaningful additional benefit over current standard of care 1.2 Incidence of SREs 1 Incidence of SREs SREs per patient per year % % Placebo Zoledronic acid 0.0 Zoledronic acid Denosumab 1. Kohno N et al. J Clin Oncol 2005;23: Stopeck AT et al. J Clin Oncol 2010;28:

22 Summary: denosumab provides meaningful additional benefit over current standard of care Denosumab demonstrated superior SRE prevention over zoledronic acid: Significantly longer time without an SRE Significantly fewer SREs overall Denosumab was generally well tolerated ONJ infrequent and rates similar to zoledronic acid Acute phase reactions 2.7 times more frequent with zoledronic acid than denosumab Hypocalcaemia more frequent with denosumab than zoledronic acid Generally not associated with symptoms or clinical sequelae Denosumab had no effect on renal function and no dose adjustments were required Stopeck AT et al. J Clin Oncol 2010;28:

23 DENOSUMAB Fragen an das Expertenpanel Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I Unterschiede im Wirkmechanismus D-mab/Bisphosphonate wie zentral ist der RANK/RANK-Ligand Mechanismus? sind Escape-Mechanismen vorstellbar/bekannt? Ist eine Antitumor-Aktivität von D-mab möglich? Gibt es präklinische/klinische Daten? wie ist das Aktivitäts-Toxizitätsprofil von D-mab zu bewerten? Akutphasereaktionen Nephrologische Aspekte ONJ ist Denosumab eine/die neue Standardtherapie bei ossär metastasiertem Mammakarzinom (und anderen Karzinomen)?

24 Everolimus Active rapamycin derivative Orally bioavailable; T 1/2 ~ 30 hours; CYP3A4 metabolism Sustained inhibition of mtor via daily administration 1,2 Crosses blood-brain barrier 3 Broad antitumor activity Inhibits cell growth and angiogenesis Potential synergy with chemotherapy, radiation, and other targeted agents Demonstrated single-agent efficacy and safety in several pivotal phase 3 trials Investigated in over 4,000 cancer patients HO O O O N O OH O O O O O OH RAD001 (Everolimus) O O 1. O Donnell et al. J Clin Oncol. 2008;26: ; 2. Tabernero et al. J Clin Oncol. 2008;26: ; 3. Data on file;

25 Aromatase Inhibition: ER+ Breast Cancer 1. Moy B et al. Clin Cancer Res. 2006;12:

26 EVEROLIMUS/RAD001: Oral mtor Inhibitor Active rapamycin derivative HO O O Orally bioavailable; T 1/2 ~ 30 hours; CYP3A4 metabolism Sustained inhibition of mtor via daily administration 1,2 O N O OH O O O O O OH RAD001 (Everolimus) O O Crosses blood-brain barrier 3 Broad antitumor activity Inhibits cell growth and angiogenesis Potential synergy with chemotherapy, radiation, and other targeted agents Demonstrated single-agent efficacy and safety in several pivotal phase 3 trials 1. O Donnell 26 et Presentation al. J Clin Oncol. Title Presenter 2008;26: ; Name Date 2. Subject Tabernero Business et al. Use J Clin Only Oncol. 2008;26: ; 3. Data on file; Investigated in over 4,000 cancer patients

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43 EVEROLIMUS Fragen an das Expertenpanel Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I Wie wichtig ist delay of chemotherapy in der Klinik? Welche Resistenz- und Escapemechanismen sind bekannt bzw. vorstellbar? Sind weitere mtor-inhibitoren in prä-/klinischer Testung? Kombination mit Zytostatika-Antikörpern-TKI sinnvoll? Daten? Klinische Studien? Einsatz in der Therapie des HER2-pos. Mammakarzinoms? Adjuvante/neoadjuvante Therapie?

44 Therapie des fortgeschrittenen Mammakarzinoms 2012 New Drugs New Hopes? nab-paclitaxel ERIBULIN Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I

45 nab-paclitaxel Vinca Alkaloide, Estramustin Taxane X X GDP GDP GTP GTP Polymerisation

46 nab-paclitaxel Vinca Alkaloide, Estramustin Taxane X X GDP GDP GTP GTP Polymerisation

47 Paclitaxel 1) "Spindelgift 2) Parmakokinetik: (i) Metabolismus durch CYP2C18 & CYP3A4 (Interaktionen) PgP/ABCB1-Substrat (i) nicht-lineare Kinetik: t½= 3-53 h; V D =2 L/kg; Altersabhängigkeit 3) Resistenzmechanismen: Mutation von β Tubulin Überexpression von PgP/ABCB1 oder von Stathmin 4) Myelosuppression, sensorische Neuropathie (Bradykardie) 5) schlecht wasserlöslich Lösungsvermittler: Ethanol/Cremophor Unverträglichkeitsreaktionen bei Injektion

48 Elsadek & Kratz (2011) J. Controlled Release, in press Albumin die Lösung für das Löslichkeitsproblem von Paclitaxel Molekülgröße = 5 nm

49 Albumin die Lösung für das Löslichkeitsproblem von Paclitaxel etc. Nanoparticle Albumin bound (nab) platform Technologie Albumin cryo TEM Mittlere Größe = nm Hydrophobe Substanzen, z. B. Paclitaxel, Docetaxel, Rapamycin etc. Dissoziation in einzelne mit Substanz beladene Albuminmoleküle

50 2) nab Paclitaxel Albumin Lösung für Löslichkeit & Pharmakokinetik Taxan Formulierungen im Vergleich Paclitaxel nab-paclitaxel Lösungsvermittler: Cremophor EL + Ethanol Lösungsvermittler assoz. Hypersensitivitätsreaktion +++ Prämedikation: ++ Pharmakokinetik: nicht linear linear t½ 3 50 h 27 h freier Anteil 2 % 6% Verteilungsvolumen ( 688) L/m L/m 2

51 Phase 3 Studie: Albumin-gebundene Paclitaxel-Nanopartikel im Vergleich zu polyethoxyliertem Rizinusöl-basiertem Paclitaxel bei Patientinnen mit Mammakarzinom Gradishar et al. J Clin Oncol. 2005;23:

52 Studiendesign nab-paclitaxel 260 mg/m 2 i.v. über eine Dauer von 30 Min. q3w Keine Standard-Prämedikation Randomisierung (1:1) n = 460 Paclitaxel 175 mg/m 2 i.v. über eine Dauer von 3 Std. q3w Standard-Prämedikation: Dexamethason, Antihistaminikum und H2-Antagonist Studienziele 1. Objektive Responserate (ORR) 2. Zeit zur Progression (TTP) und Gesamtüberlebensrate (OS) Gradishar et al. J Clin Oncol. 2005;23:

53 Vorhergehende Therapien nab-paclitaxel Gradishar et al. J Clin Oncol. 2005;23:

54 Pivotale Studie: Verabreichte Dosis nab-paclitaxel Gradishar et al. J Clin Oncol. 2005;23:

55 ABRAXANE nab-paclitaxel verbessert die ORR unabhängig von der Therapielinie und über verschiedene Untergruppen hinweg 60 P = P = P = P = ORR (± 95% CI) % 18.7% 26.5% 13.2% 34.1% 18.3% 33.5% 18.7% 0 Alle Zweitlinien- Anthracyclin- Visz Patientinnen Therapie Exposition Erkrankung ABRAXANE Paclitaxel Die höhere ORR wurde durch ein unabhängiges Prüfungskomitee bestätigt Gradishar et al. J Clin Oncol. 2005;23:

56 ABRAXANE nab-paclitaxel verlängert signifikant das Gesamtüberleben (OS) bei Zweitlinienpatientinnen 1.00 nab-paclitaxel ABRAXANE (n = 131) Paclitaxel (n = 136) Überlebenswahrscheinlichkeit Median = 46.7 Wochen ( ) Median = 56.4 Wochen ( ) P = HR = Wochen Anmerkung: P-Wert stammt aus dem Log-Rank-Test Gradishar et al. J Clin Oncol. 2005;23:

57 Hämatologische Nebenwirkungen nab-paclitaxel Cochran-Mantel-Haenszel-Test basiert auf allen Graden Gradishar et al. J Clin Oncol. 2005;23:

58 ABRAXANE wurde von älteren Patientinnen ( 65 Jahre) gut vertragen nab-paclitaxel Die aufgetretenen unerwünschten Ereignisse (AE) bei Patienten 65 Lebensjahre waren in der ABRAXANE - Gruppe geringer als in der Vergleichsgruppe. nab-paclitaxel Bei einer Behandlung mit ABRAXANE gibt es für Patientinnen ab 65 Jahren im Vergleich zu jüngeren Patientinnen keine zusätzlichen Verträglichkeitsbedenken Gradishar et al. J Clin Oncol. 2005;23:

59 Significantly Longer Progression-Free Survival with nab-paclitaxel Compared with Docetaxel as First-Line Therapy for Metastatic Breast Cancer W.J. Gradishar, D. Krasnojon, S. Cheporov, A.N. Makhson, G.M. Manikhas, A. Clawson, P. Bhar Gradishar W, et al. J Clin Oncol, 2009; 27(22):

60 Comparisons nab-paclitaxel vs docetaxel (A, B, C vs D) QW vs Q3W nab-paclitaxel (B, C vs A) low vs high dose QW nab-paclitaxel (B vs C) Study Design st line metastatic breast cancer (MBC) patients were accrued and randomized to 4 arms (300 received study drug and were evaluable) PE: ORR SE: PFS, OS R A N D O M I Z E Arm A: nab-paclitaxel 300 mg/m 2 Q3W n = 76 Arm B: nab-paclitaxel 100 mg/m 2 QW 3/4 weeks n = 76 Arm C: nab-paclitaxel 150 mg/m 2 QW 3/4 weeks n = 74 Arm D: docetaxel 100 mg/m 2 Q3W n = 74 Arms A, C, and D administered at the MTD Gradishar W, et al. J Clin Oncol, 2009; 27(22):

61 Patient Demographics Visceral Metastases: 84% Performance Status ECOG PS 1: 94% ECOG PS 2: 6% Prior Chemotherapy Adjuvant: 33% Neoadjuvant: 18% Metastatic: <1% Prior Grade 1 Sensory Neuropathy: 10% ECOG: Eastern Cooperative Oncology Group Gradishar W, et al. J Clin Oncol, 2009; 27(22):

62 QW or Q3W nab-paclitaxel vs Q3W Docetaxel: Overall Response Rate P = P < P = * 300 mg/m 2 Q3W 100 mg/m 2 QW 3/4 150 mg/m 2 QW 3/4 nab-paclitaxel *100 mg/m 2 nab-paclitaxel vs. docetaxel P = mg/m 2 Q3W Docetaxel Gradishar W, et al. J Clin Oncol, 2009; 27(22):

63 QW or Q3W nab-paclitaxel vs Q3W Docetaxel: Progression-free Survival (Independent Review) 1.00 Proportion Not Progressed, Investigator Assessment (A) nab-paclitaxel 300 mg/m 2 q3w (B) nab-paclitaxel 100 mg/m 2 qw 3/4 (C) nab-paclitaxel150 mg/m 2 qw 3/4 (D) Docetaxel 100 mg/m 2 q3w months 12.8 months 12.9 months 7.5 months Median PFS P-value Overall B vs C NS C vs D Months Gradishar W, et al. J Clin Oncol, 2009; 27(22):

64 Final Analysis of Overall Survival 1.00 Median OS (mo) P HR AB-Pac 150mg/m 2 qw (C) AB-Pac 300mg/m 2 q3w (A) Taxotere 100mg/m 2 q3w (D) Overall: C vs B: C vs D: AB-Pac 100mg/m 2 qw (B) Months The 150 mg/m 2 qw albumin-bound paclitaxel arm demonstrated: A significantly longer median OS versus the 100 mg/m 2 arm A longer OS versus docetaxel, although this difference was not statistically significant The OS benefit of the 150 mg/m 2 arm was consistent among patient subgroups: Age <65 vs 65 years Visceral vs non-visceral disease No. of visceral lesion sites <5 vs 5 Pre-menopausal vs post-menopausal No P value is reported for comparisons where a treatment difference is not detected by step-down methodology.

65 QW or Q3W nab-paclitaxel vs Q3W Docetaxel: Select Safety Results* Selected Adverse Events Sensory neuropathy *Treatment-related toxicities reported in >25% of patients 300 mg/m 2 Q3W (n = 76) P < for all 3 nab-paclitaxel arms compared to docetaxel arm nab-paclitaxel 100 mg/m 2 QW 3/4 (n = 76) 150 mg/m 2 QW 3/4 (n = 74) Docetaxel 100 mg/m 2 Q3W (n = 74) grade 3 17% 8% 14% 12% grade Fatigue grade 3 5% 0 3% 19% grade Neutropenia grade 3 39% 20% 35% 19% grade 4 5% 5% 9% 75% Mean nadir ± SD, x 10 9 /l 1.21 ± ± ± ± 0.34 Arthralgia grade 3 1% grade Gradishar W, et al. J Clin Oncol, 2009; 27(22):

66 Grade 3 Neuropathy Improved More Rapidly With nab-paclitaxel Sensory neuropathy occurred with similar frequency in all study arms rate of improvement of sensory neuropathy after treatment was greater in all nab-paclitaxel arms vs docetaxel Median time to improvement nab-paclitaxel 300 mg/m 2 q3w was 22 days nab-paclitaxel 100 mg/m 2 qw was 22 days nab-paclitaxel 150 mg/m 2 qw was 19 days Docetaxel at 100 mg/m 2 q3w was 37 days Proportion not improved nab-paclitaxel 300 mg/m 2 Q3W (n = 13) nab-paclitaxel 100 mg/m 2 QW 3/4 (n = 6) nab-paclitaxel 150 mg/m 2 QW 3/4 (n = 10) Docetaxel 100 mg/m 2 Q3W (n = 9) Days Gradishar W, et al. J Clin Oncol, 2009; 27(22):

67 Zusammenfassung nab-paclitaxel im Vergleich zu Paclitaxel: nab-paclitaxel zeigte signifikant höhere ORR (33% vs. 19%) und längere TTP (23.0 vs Wochen) nab-paclitaxel verlängerte signifikant das Gesamtüberleben von Zweitlinienpatientinnen mit MBC (56,4 vs 46,7 Wochen) Das Auftreten von Neutropenie Grad 4 war im nab-paclitaxel Arm trotz der um 49% höheren Dosis signifikant niedriger Höhere Inzidenz mit nab-paclitaxel -Arm sensorischer Neuropathien vom Grad, doch raschere Besserung (22 vs. 79 Tage) Gradishar et al. J Clin Oncol. 2005;23:

68 nab-paclitaxel Fragen an das Expertenpanel Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I Welche Vorteile bzw. Nachteile bestehen zwichen Paclitaxel und nab- Paclitaxel? präklinisch/pharmakokinetisch klinisch Ist die nab-technologie auch auf andere Substanzen anwendbar? wie kann man nab-paclitaxel im Vergleich mit Docetaxel q 3w und Paclitaxel weekly dzt. positionieren? palliativ? adjuvant/neoadjuvant

69 ERIBULIN

70 Eribulin - MoA Eribulin: non-taxane microtubule dynamics inhibitor Growing microtubule Eribulin Eribulin inhibits microtubule growth Tubulin polymerization Spindle pole Shortening microtubule Tubulin depolymerisation Nonproductive tubulin aggregates Eribulin Eribulin causes nonproductive tubulin aggregates Inhibition of microtubule formation irreversible block of cell division and apoptosis May be effective against cancer that is resistant to taxanes Adapted from Jordan, et al. Nat Rev Cancer 2004

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81 Ongoing phase III trial of capecitabine versus eribulin in previously treated mbc Locally advanced or mbc Previously treated (up to three lines; 2 in mbc) Must include taxanes and anthracyclines (N=1,100) R Capecitabine (1,250mg/m 2 b.i.d.; days 1 14) q3w Eribulin (1.4mg/m 2 on day 1 and day 8) q3w Primary endpoints: OS, PFS Study start date: June 2006 Estimated data release: SABCS 2011 Source: NCT identifier: NCT

82 ERIBULIN Fragen an das Expertenpanel Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I Sind die Daten der Phase 3-Studie valide (z.b. freie Wahl der Th. im Kontrollarm,..)? wenn ja, warum? wenn nein, warum nicht? wird Eribulin bereits klinisch eingesetzt? wann? wit welchen Substanzen erscheint Eribulin kombinierbar? HER2-positiv?

83 Therapie des fortgeschrittenen Mammakarzinoms 2012 New Drugs New Hopes? PERTUZUMAB TRASTUZUMAB- EMTANSINE (T-DM1) Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I

84 Pertuzumab Trastuzumab and pertuzumab bind to distinct epitopes on HER2 Trastuzumab extracellular domain Pertuzumab Activates antibody-dependent cellular cytotoxicity Inhibits HER2-mediated signalling Inhibits shedding and, thus, formation of new p95 Inhibits HER2-related angiogenesis Activates antibody-dependent cellular cytotoxicity Prevents receptor dimerisation Potent inhibitor of HER2/HER2- and HER2/HER3-mediated signalling pathways

85 Pertuzumab and Herceptin bind to different regions on HER2 and have synergistic activity Trastuzumab activates the immune system blocks HER2 signaling HER2 Pertuzumab HER3 Subdomain IV of HER2 Dimerization domain of HER2

86 Pertuzumab and Herceptin bind to different regions on HER2 and have synergistic activity Pertuzumab Herceptin HER2 Inhibits HER2/HER3 dimerization HER3

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

88 In preclinical models, pertuzumab and trastuzumab have a synergistic effect Mean tumor volume (mm 3 ) ± SEM Pertuzumab + trastuzumab initial combination Vehicle control Pertuzumab (30/15 mg/kg/w i.p.) Trastuzumab (30/15 mg/kg/w i.p.) Pertuzumab (30/15 mg/kg/w i.p.) + trastuzumab (30/15 mg/kg/w i.p.) 6/10 animals cured Treatment period (days) Mean tumor volume (mm 3 ) ± SEM Pertuzumab treatment after progression following trastuzumab treatment 0 Vehicle control Trastuzumab (30/15 mg/kg/w i.p.) Pertuzumab (30/15 mg/kg/w i.p.) + trastuzumab (30/15 mg/kg/w i.p.) Treatment period (days) Xenograft model KPL 4 i.p., intraperitoneally; w, week Scheuer et al, Clin Cancer Research 2009 (in press)

89 BO17929: a Phase II trial of pertuzumab plus trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy Cohorts 1 and 2 1,2 HER2 positive MBC progressing on trastuzumab plus chemotherapy (Cohort 1, n=24; Cohort 2, n=42) Pertuzumab plus trastuzumab HER2 positive MBC Cohort progressing on Pertuzumab 3 3 trastuzumab plus chemotherapy (n=29) PD Pertuzumab plus trastuzumab Primary objectives Safety (evaluate safety of combined antibody treatment) Efficacy (response rate plus stabilization of disease = clinical benefit rate) Heavily pretreated population Median 3 prior lines of therapy in the metastatic setting 1 Gelmon et al 2008; 2 Baselga et al 2009; 3 Cortés et al 2009;

90 BO17929: pertuzumab plus trastuzumab provides clinical benefit to patients progressing on trastuzumab-based therapy Response, n (%) Complete response (CR)* Lymph Lung Partial response (PR)* Lymph Lung Liver Breast Mediastinum Cohort 1 and 2 n=66 5 (7.6%) (16.7%) ORR 16 (24.2%) Stable disease (SD) for 6 months ( cycle 8) 17 (25.8%) Clinical benefit rate 33 (50.0%) Progressive disease 33 (50.0%) Median PFS 24 weeks *Sites of target lesions shown for patients with objective response Baselga et al 2009; Gelmon et al 2008

91 Trastuzumab + pertuzumab : Toxicity Patients (%) Adverse events, all grades Adverse events, grades 3/ Diarrhoea Fatigue Nausea Rash Headache Arthralgia Cough Anorexia Asthenia Dizziness Muscle spasms Myalgia Paraesthesia Pruritus Vomiting Gelmon et al 2008

92 S u b s t a n c e i n c I i n i c a l d e v e l o p m e n t San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA) J Baselga, 1 S-B Kim, 2 S-A Im, 3 R Hegg, 4 Y-H Im, 5 L Roman, 6 J L Pedrini, 7 J Cortés, 8 A Knott, 9 E Clark, 9 G Ross 9 and S M Swain 10 1 Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2 Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; 3 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 4 Hospital Pérola Byington, São Paulo, Brazil; 5 Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 6 Leningrad Regional Oncology Dispensary, St Petersburg, Russian Federation; 7 CPMEC-Mastology Unit of Conceição Hospital, Porto Alegre, Brazil; 8 Department of Oncology, Vall d Hebron University Hospital, Barcelona, Spain; 9 Roche Products Limited, Welwyn, UK; 10 Washington Cancer Institute, Washington Hospital Center, Washington D.C., USA Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute.

93 S u b s t a n c e i n c I i n i c a l d e v e l o p m e n t Study design Patients with HER2-positive MBC centrally confirmed (N = 808) Primary endpoint: PFS MBC, metastatic breast cancer; PD, progressive disease San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 n=406 Placebo + trastuzumab Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: Pertuzumab/Placebo: Trastuzumab: Docetaxel: 1:1 n=402 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab Docetaxel* 6 cycles recommended 840 mg loading dose, 420 mg maintenance 8 mg/kg loading dose, 6 mg/kg maintenance 75 mg/m 2, escalating to 100 mg/m 2 if tolerated * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion PD PD Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 93

94 S u b s t a n c e i n c I i n i c a l d e v e l o p m e n t San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Baseline characteristics (II) HER2 status IHC, n (%) 0 and No data HER2 status FISH, n (%) Positive Negative No data Hormone receptor status, n (%) ER- and/or PgR-positive ER- and PgR-negative Unknown Disease type at screening, n (%) Non-visceral Visceral Measurable Non-measurable Unknown Placebo + trastuzumab + docetaxel (n = 406) 2 (0.5) 32 (7.9) 371 (91.4) 1 (0.2) 383 (94.3) 4 (1.0) 19 (4.7) 199 (49.0) 196 (48.3) 11 (2.7) 90 (22.2) 316 (77.8) 336 (82.8) 43 (10.6) 27 (6.7) ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor Pertuzumab + trastuzumab + docetaxel (n = 402) 4 (1.0) 47 (11.7) 350 (87.1) 1 (0.2) 384 (95.5) 1 (0.2) 17 (4.2) 189 (47.0) 212 (52.7) 1 (0.2) 88 (21.9) 314 (78.1) 343 (85.3) 44 (10.9) 15 (3.7) Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 94

95 S u b s t a n c e i n c I i n i c a l d e v e l o p m e n t San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Primary endpoint: Independently assessed PFS n = 433 PFS events Progression-free survival (%) n at risk Ptz + T + D Pla + T + D Time (months) D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months = 6.1 months HR = % CI p< Stratified by prior treatment status and region Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 95

96 S u b s t a n c e i n c I i n i c a l d e v e l o p m e n t San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Independently assessed PFS in predefined subgroups Prior (neo)adjuvant chemotherapy Region Age group Race Disease type ER/PgR status HER2 status All No Yes Europe North America South America Asia <65 years 65 years <75 years 75 years White Black Asian Other Visceral disease Non-visceral disease Positive Negative Unknown IHC 3+ FISH-positive Favors pertuzumab Favors placebo ER, estrogen receptor; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; PgR, progesterone receptor; PFS, progression-free survival n HR 95% CI Unstratified analyses Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 96

97 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 S u b s t a n c e i n c I i n i c a l d e v e l o p m e n t Overall survival: Predefined interim analysis Median follow-up: 19.3 months, n = 165 OS events Overall survival (%) n at risk Ptz + T + D: 69 events Pla + T + D: 96 events Pertuzumab + T + D Placebo + T + D * The interim OS analysis did not cross the pre-specified O Brien-Fleming stopping boundary (HR 0.603; p ) D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Time (months) HR = 0.64* 95% CI p = * Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 97

98 S u b s t a n c e i n c I i n i c a l San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Grade 3 adverse events (incidence 5%) Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Neutropenia 182 (45.8) 199 (48.9) Febrile neutropenia 30 (7.6) 56 (13.8) Leukopenia 58 (14.6) 50 (12.3) Diarrhea 20 (5.0) 32 (7.9) d e v e l o p m e n t Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 98

99 S u b s t a n c e i n c I i n i c a l d e v e l o p m e n t Cardiac tolerability Investigator-assessed symptomatic LVSD* Independently adjudicated symptomatic LVSD* Fall in LVEF to <50% and by 10 percentage points from baseline * LVSD was defined as NYHA class III/IV San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Placebo + trastuzumab + docetaxel (n = 397) LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction Pertuzumab + trastuzumab + docetaxel (n = 407) 1.8% 1.0% 1.0% 1.0% 6.6% 3.8% Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 99

100 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Neoadjuvant pertuzumab (P) and trastuzumab (H): Antitumor and safety analysis of a randomized phase II study ( NeoSphere ) L Gianni, T Pienkowski, Y H Im, L Roman, L M Tseng, M C Liu, A Lluch Hernandez, V Semiglazov, T Szado, G Ross on behalf of the NeoSphere study investigators This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.

101 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NeoSphere: study design and objectives Patients with operable or locally advanced /inflammatory* HER2 positive BC Chemo naïve & primary tumors >2cm (N=417) TH (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6mg/kg) THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6mg/kg) pertuzumab ( mg) TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) S U R G E R Y Phase II design Primary endpoint: comparison of pcr rates TH vs THP TH vs HP THP vs TP Secondary endpoints: Clinical response DFS Breast conservation rate Biomarker evaluation Study dosing: q3w x 4 BC, breast cancer; FEC, 5 fluorouracil, epirubicin and cyclophosphamide *Locally advanced=t2 3, N2 3, M0 or T4a c, any N, M0; operable=t2 3, N0 1, M0; inflammatory = T4d, any N, M0 H, trastuzumab; P, pertuzumab; T, docetaxel This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. 4

102 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NeoSphere pcr rates: ITT population summary p = p = p = pcr, % ± 95% CI H, trastuzumab; P, pertuzumab; T, docetaxel TH THP HP TP This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. 6

103 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 NeoSphere: pcr and hormone receptors status 70 pcr, % ± 95% CI H, trastuzumab; P, pertuzumab; T, docetaxel ER or PR pos ER and PR neg TH THP HP TP This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute

104 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 8-12, 2010 Tolerability of neoadjuvant treatment by arm 10 most common grade 3 adverse events TH (n=107) THP (n=107) Patients, % HP (n=108) TP (n=94) Neutropenia Febrile neutropenia Leukopenia Diarrhea Aesthenia Granulocytopenia Rash Menstruation irregular Drug hypersensitivity ALT increased AE, adverse event; ALT, alanine aminotransferase H, trastuzumab; P, pertuzumab; T, docetaxel This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute. 11

105 PERTUZUMAB Fragen an das Expertenpanel Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I wie kann man das Aktivitäts/Toxizitätsprofil bewerten? wie muss man sich im Vergleich zu Trastuzumab mögliche primäre/sekundäre Resistenzen vorstellen? wenn verfügbar, valide Therapieoption? Palliativ 1st/2nd/3rd/ -line? adjuvant/neoadjuvant? wie kann man dzt. die mögliche Kosteneffektivität beurteilen?

106 Trastuzumab-Emtansine (T-DM1) First-in-class antibody drug conjugate (ADC) Target expression: HER2 Monoclonal antibody: trastuzumab Cytotoxic agent: DM1 Highly potent chemotherapy (maytansine derivative) Linker Systemically stable Breaks down in target cancer cell T DM1

107 Conjugation of T-DM1 components markedly increases efficacy in a preclinical model T DM1 demonstrated a rapid and durable reduction in tumor volume in the Fo5 animal breast cancer model, which was specifically engineered to be insensitive to trastuzumab Mean tumor volume (mm 3 ) ± SEM Vehicle Trastuzumab 15 mg/kg Trastuzumab 15 mg/kg + free DM1 817 µg/m 2 Free DM1 817 µg/m 2 Free DM1 (near MTD) 1947 µg/m 2 Trastuzumab DM1 15 mg/kg/817 µg/m i.v. dosing Time (days) Parsons et al. AACR 2007

108 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 positive tumor cell

109 TDM4374g A Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody Drug Conjugate, in Patients with HER2+ Metastatic Breast Cancer who Were Previously Treated with an Anthracycline, a Taxane, Capecitabine, Lapatinib, and Trastuzumab Ian Krop, 1 Patricia LoRusso, 2 Kathy D. Miller, 3 Shanu Modi, 4 Denise Yardley, 5 Gladys Rodriguez, 6 Sam Agresta, 7 Michael Lu, 7 Maoxia Zheng, 7 Lukas Amler, 7 Eric Winer, 1 Hope Rugo 8 1 Dana Farber Cancer Institute, Boston, MA; 2 Karmanos Cancer Institute, Detroit, MI; 3 Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; 4 Memorial Sloan-Kettering Cancer Center, New York, NY; 5 Sarah Cannon Research Institute, Nashville, TN; 6 South Texas Oncology/Hematology, San Antonio, TX; 7 Genentech, South San Francisco, California; 8 University of California San Francisco Comprehensive Cancer Center, San Francisco, CA

110 Antitumor Activity in Treated Patients by Retrospectively Confirmed HER2 Status IRF INV Patients centrally confirmed as HER2 + n=80 n=80 ORR, % Clinical benefit rate, % Patients with unconfirmed HER2 status n=15 n=14 ORR, % Clinical benefit rate, % IRF - Independent Review Facility Objective Response = CR or PR determined by two consecutive tumor assessments at least 28 days apart. Clinical Benefit = objective response or SD maintained for at least 6 months.

111 TDM4450g Efficacy and Safety of Trastuzumab-DM1 Versus Trastuzumab plus Docetaxel in HER2-Positive Metastatic Breast Cancer Patients with No Prior Chemotherapy for Metastatic Disease: Preliminary Results of a Randomized, Multicenter, Open-Label Phase 2 Study EA Perez, 1 L Dirix, 2 J Kocsis, 3 L Gianni, 4 J Lu, 5 J Vinholes, 6 V Ng, 7 C Linehan, 7 S Agresta, 7 S Hurvitz 8 1 Mayo Clinic, Jacksonville, FL, USA; 2 Sint-Augustinus Hospital, Antwerp, Belgium; 3 Semmelweis University Hospital, Budapest, Hungary; 4 Istituto Nazionale dei Tumori, Milan, Italy; 5 Division of Hematology and Oncology, State University of New York at Stony Brook, Stony Brook, NY, USA; 6 Clinica de Oncologia de Porto Alegre, Brasil; 7 Genentech, Inc., South San Francisco, CA, USA; 8 UCLA Translational Oncology Research International, Los Angeles, CA, USA Perez EA, et al. Abstr LBA3. ESMO 2010

112 Study Design HER2-positive, recurrent locally advanced BC or MBC (n=137) 1:1 T-DM1 3.6 mg/kg Q3W until PD Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m 2 Q3W PD Crossover T-DM1 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 112 Perez EA, et al. Abstr LBA3. ESMO 2010

113 Objective Response by Investigator (ITT) Randomized Patients 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) * 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

114 AE Summary Safety Evaluable Patients 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 Three most common AEs (any grade) in trastuzumab + docetaxel arm Alopecia Neutropenia Diarrhea 32 (47.8) 31 (46.3) 24 (35.8) 1 (1.5) 5 (7.5) 7 (10.4) 27 (39.7) 29 (46.2) 14 (20.6) 45 (66.2) 39 (57.4) 31 (45.6) * 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 114 Perez EA, et al. Abstr LBA3. ESMO 2010

115 Grade >3 AEs Occurring with 10% Difference in Incidence Between Treatment Arms Occurring with 10% Difference in Incidence between Arms, n (%) Neutropenia Leukopenia Febrile neutropenia Safety Evaluable Patients NCI CTCAE Grade Total Total Total T-DM1 (n=67) Trastuzumab + Docetaxel (n=68) 36 (52.9) 6 (8.8) 30 (44.1) 17 (25.0) 12 (17.6) 5 (7.4) 7 (10.3) 6 (8.8) 1 (1.5) Most common Gr >3 AEs in T-DM1 arm (vs. trastuzumab + docetaxel arm) AST increased (7.5% vs. 0%), thrombocytopenia (6.0% vs. 1.5%), ALT increased (4.5% vs. 0%), fatigue (4.5% vs. 4.4%), and pneumonia (4.5% vs. 1.5%) 115 Perez EA, et al. Abstr LBA3. ESMO 2010

116 TDM4373g: a Phase Ib/II trial of T DM1 + pertuzumab in patients with locally advanced and MBC who were previously treated with trastuzumab Phase Ib/II: HER2 positive MBC in all therapeutic lines (n=67) Dose escalation phase (completed) T DM1 + pertuzumab (n=9) Expansion phase (completed) 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 Phase II 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) 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

117 TDM4373g: T DM1 + pertuzumab shows promising efficacy in patients pretreated with trastuzumab + lapatinib Cohort I, n (%) (n=3) Cohort II, n (%) (n=25) Total, n (%) (n=28) PR 2 (66.7) 8 (32.0) 10 (35.7) SD 1 (33.3) 12 (48.0) 13 (46.4) PD 0 4 (16.0) 4 (14.3) Missing 0 1 (4.0) 1 (3.6) Miller et al. ASCO 2010

118 1 st Line mbc Phase III MARIANNE Study: BO22589/TDM4788g HER2-positive, first-line, metastatic breast cancer N=1092 Trastuzumab + taxane (until PD) n=364 T-DM1 + pertuzumab (until PD) n=364 T-DM1 + pertuzumab placebo (until PD) n=364 Primary endpoints: PFS as assessed by IRF; Safety Secondary endpoints: OS; PFS by investigator; patient reported outcomes analysis; biomarkers 118

119 TRASTUZUMAB-EMTANSINE (T-DM1) Fragen an das Expertenpanel Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I sind auch andere Zytostatika konjugierbar? wie muss man sich mögliche primäre/sekundäre Resistenzen vorstellen? Antikörper-assoziiert? Zytostatikum-assoziiert? beides? wie kann man das Aktivitäts/Toxizitätsprofil bewerten? welche Substanzen bieten sich als potentielle Kombinationspartner an?

120 Therapie des fortgeschrittenen Mammakarzinoms 2012 Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I New Drugs New Hopes? Denosumab (Xgeva R ) seit 7/2011 registriert, seit in Österreich verschreibbar (grüne Box) Everolimus (Afinitor R ) Registrierung läuft, verfügbar, verschreibbar mit Wirksamkeitsnachweis (nach 2 Monaten) nab-paclitaxel (Abraxane R ) Registriert sein 2006, verfügbar seit 8/2011

121 Therapie des fortgeschrittenen Mammakarzinoms 2012 Medizinische Universität Wien UNIV. KLINIK FÜR INNERE MEDIZIN I New Drugs New Hopes? Eribulin (Halaven R ) Registriert seit 2011, verfügbar (patientenbezogene Anforderung) Pertuzumab Registrierung läuft, Patient Access Program ab 5/2012 Trastuzumab-Emtansine Registrierung läuft, Patient Access Program ab 6/2012

122 Regulatory approvals in mbc over the past decade irst-line therapy Chemotherapy only Chemotherapy and targeted therapy Bone treatment Hormonal and targeted therapies Hormonal herapy only Capecitabine + docetaxel* Gemcitabine + paclitaxel EU Second-line and later therapy Fulvestrant Nab-paclitaxel Bevacizumab + paclitaxel FDA EU EU FDA/EU FDA EU FDA FDA EU Ixabepilone Ixabepilone + capecitabine Lapatinib + letrozole Lapatinib + capecitabine Bevacizumab + capecitabine FDA EU Eribulin Denosumab *In the US, approved for use after failure of anthracycline-containing therapy, so could be given in first line Can be given first-line in patients with disease progression <6 months after adjuvant therapy Marketing application withdrawn in EU Approved for use after failure of anthracycline- and taxane-containing therapies, so could be given first line T DM1 Everolimus Pertuzumab

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