Pr Jean-Philippe SPANO Hôpital Pitié-Salpêtrière, Paris CLEOPATRA in 2012 Targeted Therapies (Mob) Or How to separate the present and future from the past? Pr Jean-Philippe SPANO Hôpital Pitié-Salpêtrière, Paris

The ways we are…..

The ways we ll be….

trastuzumab®: Anticorps humanisé anti-HER 2 Cibles de l’oncoprotéine HER 2 Haute affinité et spécificité Composition: 95% humaine, 5% murine

Phase métastatique Patientes Her 2 (+) :  Taxane – trastuzumab: - 2 études de phase III: 1. Slamon (paclitaxel– trastuzumab) 2. Marty (docetaxel – trastuzumab):

Herceptin et Chimiothérapie Bénéfices cliniques - toutes patientes (2+/3+) et HER 2 (3+) H+AC (n=143) AC (n=1138) H+P (n=92) P (n=96) H+CT (n=235) CT (n=234) Median TTP (months) all 3+ 7,8* 8,1* 6,1 6,0 6,9* 7,1* 2,7 3,0 7,4* 4,6 RR (%) 56 60 42 41 49 17 50 32 31 Median DR (months) 9,1 9,3 6,7 5,9 10,5 10,9 4,5 10,0 6,4 5,6 Median TTF (months) 7,0* 7,1 5,1 5,3* 2,8 6,6* 7,0 4,4 Survival (months) 27 31* 21 22 25 18 25* 29* 20 Slamon D et al., NEJM 2001 ; 344 : 783-92

Probability of survival Pivotal phase III combination trial (H0468g): overall survival in HER2 3+ patients 1.0 0.8 0.6 0.4 0.2 Paclitaxel subgroup Herceptin® + paclitaxel Paclitaxel Probability of survival ­ 40% 17.9 24.8 0 5 10 15 20 25 30 35 40 45 50 Time (months) Smith IE. Anticancer Drugs 2001;12:S3–10

Taxotere + Herceptine versus Taxotere en première ligne métastatique M Marty M77001, Patientes HER 2 positives (IHC 3+/FISH+) n=188 Deux patientes n’ont pas reçu le traitement Taxotere 100mg/m2 toutes les 3 semaines x 6 cycles Taxotere 100mg/m2 toutes les 3 semaines x 6 cycles Trial M77001 was initiated to compare Herceptin® plus docetaxel with docetaxel alone. Patients were randomised to receive six cycles of docetaxel, 100mg/m2 3 weekly, or the same schedule plus weekly Herceptin® administered as a 4mg/kg loading dose, followed by 2mg/kg weekly given until disease progression. Patients could receive docetaxel beyond six cycles at the discretion of the investigator. Patients progressing on docetaxel alone were given the option to crossover to receive Herceptin®, at the discretion of their clinician. 188 patients were accrued to the trial (94 in each arm), although two patients in the combination arm did not receive study treatment – one patient had abnormal LFT results which ruled her out and one patient refused treatment. + Herceptine® 4mg/kg i.v. puis 2mg/kg/semaine jusqu’à progression *Les patientes ayant progressé sous Taxotere seul pouvaient recevoir un traitement par Herceptine en crossover

M77001: response rates in patients with IHC 3+/FISH+ disease Patients with measurable IHC 3+/FISH+ disease; radiological responses were independently reviewed

M77001: time to disease progression 1.0 0.8 0.6 0.4 0.2 Herceptin® + docetaxel Docetaxel alone Estimated probability p=0.0001 6.1 10.6 0 3 6 9 12 15 18 21 24 27 30 Time (months) Intent-to-treat population

Estimated probability M77001: overall survival 1.0 0.8 0.6 0.4 0.2 Herceptin® + docetaxel Docetaxel alone Estimated probability p=0.0001 24.1 13.2 0 3 6 9 12 15 18 21 24 27 30 Time (months) 10.9 months Documented crossover = 44% Intent-to-treat population M Marty, J Clin Oncol, 2005

NOUVELLES COMBINAISONS ANTI-HER2

T-DM1 Actualités et perspectives

Introduction (TDM-1) Trastuzumab-DM1 (T-DM1) est un anticorps conjugué (Antibody-Drug Conjugate (ADC)) anti-HER2, en développement dans le traitement du cancer du sein HER2-positif1,2. T-DM1 associe les propriétés de ciblage HER2 du trastuzumab3 et la délivrance ciblée d’un composant anti-microtubule hautement efficace DM13-5. Après liaison à HER2, T-DM1 subit une internalisation6 résultant en une libération intracellulaire du DM1. Highly potent cytotoxic agent Cytotoxic agent: DM1 Monoclonal antibody: Trastuzumab Target expression: HER2 Systemically stable Linker: MCC average drug:antibody ratio ≅3.5:1 1. Krop I. et al. J Clin Oncol 2008. 28:2698-2704 2. Burris HA. et al. J Clin Oncol, 2010, in press 2010 3. Lewis Phillips et al. Cancer Res. 2008. 68:9280-90. 4 . Junttila TT. et al. Breast Cancer Res Treat, 2010 5. Remillard S. et al. 1975. Science 189:1002–1005.3. 6. Austin CD. et al. 2004. Mol Biol Cell 15(12):5268–5282. 14 14

Conjugation of T-DM1 Components Increases Efficacy 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 1500 Vehicle T-DM1 15 mg/kg / 817 µg/m2 Trastuzumab 15 mg/kg 1000 Trastuzumab 15 mg/kg + free DM1 817 µg/m2 Free DM1 817 µg/m2 Mean tumor volume (mm3) ± SEM Free DM1 (near MTD) 1947 µg/m2 Against an animal model of HER2-positive breast cancer specifically engineered to be insensitive to trastuzumab, the components of T-DM1, administered singly or unconjugated but in combination, were ineffective.1 However, in this model, T–DM1 demonstrated a rapid and durable reduction in tumor volume.1 Reference Parsons K, Crocker L, Liepold D, et al. Trastuzumab directed cytotoxic therapy: efficacy against HER2-positive trastuzumab-insensitive breast cancer models and enhanced response in trastuzumab-sensitive models. Presented at: American Association for Cancer Research Annual Meeting; April 14–18, 2007; Los Angeles, CA. Abstract 649. 500 5 10 15 20 25 30 IV dosing Time (days) MTD, maximum tolerated dose; SEM, standard error of means. Parsons et al. Presented at: 2007 AACR Annual Meeting; April 14–18, 2007; Los Angeles, CA. Abstract 649.

Summary of T-DM1 development trials in HER2-positive breast cancer eBC 1st L mBC 2nd L mBC 3rd L mBC BO22857/TDM4874g Phase II cardiac safety TDM4450g (n=137) T-DM1 vs H + docetaxel EMILIA (n=580) T-DM1 vs X + L TDM3569g (n=52) T-DM1 mono weekly vs q3w MARIANNE (n=1092) H + T vs T-DM1 vs T-DM1 + Pertuzumab TDM4258g (n=112) T-DM1 mono 3.6mg/KG q3w TDM4373g (n=67) T-DM1 + Pertuzumab TDM4374g (n=100) T-DM1 mono 3.6mg/KG q3w T-DM1 + paclitaxel + Pertuzumab T-DM1 + docetaxel + Pertuzumab T-DM1 + GDC0941 Enrolling Enrolment completed QTc Study (n=51) T-DM1 mono T = Taxane; X = capecitabine H = Herceptin; L = lapatinib

Pertuzumab Actualités et perspectives

Activité de signalisation Les dimères HER2:HER3 ont la plus forte activité de signalisation mitogénique Homodimères Hétérodimères HER1:HER3 HER4:HER4 HER1:HER2 HER1:HER4 HER3:HER3 HER2:HER3 HER2:HER2 HER2:HER4 HER1:HER1 HER3:HER4 + + + + + + + + In general, the mitogenic signal triggered by receptor heterodimers is superior to that of homodimers1,2 Despite the existence of most, if not all possible dimer combinations of HER proteins, HER2-containing heterodimers are predominant1,2 Receptor overexpression in tumor cells may bias the formation of certain dimers1 HER2 is the only receptor that exhibits tyrosine phosphorylation upon overexpression1 HER2-containing heterodimers are the most potent. HER2:HER1 and HER2:HER3 heterodimers exhibit synergistic mitogenic and transforming effects.1 Out of these 2, HER2:HER3 is the most potent pair1 Transphosphorylation between HER3 and HER1 is relatively limited1 HER3:HER4 dimers occur, although they are mitogenically unproductive1 HER3 homodimers are incapable of signal transduction due to their inactive tyrosine kinase domains2 The variation in dimer mitogenic potential can be explained in part by alternative receptor endocytic routes2 Some ligands trigger receptor degradation, while others induce receptor recycling to the cell surface HER2 dimerization promotes receptor recycling, a possible explanation for its enhanced activity + + + + + + + Activité de signalisation Tzahar et al. Mol Cell Biol. 1996;16:5276-5287. Lenferink et al. EMBO J. 1998;17:3385-3397. References: 1. Tzahar E, Waterman H, Chen X, et al. A hierarchical network of interreceptor interactions determines signal transduction by neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996;16:5276-5287. 2. Lenferink AEG, Pinkas-Kramarski R, van de Poll MLM, et al. Differential endocytic routing of homo- and heterodimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J. 1998;17:3385-3397.

Trastuzumab and pertuzumab bind to different epitopes on HER2 and show complementary mechanism of actions Pertuzumab HER2 Trastuzumab HER3 Dimerisation domain Subdomain IV Trastuzumab does not inhibit ligand-activated HER2 dimerisation Trastuzumab prevents HER2 activation by extracellular domain shedding Trastuzumab inhibits ligand-independent HER2 signalling and flags cells for destruction by the immune system Pertuzumab inhibits ligand-activated HER2 dimerisation Pertuzumab flags cells for destruction by the immune system Pertuzumab suppresses multiple HER signalling pathways, leading to a more comprehensive blockade of HER2-driven signalling Cho et al. Nature 2003;421:756–760; Fendly et al. Cancer Res 1990;50:1550–1558; Franklin et al. Cancer Cell 2004;5:317–328; Nahta et al. Cancer Res 2004;64:2343–2346; Scheuer et al. Cancer Res 2009;69:9330–9336

KPL-4 breast cancer xenograft model Pertuzumab demonstrates synergistic preclinical efficacy in combination with trastuzumab KPL-4 breast cancer xenograft model 600 Vehicle control Pertuzumab (30a/15 mg/kg/w ip) Trastuzumab (30a/15 mg/kg/w ip) Pertuzumab (30a/15 mg/kg/w ip) + trastuzumab (30a/15 mg/kg/w ip) 500 400 Mean tumour volume (mm3) ± SEM 300 200 The breast cancer xenograft model KPL-4 expresses high levels of both HER1, HER2 and HER3. Pertuzumab and trastuzumab (15 mg/kg, intraperitoneal administration) were administered once weekly after a twofold loading dose in KPL-4 xenograft models. Single-agent tumour growth inhibition was 38% for pertuzumab and 45% for trastuzumab. The combination of pertuzumab + trastuzumab was more than additive, with tumour growth inhibition of >100% and complete tumour remission in 6/10 animals. By Day 43, lung metastases were detected in animals treated with trastuzumab or pertuzumab monotherapy. In contrast, no metastases were detected in the lungs of animals receiving the combination of trastuzumab and pertuzumab even at Day 99. Reference Scheuer W, Friess F, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumour activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumour models. Cancer Res 2009;69:9330–9336. 100 10 20 30 40 50 60 70 80 Treatment period (days) Single-agent pertuzumab and trastuzumab demonstrate similar efficacy; combination of the two leads to a a more comprehensive blockade of HER2 signalling ip = intraperitoneal; SEM = standard error of the mean; aLoading dose Scheuer et al. Cancer Res 2009;69:9330–9336

KPL-4 breast cancer xenograft model The pertuzumab and trastuzumab combination is effective following progression on trastuzumab KPL-4 breast cancer xenograft model Vehicle control Trastuzumab (30a/15 mg/kg/w ip) Trastuzumab (30a/15 mg/kg/w ip) with addition of pertuzumab (30a/15 mg/kg/w ip) at Day 35 1400 1200 1000 800 Mean tumour volume (mm3) ± SEM 600 The breast cancer xenograft model KPL-4 expresses high levels of both HER1, HER2 and HER3. SCID mice bearing KPL-4 xenograft tumours were treated with trastuzumab (30 mg/kg loading dose followed by 15 mg/kg weekly, intraperitoneal administration) until progression (day 35). Mice either continued treatment with trastuzumab alone or with trastuzumab in combination with pertuzumab (30 mg/kg loading dose followed by 15 mg/kg weekly, intraperitoneal administration). The combination of the two agents inhibited tumour growth and reduced tumour mass for a further 45 days. Reference Scheuer W, Friess F, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumour activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumour models. Cancer Res 2009;69:9330–9336. 400 200 10 20 30 40 50 60 70 80 90 Treatment period (days) Use of pertuzumab + trastuzumab in combination has antitumour effects following progression on trastuzumab alone ip = intraperitoneal; SEM = standard error of the mean; aLoading dose Scheuer et al. Cancer Res 2009;69:9330–9336

D + H vs D + H + P vs H + P vs D + P Summary of pertuzumab development trials in HER2-positive breast cancer eBC 1st L mBC 2nd L mBC 3rd L mBC NEOSPHERE (n=417) D + H vs D + H + P vs H + P vs D + P CLEOPATRA (n=808) D + H ± P PHEREXA (n=450) Xeloda + H ± P BO17929 cohort 1+2 (n=66) P + H TRYPHAENA (n=225) FEC + D + H + P vs CB + D + H + P BO17929 cohort 3 (n=29) P monotherapy then P + H BIG4-11/BO25126 (n=3916 ) SWAIN Study (n=11) P + H Enrolling Enrolment completed Planned D = docetaxel; Cap = capecitabine; H = Herceptin; P = pertuzumab; FEC=5-fluorouracil, epirubicin and cyclophosphamide

Caractéristiques des patientes Baselga J, NEJM 2012

Cleopatra: la reine des combinaisons Baselga, NEJM, 2012

Sous-groupes: survie sans progression Baselga, NEJM 2012

Cleopatra: la reine des combinaisons Baselga, NEJM, 2012

Taux de réponse globale Baselga, NEJM, 2012

DISCUSSION Augmentation de la médiane SSP: 6 mois Une SSP équivalente du groupe contrôle aux autres études phase III (Marty, Valero, JCO) Pas d’augmentation de la SG mais analyse intermédiaire Un profil de toxicité : pas de majoration de la cardiotoxicité mais incidence plus élevée dans le bras pertu pour: NF, diarrhée Rationnel fort : HER2-HER3 le plus fréquent des hétérodimères inhibé par pertu Peu de patientes traitées par trastuzumab (adj ou neoadj) Perspectives : Aphinity Baselga, NEJM, 2012

CONCLUSION Certains résultats conduisent dès à présent à rediscuter nos standards thérapeutiques Le développement rationnel d'agents sur des critères moléculaires ouvrent de nouvelles indications: meilleure compréhension du mode d’actions des cibles (HER2) L'émergence de nouvelles cibles nourrit l'excitation Manque de données chez des patientes préalablement traitées par trastuzumab