1. Malattia HER-2 positiva Terapia per la fase metastatica Cosa sapremo presto: nuovi farmaci U.O. di Oncologia Medica “Sandro Pitigliani” Dipartimento di Oncologia USL 4 Prato Angelo Di Leo

2. Ongoing – Future strategies Complete HER-2 receptor blockade Inhibiting HER-2 dimerization Multi-targeted bio-therapy without chemotherapy A more potent trastuzumab : TDM-1

3. Lapatinib 1000 mg qd + continuation of trastuzumab 2 mg/kg qw (n=148) MBC HER2-positive (IHC 3+ / FISH positive) Progression on prior Herceptin-based regimen a (n=296) Lapatinib 1500 mg qd (n=148) R EGF104900: study design a Patients received a median of 3 prior lines of trastuzumabor 4-5 prior lines of chemotherapy; IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; qd, every day; qw, every week; PD, progression of disease Crossover if PD after 4 weeks of therapy (77 patients) Blackwell K et al, J Clin Oncol 28: 1124-30, 2010

4. Probability of PFS 02468 Time (months) 0.0 0.2 0.4 0.6 0.8 1.0 1012 EGF104900: PFS 2.8 a 1.9 a trastuzumab+ lapatinib (n=146) Lapatinib (n=145) HR=0.73; p=0.008 a Median PFS in months 148 73 53 42 21 27 13 8585 2020 Blackwell K et al, J Clin Oncol 28: 1124-30, 2010

5. EGF104900: Updated OS (SABCS2009) 0.0 0.2 0.4 0.6 0.8 1.0 0102025 Time (months) 5153035 148 88 65 43 28 125 13 64 47 121 102 Probability of survival 14.0 a 9.5 a a Median OS in months trastuzumab+ lapatinib (n=146) Lapatinib (n=145) HR=0.74; p=0.026 Blackwell K et al, J Clin Oncol 28: 1124-30, 2010

6. EGF104900: results ORR, % CBR, % Median PFS, months Median OS, months Lapatinib 6.9 12.4 1.9 9.5 Lapatinib + Herceptin 10.3 24.7 2.8 14.0 p value 0.46 0.01 0.008 0.026 HR 0.73 0.74 Blackwell K et al, J Clin Oncol 28: 1124-30, 2010

7. EGF104900: safety profile Grade 3/4, diarrhoea, n (%) Symptomatic LVEF decline (LV dysfunction ≥ grade 3 or LVEF decrease ≥ 20% and below LLN), n (%) Cardiac-related deaths, n (%) Lapatinib 10 (7) 3 (2) 0 (0) Lapatinib + Herceptin 12 (8) 10 (7) 1 (0.7) a LLN, lower limit of normal a Death due to pulmonary thromboembolism Blackwell K et al, J Clin Oncol 28: 1124-30, 2010

8. Complete HER-2 receptor blockade : key message Concomitant inhibition of the HER-2 external domain and the HER-2 tyrosine kinase more active than single inhibition either as upfront or as a further-line treatment

9. BO17929: A multicentre Phase II trial of trastuzumab + pertuzumab in HER2-positive MBC that progressed during trastuzumab-based therapy Primary endpoint: –Response rate and clinical benefit rate (response rate + disease stabilisation) HER2-positive MBC progressing on trastuzumab + chemotherapy (Cohort 1, n=24; Cohort 2, n=42) Pertuzumab + trastuzumab 16 patients received pertuzumab + trastuzumab HER2-positive MBC progressing on trastuzumab + chemotherapy (n=29) Pertuzumab PD MBC = metastatic breast cancer; PD = progressive disease 1. Baselga et al. J Clin Oncol 2010;28:1138–1144; 2. Baselga et al. SABCS 2009. Abstract 5114 Cohorts 1 and 2 1 Cohort 3 (added after protocol amendment) 2 Inhibiting HER-2 / HER-3 dimerization: Pertuzumab

10. BO17929 (cohorts 1 and 2): The combination of pertuzumab and trastuzumab demonstrates encouraging efficacy Response n (%) (n=66) Complete response a,b 4 (6.1) Partial response a,b 12 (18.2) Objective response rate16 (24.2) Stable disease for  8 cycles or ~6 months 17 (25.8) Clinical benefit rate (CR + PR + SD ≥6 months)33 (50.0) Progressive disease33 (50.0) Baselga et al. J Clin Oncol 2010;28:1138–1144 Cortes J et al. J Clin Oncol 2010;28(7S):Abstract 1066 a Median duration of response was 5.8 months (2.9–15.3 months); b One patient was reclassified from a CR to a PR CR = complete response; PR = partial response; SD = stable disease

11. BO17929 (cohorts 1 and 2): Adverse events were generally grade 1/2 The most frequent adverse events were grade 1/2 and included diarrhoea, fatigue, nausea, and rash Only 4 of 66 patients had treatment-related adverse events grade  3 Grade 3 adverse events were: Adverse eventn (%)OutcomeTreatment continued Diarrhoea2 (3)ResolvedYes Central line infection 1 (2)ResolvedYes Pruritic rash a 1 (2)ResolvedYes a One patient had a grade 3 pruritic rash following injection of contrast before receiving pertuzumab SAE = serious adverse event; NR = Not reported Baselga et al. J Clin Oncol 2010;28:1138–1144

12. BO17929: A multicentre Phase II trial of trastuzumab + pertuzumab in HER2-positive MBC that progressed during trastuzumab-based therapy Primary endpoint: –Response rate and clinical benefit rate (response rate + disease stabilisation) 1. Baselga et al. J Clin Oncol 2010;28:1138–1144; 2. Baselga et al. SABCS 2009. Abstract 5114 MBC = metastatic breast cancer; PD = progressive disease HER2-positive MBC progressing on trastuzumab + chemotherapy (Cohort 1, n=24; Cohort 2, n=42) Pertuzumab + trastuzumab 16 patients received pertuzumab + trastuzumab HER2-positive MBC progressing on trastuzumab + chemotherapy (n=29) Pertuzumab PD Cohorts 1 and 2 1 Cohort 3 (added after protocol amendment) 2

13. BO17929: Pertuzumab plus trastuzumab demonstrated encouraging efficacy Response, n (%) Cohorts 1 and 2 1,2 (n=66) Cohort 3 2 (pertuzumab) (n=29 a ) Cohort 3 2 (pertuzumab + trastuzumab) (n=16 b ) Complete response4 (6.1) c 0 (0.0) Partial response12 (18.2) c 1 (3.4)3 (21.4) Objective response rate16 (24.2)1 (3.4)3 (21.4) Stable disease for  8 cycles (  6 months) 17 (25.8)2 (6.9)3 (21.4) Clinical benefit rate33 (50.0)3 (10.3)6 (42.8) Progressive disease33 (50.0)24 (82.8)8 (57.1) a Only 27 patients are evaluable: 1 patient did not progress on pertuzumab monotherapy before moving on to combination therapy and 1 patient’s tumour was unassessable after Cycle 2 b n=14 as at data cut-off; 1 patient had not reached overall best response endpoint (8 cycles of assessment during this phase) and 1 patient died before efficacy assessment c One patient was reclassified from a CR to a PR 1. Baselga et al. J Clin Oncol 2010;28:1138–1144; 2. Cortes J et al. J Clin Oncol 2010;28(7S):Abstract 1066 3. Baselga et al. SABCS 2009. Abstract 5114

14. BO17929 (cohort 3): Pertuzumab monotherapy and combination therapy with trastuzumab were both well tolerated Pertuzumab (n=29) n (%) Pertuzumab + trastuzumab (n=16) n (%) Adverse eventAny grade a Grade 3/4Any grade a Grade 3/4 Diarrhoea14 (48)1 (3)5 (31)1 (6) Nausea10 (34)-5 (31)- Vomiting7 (24)-4 (25)- Fatigue5 (17)1 (3)4 (25)1 (6) Asthenia5 (17)-2 (13)- Back pain5 (17)-2 (13)1 (6) Rash3 (10)-3 (19)- Chills--3 (19)- Weight decrease--3 (19)- Baselga et al. SABCS 2009. Abstract 5114 a Adverse event occurring in  15% patients

15. BO17929: Conclusions The combination of trastuzumab and pertuzumab is active in patients with HER2-positive breast cancer who have experienced progression during: –Prior trastuzumab therapy 1 –Prior sequential treatment with single-agent trastuzumab and pertuzumab 2 Pertuzumab monotherapy and combination therapy with trastuzumab were well tolerated and there were no significant cardiac events 1,2 The partnership of pertuzumab and trastuzumab may offer an effective new treatment option for patients with HER2-positive MBC 1. Baselga et al. J Clin Oncol 2010;28:1138–1144; 2. Baselga et al. SABCS 2009. Abstract 5114 MBC = metastatic breast cancer

16. Trastuzumab-DM1 (T-DM1) is a novel anti-HER2 antibody drug–conjugate in development for the treatment of HER2-positive metastatic breast cancer (MBC) 1,2 –Combines the HER2-targeting properties of trastuzumab 3 with targeted delivery of a highly potent anti-microtubule derivative, DM1 3-5 –After binding to HER2, T-DM1 undergoes receptor-mediated internalization, 6 resulting in intracellular release of DM1 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, epub ahead of press 5. Remillard S, et al. 1975. Science 189:1002–1005.3. 6. Austin CD, et al. 2004. Mol Biol Cell 15(12):5268–5282. A more potent trastuzumab: TDM 1

17. TDM4258gTDM4374g N=112N=110 ORR, %25.9%32.7% Clinical benefit rate, %39.3%48.2% Median Duration of Response (95% CI) NR (6.2, NE) NR (4.6, NE) Median PFS (95% CI) 4.6 m (3.9, 8.6) 6.9 m (4.2, 9.5) ORR in patients with retrospectively confirmed HER2+ 32.1%40.3% Studies TDM4374g and TDM4258g: Antitumor Activity by IRF Assessment

18. T-DM1 ISS AE Summary The majority of AEs were grade (Gr) 1−2 Most common AEs (≥ 20% pts) of all grades were fatigue (63.3%), nausea (43.9%), and headache (31.2%) 109 pts (46.0%) experienced at least one Gr ≥ 3 AE –Most common Gr ≥ 3 AEs: thrombocytopenia (7.6%), hypokalaemia (4.6%), fatigue (4.2%), cellulitis (3.4%) SAE were reported in 61 pts (25.7%) –Most common SAEs : cellulitis (3.4%), convulsion (2.5%), pneumonia (2.5%), and dyspnoea (1.7%) 20/237 (8%) patients discontinued treatment for adverse events 5 total deaths within 30 days of last protocol therapy –4 patients attributable to progressive disease or underlying disease –1 due to Grade 5 AE (Hepatotoxicity)

19. Randomized, phase II, international, open-label study HER2+, measurable disease required Stratification factors: –World region, prior adjuvant trastuzumab therapy, disease-free interval Key Primary endpoint: PFS by INV Key Secondary endpoints: ORR, CBR, OS TDM4450g: Study Design HER2-positive, recurrent locally advanced BC or MBC (n=137) Previously untreated T-DM1 3.6 mg/kg Q3W until PD Trastuzumab 8 mg/kg loading dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m 2 Q3W Crossover T-DM1 PD Hurvitz SA et al, proc. ESMO/ECCO 2011, abstr. 5.001

20. Objective Response by Investigator Patients With Measurable Disease at Baseline Trastuzumab + docetaxel (n=69) a T-DM1 (n=67) Patients with an objective response, b n (%)40 (58.0)43 (64.2) 95% CI45.5–69.251.8–74.8 Objective responses, n (%) Complete response3 (4.3)7 (10.4) Partial response37 (53.6)36 (53.7) Stable disease23 (33.3)13 (19.4) Progressive disease4 (5.8)8 (11.9) Unable to evaluate or missing2 (2.9)3 (4.5) Patients with clinical benefit, c n (%)56 (81.2)50 (74.6) 95% CI70.7–89.163.2–84.2 a One patient was not included in the efficacy analysis due to study site withdrawal. b Defined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4 weeks apart. c Defined as objective response any time during the study or maintained stable disease for at least 6 months from randomization.

21. Time (months) Progression-Free Survival by Investigator Randomized Patients Proportion progression-free 1.0 0.8 0.6 0.4 0.2 0.0 02468101214161820 Number of patients at risk T+D706663534327124220 T-DM16760514642352215630 Hazard ratio and log-rank P value were from stratified analysis. Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Median PFS, mos Hazard ratio95% CI Log-rank P value 9.2 14.2 0.594 0.364– 0.968 0.0353

22. Incidence of Hematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of Patients a Green represents those AEs with ≥20% difference between treatment arms. a In either treatment arm. b No adverse events listed were grade 5. c Two patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses. d Includes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel. e Neutropenia includes events classified as MedDRA preferred terms neutropenia or neutrophil count decreased; thrombocytopenia includes events classified as MedDRA preferred terms thrombocytopenia, platelet count decreased or heparin-induced thrombocytopenia; leukopenia includes events classified as MedDRA preferred terms leukopenia or white blood cell count decreased. f All of these events were grade 3. AE All grade, n (%)Grade ≥3 b, n (%) Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Neutropenia e 42 (63.6)12 (17.4)40 (60.6)4 (5.8) Febrile neutropenia9 (13.6)0 0 Thrombocytopenia e 4 (6.1)21 (30.4)2 (3.0) f 6 (8.7) f Leukopenia e 18 (27.3)6 (8.7)17 (25.8)0

23. Incidence of Nonhematologic Adverse Events: ≥30% (All Grade) and/or ≥5% (Grade ≥3) of Patients a Green represents those AEs with ≥20% difference between treatment arms. a In either treatment arm. b No adverse events listed were grade 5. c Two patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses. d Includes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel. e National Cancer Institute Common Terminology Criteria for Adverse Events v.3 only categorizes alopecia as grade 1 or grade 2; there is no grade ≥3 for this AE. AE All grade, n (%)Grade ≥3 b, n (%) Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Trastuzumab + docetaxel (n=66) c T-DM1 (n=69) c,d Alopecia44 (66.7)3 (4.3) ee Fatigue30 (45.5)34 (49.3)3 (4.5)3 (4.3) Nausea29 (43.9)33 (47.8)02 (2.9) Diarrhea30 (45.5)11 (15.9)2 (3.0)0 Peripheral edema29 (43.9)7 (10.1)3 (4.5)0 Increased AST4 (6.1)27 (39.1)06 (8.7) Pyrexia15 (22.7)27 (39.1)1 (1.5)0 Headache12 (18.2)25 (36.2)00 Back pain20 (30.3)18 (26.1)3 (4.5)1 (1.4) Increased ALT4 (6.1)16 (23.2)06 (8.7) Pneumonia1 (1.5)6 (8.7)04 (5.8)

24. Cardiac Safety Cardiac function was assessed locally and centrally based on cardiac ECHO/MUGA Prior anthracycline in the adjuvant setting was 44.8% and 48.6% in the T-DM1 and trastuzumab + docetaxel arms, respectively Asymptomatic LV dysfunction There were no clinically significant cardiac events reported LVEF assessment Trastuzumab + docetaxel T-DM1 Local assessment Patients assessed6567 Patients with post-baseline LVEF ≤40%2a2a 0 Central assessment Patients assessed6065 Patients with post-baseline LVEF ≤40%1b1b 0 a Both patients had prior anthracycline therapy in the adjuvant setting; 1 patient received prior trastuzumab therapy in the adjuvant setting. b This patient did not receive prior treatment with an anthracycline.

25. The future: Do we need more anti-HER-2 compounds or more bio-markers driving our treatment choices? Anti-HER-2 sensitive population: Trastuzumab alone vs. combination Anti-HER-2 partially sensitive/resistant population: Trastuzumab in combination with agents such as Anti-HER-2 ± chemotherapy If Trastuzumab with chemotherapy lapatinib pertuzumab PI3K inhibitors HSP 90 inhibitors anti IGF-1R inhibitors which regimen taxane anthracyclines TDM1 others (DNA damaging agents, vinorelbine,….)