Θεραπεία του μεταστατικού καρκίνου του μαστού. Νικόλαος Δεσσές Παθολόγος - Ογκολόγος Επιστημονικός συνεργάτης ΙΑΣΩ GENERAL

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1 Θεραπεία του μεταστατικού καρκίνου του μαστού Νικόλαος Δεσσές Παθολόγος - Ογκολόγος Επιστημονικός συνεργάτης ΙΑΣΩ GENERAL 1

2 Factors Determining Choice of Treatment in ABC Disease Characteristics Patient Characteristics Prior adjuvant therapy Disease burden Prior therapies and response Aggressiveness of disease ER/PgR, HER2 receptor status Patient preference (eg, oral vs IV treatment) Socioeconomic and psychologic factors (eg, distance between home-hospital; costs) Age, PS, comorbidities Disease-free interval Guidelines/availability and cost of therapy Menopausal status IV, intravenous; PgR, progesterone receptor; PS, performance status. GR

3 Biology of Breast Cancer Inhibition of Multiple Pathways RTKs: EGFR, HER2, IGF1-R ER Src CoA PTEN ER P Endocrine therapy E TSC1/2 S6KI ER PI3K AKT P mtor Ras MAPK P P mtor inhibitor We have entered a new era where endocrine therapy can be combined with targeted therapy ER P EREs P CoA P ER P P CoA AP-1/SP-1 CoA TFs-REs AKT, protein kinase B; CoA, coenzyme A; EGFR, epidermal growth factor receptor; IGF1-R, insulin-like growth factor type 1 receptor; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; S6KI, ribosomal S6 kinase; TSC, tuberous sclerosis protein. Figure adapted from Wander SA, et al. J Clin Invest. 2011;121: ; Osborne CK, et al. Ann Rev Med. 2011;62: ; Yamnik RL, et al. J Biol Chem. 2009;284: GR

4 Possible Mechanisms for Disease Progression During Endocrine Therapy 1. Loss of HR expression 2. Expression of constitutively active HR variants 3. Increased phosphorylation of coactivators for ER 4. Crosstalk between the signal transduction pathways 5. Hyperactivation of the PI3K/AKT/mTOR pathway Fedele P, et al. CROH. 2012;84(2): GR

5 Crosstalk Between ER and PI3K/AKT/mTOR Signalling: Rationale for Dual Inhibition mtor can activate ER signalling in an estrogen-independent manner 1 Blocking the PI3K/AKT/mTOR pathway induces apoptosis Estradiol suppresses this effect 2 Hyperactivation of the PI3K/AKT/mTOR pathway is observed in endocrine-resistant breast cancer cells 3 mtor is a rational target to enhance the efficacy of endocrine therapy EGFR, epidermal growth factor receptor; IGF-1R, insulin-like growth factor-1 receptor; MAPK, mitogen-activated protein kinase. 1. Yamnik RL, et al. J Biol Chem. 2009;284(10): ; 2. Crowder RJ, et al. Cancer Res. 2009;69(9): ; 3. Miller TW, et al. J Clin Invest. 2010;120(7): GR

6 Overcoming Disease Progression in the Context of Endocrine Therapy in HR+ Breast Cancer RTKs: EGFR, HER2, IGF1-R Src ER CoA ER P PI3K Ras AKT MAPK E S6KI ER P P P P P P ER CoA ER P CoA AP-1 TFs P CoA HER2, human epidermal growth factor receptor 2; mtor, mammalian target of rapamycin; TSC, tuberous sclerosis complex; CoA, coenzyme A. Osborne CK, et al. Annu Rev Med. 2011;62: ; Yamnik RL, et al. J Biol Chem. 2009;284: GR

7 HR+/HER2 ABC Treatment Paradigm* Progression After Endocrine Treatment Progression on endocrine therapy in adjuvant/ advanced setting Yes Resistance to ER-directed therapy No Alternate endocrine options Exemestane Fulvestrant Everolimus + exemestane Chemotherapy Restricted to patients in need of rapid symptom control NCCN 1 ABC-1 2 Updates in ABC2 3 Recommend 3 consecutive endocrine therapy regimens before switching to chemotherapy Consider the addition of everolimus to exemestane in women who fulfill the entry criteria for BOLERO-2 No consensus following initial AI therapy; options include TAM Another AI Fulvestrant Megestrol acetate The preferred first-line ET for PMW is an AI or TAM, depending on the type and duration of adjuvant ET. FUL is also an option The addition of EVE to an AI is a valid option for some PMW with disease progression after a NSAI EVE, everolimus; NSAI, nonsteroidal aromatase inhibitor; PMW, postmenopausal women; TAM, tamoxifen. *Guidelines refer to postmenopausal HR+ ABC, and recommend endocrine therapy for patients who are not in visceral crisis. The decision to treat must take into account the relevant toxicities associated with this combination and should be made on a case-by-case basis. 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V ; 2. Cardoso F, et al. Breast. 2012;21(3): ; 3. Cardoso F, et al. Ann Oncol. 2014;25(10): GR

8 NCCN Guidelines Recommend Serial Endocrine Therapy for HR+/HER2 ABC Not in Visceral Crisis Advanced HR+/HER2 Breast Cancer Visceral crisis YES NO Consider chemotherap y Serial endocrine therapy * Progression or unacceptable toxicity No clinical benefit after 3 consecutive endocrine therapy regimens Chemotherap y *Consider the addition of everolimus to exemestane in women who fulfill the entry criteria for BOLERO National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V3.2014; 2. Osborne CK, et al. Annu Rev Med. 2011;62: GR

9 Evidence for BEVACIZUMAB in mbc Phase III randomised trials in first-line mbc E2100 Bevacizumab combined with paclitaxel RIBBON-1 Bevacizumab combined with capecitabine TURANDOT Bevacizumab combined with paclitaxel or capecitabine

10 E2100: trial design 2:1 Randomisation Previously untreated LR/mBC n=722 Paclitaxel (n=354) Bevacizumab + paclitaxel (n=368) Primary endpoint: Secondary endpoint: Stratification factors: PFS* ORR, OS, QoL, safety DFI 24, >24 months; no. of metastatic sites; adjuvant CTX (yes vs no); ER status LR, locally resectable. Avastin 10 mg/kg q2w; Paclitaxel 90 mg/m 2 weekly for 3 weeks of a 4-week cycle; * Independent Review Facility (IRF) Miller, et al. NEJM 2007

11 PFS estimate E2100: Bevacizumab + paclitaxel doubles PFS to >11 months in first-line mbc Bevacizumab + paclitaxel (n=368) Paclitaxel (n=354) Stratified HR * =0.48 ( ) p< % reduction in the risk of progression Time (months) PFS scans available for 90% of patients; * Censored for non-protocol therapy prior to disease progression. Gray, et al. JCO 2009.

12 Median PFS (months) E2100: Bevacizumab doubles PFS 13, 9,8 +95% 11,3 +100% 10,6 +64% 12,1 6,5 7,4 5,8 5,3 3,3 0, n=354 n=368 n=110 n=122 n=227 n=232 Pac Bev + Pac Pac Bev + Pac Pac Bev + Pac HR (95% CI) Overall ( ) TNBC ( ) HR ( ) 1. Cameron, Eur J Cancer Suppl 2008; 2. Gray, et al. JCO 2009; 3. O Shaughnessy, et al. Cancer Res 2009

13 Objective response (%) E2100: Bevacizumab doubles ORR % % % n=354 n=368 n=110 n=122 n=227 n=232 Pac Bev + Pac Pac Bev + Pac Pac Bev + Pac Overall TNBC HR+ Gray, et al. JCO 2009; Miles, et al. Ann Oncol 2013

14 RIBBON-1: trial design 1:1 Randomisation Investigator s choice of chemotherapy Taxane/anthra + placebo Previously untreated LR/mBC n=1,237 Taxane/anthra + Bevacizumab Placebo + Capecitabine Bevacizumab + Xeloda Primary endpoint: Secondary endpoint: Stratification factors: PFS* ORR, OS, QoL, 1-year survival, duration of response, safety DFI 12, >12 months; previous adjuvant CTX; no. of metastatic sites *Investigator assessed; Capecitabine, taxane or anthra. Bevacizumabn 15 mg/kg q3w; Capecitabine: 1,000 mg/m 2 b.i.d days 1 14 of a 3- week cycle. Patients treated until disease progression; optional second-line CTX + Bevacizumab. Robert, et al. J Clin Oncol 2011.

15 PFS estimate RIBBON-1: Bevacizumab + Capecitabine significantly improves PFS in first-line mbc Bevacizumab + Capecitabine* (n=409) Capecitabine (n=206) Stratified HR * =0.69 ( ) p< % reduction in the risk of progression Time (months) *Censored for non-protocol therapy prior to disease; Robert, et al. J Clin Oncol 2011.

16 Median PFS ( months) RIBBON-1: Bevacizumab + Capecitabine prolongs PFS 10, 7,5 +51% 8,6 +48% 9,2 5, 5,7 +45% 6,1 6,2 4,2 2,5 0, n=206 n=409 n=50 n=87 n=146 n=312 Cap Bev + Cap Cap Bev + Cap Cap Bev + Cap HR (95% CI) Overall 0.69 ( ) TNBC 0.72 ( ) HR ( ) Bevacizumab 15 mg/kg arm Robert, et al. J Clin Oncol 2011

17 Grade 3 adverse events* (%) E2100 and RIBBON-1: Bevacizumab has a well-defined and manageable safety profile 100, RIBBON-1 Bev+Cap RIBBON-1 Cap E2100 Bev+Pac E2100 Pac (n=404) 1 (n=201) 1 (n=365) 2 (n=348) 2 75, 50, 25, 0, 10,1 16, 24,2 17,5 17,4 3, 1 1,4 1,2 2,2 3, 1 1 2,3 0 0, 0,2 1 0,3 Hypertension Sensory neuropathy 8, Neutropenia Proteinuria Bleeding ATE/ VTE 6,5 5 6,6 4,3 NR NR 1,1 0, Wound healing complications NR, not reported; ATE, arterial thromboembolism; VTE, venous thromboembolism;*grade 3 AEs of special interest in Avastin treated patients in clinical trials; With or without infection in E2100; ATE grade >2. 1. Robert, el al. J Clin Oncol 2011; 2. Miles. Eur J Canc Suppl 2008.

18 HER2 OVEREXPRESSION IN BREAST CANCER Approximately 15-20% of breast cancers overexpress HER2 normal (1x) ~ 25,000-50,000 HER2 receptors overexpressed HER2 (10-100x) Up to ~ 2,000,000 HER2 receptors Pegram MD, et al. Cancer Treat Res. 2000;103: Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235: Excessive cellular division

19 An Important Finding HER2 gene amplification FISH Shortened Median Survival* HER2 positive 3 years HER2 normal 6 7 years HER2-positive protein overexpression IHC Key Decision: Target the cell surface constitutively active HER2/ErbB2 protein with a monoclonal antibody Slamon D, et al. Science 1987; 235: ; Pauletti, G et al. J Clin Oncol 2000; 18: * Combined metastatic and adjuvant patients.

20 HER2 The HER2 receptor has a key role in tumour progression and is an important therapeutic target in breast cancer Effective and comprehensive blockade of HER2 is an important objective in HER2-positive breast cancer 1 Blocking both ligand-dependent and ligand-independent HER2 signalling pathways suppresses cancer cell proliferation and survival 1 6 HER2-targeted monoclonal antibodies have the potential to activate antibodydependent cellular cytotoxicity (ADCC) 7 HER2-targeted therapies include: Trastuzumab Lapatinib Pertuzumab Trastuzumab emtansine (T-DM1) 1. Baselga. Cancer Cell 2002; 2:93 95; 2. Agus et al. Cancer Cell 2002; 2: ; 3. Hughes et al. Mol Cancer Ther 2009; 8: ; 4. Herbst RS et al. Clinical Cancer Res 2007; 13: ;5. Citri et al. Exp Cell Res 2003; 284:54 65; 6. Franklin et al. Cancer Cell 2004; 5: ; 7. Scheuer et al. Cancer Res 2009; 69:

21 State of the art before trastuzumab

22 State of the art before trastuzumab In the overall mbc population, irrespective of HER2 status: Median OS was up to approximately 2 years in overall population of mbc 1 5 Median PFS in first line chemotherapy was up to approximately 10 months for the more effective options Ackland S, et al. J Clin Oncol 2001; 19: ; 2. French Epirubicin Study Group. J Clin Oncol 2000; 17: ; 3. Piccart-Gebhart, MJ, et al. J Clin Oncol 2008; 26: ; 4. O Shaugnessy J, et al. J Clin Oncol 2002; 20: ; 5. Chan S, et al. J Clin Oncol 2009; 27:

23 Sixteen years of innovation in the development of HER2-targeted agents Lapatinib in combination with trastuzumab approved for HER2- positive, HR-negative mbc (EMA) 12 Lapatinib: the first approved TKI for HER2-positive mbc 5,6 Trastuzumab emtansine (T-DM1) : the first approved ADC for HER2-positive mbc 9, Trastuzumab: the first approved mab for HER2-positive mbc 1,2 Trastuzumab approved in HER2-positive ebc 3,4 Pertuzumab : the first approved HDI for HER2-positive mbc 7,8 ADC, antibody drug conjugate; HDI, HER2 dimerisation inhibitor; FDA, Food and Drug Administration; mab, monoclonal antibody; TKI, tyrosine kinase inhibitor 1. Slamon DJ, et al. N Engl J Med 2001; 344: ; 2. FDA Herceptin PI; 3. FDA news release. Nov nouncements/2006/ucm htm; 4. Roche press release. May Geyer C, et al. N Engl J Med 2006; 355: ; 6. FDA Tykerb PI; 7. Baselga J, et al. N Engl J Med 2012; 366: ; 8. FDA PERJETA PI; 9. Verma S, et al. N Engl J Med 2012; 367: Erratum in: N Engl J Med 2013; 368:2442; 10. FDA Kadcyla PI; 11. FDA news release. Sept ouncements/ucm htm; 12. GSK press release. Aug Pertuzumab approved in the neoadjuvant breast cancer setting (FDA) 11

24 From HER2 to TRASTUZUMAB HER2 gene is cloned 2 HER2 protein found to be overexpressed in breast tumours 3 Anti-HER2 monoclonal mouse antibody developed 5 Herceptin clinical trials begin HER2/neu gene identified 1 HER2 overexpression associated with more aggressive phenotype 4 Anti-HER2 monoclonal mouse antibody humanised: Herceptin 6 1. Ullrich A, et al. 1984; 2. Ishii S, et al. 1985; 3. Sainsbury JR, et al Di Fiore PP, et al. 1987; 5. Hudziak RM, et al. 1989; 6. Carter P, et al. 1992

25 HERCEPTIN is an anti-her2 antibody with several distinct mechanisms of action Activation of antibody-dependent cellular cytotoxicity (ADCC) Induction of apoptosis Inhibition of cell proliferation by preventing HER2-activated intracellular signalling Inhibition of HER2-regulated angiogenesis Trastuzumab binds to subdomain IV of HER2 1. Nahta and Esteva. Cancer Lett 2006; 232: ; 2. Fry. Breast Cancer Res 2001; 3: ; 3. Gershtein et al. Clin Chim Acta 1999; 287:59 67; 4. Yakes et al. Cancer Res 2002; 62: ; 5. Longva et al. Int J Cancer 2005; 116: ; 6. Molina et al. Cancer Res 2001; 61: ; 7. Nahta and Esteva. Breast Cancer Res 2006; 8:215; 8. Clynes et al. Nat Med 2000; 6: ; 9. Gennari et al. Clin Cancer Res 2004; 10: ; 10.Arnould et al. Br J Cancer 2006; 94:

26 TRASTUZUMAB In patients with HER2-positive breast cancer, treatment with trastuzumab in addition to chemotherapy, and trastuzumab in addition to aromatase inhibitors, has been proven to: 1 4 Increase objective response rate and duration of response Significantly increase progression-free survival Significantly increase time to progression Significantly increase overall survival* Result in a manageable safety and tolerability profile * Shown for trastuzumab in addition to chemotherapy only 1. Kaufman B, et al. J Clin Oncol 2009; 27: ; 2. Marty M, et al. J Clin Oncol 2005; 23: ; 3. Slamon DJ, et al. N Engl J Med 2001; 344: ; 4. Smith IE. Anticancer Drugs 2001; 12(Suppl. 4):S3

27 Adjuvant trastuzumab for 1 year: the standard of care in HER2(+)EBC-4 pivotal studies HERA (ex-usa) 1 BCIRG 006 (global) 2 IHC / FISH N = 5102 Observation 1 year 2 years* FISH N = year 1 year NCCTG N9831 (USA) 3 NSABP B-31 (USA) 3 IHC / FISH N = year IHC / FISH N = year 1 year Chemotherapy +/- RT Doxorubicin + cyclophosphamide Docetaxel Docetaxel + carboplatin Tratuzumab Paclitaxel EBC, early breast cancer; IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation *HERA 2-year data are pending 1. Gianni L, et al Slamon D, et al Perez EA, et al. 2011

28 Consistent DFS benefit with trastuzumab 1 year versus observation Study Follow-up (years) N HR HERA CT* ± RT H (1 year) vs. CT* ± RT BCIRG AC TH vs. AC T TCH vs. AC T Joint analysis 7 9 (NCCTG N9831/ NSABP B-31) HR (95% CI) 0 Favours trastuzumab 1 Favours observation 2 AC PH vs. AC P * Selected from a list of approved regimens consisting of 4 cycles 1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353: ; 2. Smith I, et al. Lancet 2007; 369:29 36; 3. Gianni L, et al. Lancet Oncol 2011; 12: ; 4. Goldhirsch A, et al. Lancet 2013; 382: ; 5. Piccart-Gebhart MJ, et al. SABCS 2012 (Abstract S5-2); 6. Slamon D, et al. N Eng J Med 2011; 365: ; 7. Romond EH, et al. N Engl J Med 2005; 353: ; 8. Perez EA, et al. J Clin Oncol 2011; 29: ; 9. Perez EA, et al. J Clin Oncol 2014; 32:

29 Consistent OS benefit with trastuzumab 1 year versus observation Study Follow-up (years) N HR HERA 1 5 CT* ± RT H (1 year) vs. CT* ± RT BCIRG AC TH vs. AC T TCH vs. AC T Joint analysis 6,7 (NCCTG N9831/ NSABP B-31) HR (95% CI) 0 Favours trastuzumab 1 Favours observation 2 AC PH vs. AC P * Selected from a list of approved regimens consisting of 4 cycles 1. Smith I, et al. Lancet 2007; 369:29 36; 2. Gianni L, et al. Lancet Oncol 2011; 12: ; 3. Goldhirsch A, et al. Lancet 2013; 382: ; 4. Piccart-Gebhart MJ, et al. SABCS 2012 (Abstract S5-2); 5. Slamon D, et al. N Eng J Med 2011; 365: ; 6. Perez EA, et al. J Clin Oncol 2011; 29: ; 7. Perez EA, et al. J Clin Oncol 2014; 32:

30 HannaH Ismael G. et al. Lancet Oncol 2012;13:

31 Surgery HannaH : Study design Randomised, open label, ph III, non-inferiority study to compare the PK, efficacy and safety of trastuzumab SC and IV in HER2(+) EBC Trastuzumab SC HER2- positive EBC (N=596) R 1:1 Trastuzumab IV Follow-up: 60 mo (24 mo for EFS, OS) Trastuzumab SC Fixed dose of 600 mg (5 ml over 5 minutes) Trastuzumab IV 8 mg/kg loading dose; 6 mg/kg maintenance dose Docetaxel 75 mg/m 2 FEC 500/75/500 1 year (18 cycles) Trastuzumab Safety, tumour response pcr Safety, EFS, OS PK Primary endpoint Show non-inferiority of SC vs. IV based on co-primary endpoints PK: observed trastuzumab C trough pre-dose Cycle 8 (pre-surgery) Efficacy: pathological complete response (pcr) in the breast pcr, pathological complete response EFS, event-free survival; OS, overall survival Ismael G, et al. 2012

32 HannaH: Primary and secondary efficacy endpoints Parameter Trastuzumab IV n=263 Trastuzumab SC n=260 Primary endpoint pcr in the breast, * n (%) 107 (40.7%) 118 (45.4%) Difference in pcr rates, SC IV (95% CI)* 4.7% ( 4.0%; 13.4%) Non-inferiority of SC vs. IV demonstrated: lower bound of 95% CI greater than pre-specified non-inferiority margin of 12.5% Secondary endpoints tpcr (pcr in breast and axilla),* n (%) 90 (34.2%) 102 (39.2%) Difference in tpcr rates, SC IV (95% CI) 5.0% ( 3.5; 13.5) Overall response rate, n (%) 231 (88.8%) 225 (87.2%) Time to response Median (weeks) Event-free survival, overall survival Median Not reached Not reached * Efficacy per protocol population; pathological tumour response was assessed locally Residual ductal carcinoma in situ (DCIS) is acceptable for pcr Ismael G, et al. 2012

33 Serum C trough levels pcr in the breast HannaH: Both co-primary endpoints met Trastuzumab SC demonstrated a comparable efficacy and PK profile to the IV formulation PK Efficacy 100 Geometric mean ratio: 1.33* (90% CI: 1.24, 1.44) 100 Difference in pcr rate: 4.7% (95% CI: 4.0, 13.4) µg/ml µg/ml % 40.7% Trastuzumab SC (n = 234) Trastuzumab IV (n = 235) Trastuzumab SC (n = 260) Trastuzumab IV (n = 263) * Non-inferiority margin for the ratio between groups of 0.80 Non-inferiority margin for the difference between groups of 12.5% CI, confidence interval Ismael G, et al. Lancet Oncol 2012; 13:

34 HannaH: Safety and tolerability 12 months follow-up trastuzumab IV n=298 trastuzumab SC n=297 Total patients with at least one AE, n (%) (93.9) 289 (97.3) Severe (Grade 3) AE 155 (52.0) 154 (51.9) Serious AEs (SAEs) 37 (12.4) 62 (20.9) Deaths due to AEs 1 (< 1) 3 (1.0) Imbalance in SAE reports was not explained by underlying patient baseline or treatment characteristics Cardiac safety, n (%) Asymptomatic LVEF decrease* 1 6 (2.1) 7 (2.4) Symptomatic CHF, NYHA class II (0.7) Cardiac AEs (Grade 3) 2 3 (1.0) 5 (1.7) Overall, the safety profiles of the trastuzumab SC and IV formulations are comparable, and consistent with the known safety profile of trastuzumab IV * LVEF decrease of 10 points from baseline to below 50% 1. Ismael G, et al. 2012; 2. Jackisch C, et al. 2012

35 Is there a need to do more in HER2-positive mbc? Despite the use of trastuzumab, approximately 50% of patients diagnosed with HER2- positive mbc progress within 12 months Slamon Chemotherapy +/ trastuzumab Marty Chemotherapy +/ trastuzumab Can time to progression and overall survival in HER2-positive mbc be improved? 3 Chemotherapy alone Chemotherapy plus trastuzumab Pertuzumab-based regimen: pertuzumab plus trastuzumab combined with chemotherapy Median time to progression (months) 1. Slamon D, et al. N Engl J Med 2001; 344: ; 2. Marty M, et al. J Clin Oncol 2005; 23: ; 3. Baselga J, et al. N Engl J Med 2012; 366:

36 De novo and acquired resistance is observed and represents an important clinical challenge Rexer BN, Artega CL; Crit Rev Oncog, 2012

37 Anti-HER 2 drugs in late-stage clinical development or already approved for clinical practice Pertuzumab* IGF-1R HER2 EGFR VEGFR Trastuzumab emtansine* FLT-3 c-kit Lapatinib* PDGFR- Tumour cell membrane PI3K PIP 2 Ras IP 3 DAG Afatinib/Neratinib Akt RAF Src Endothelial cell and pericyte membrane PKC mtor MEK Approved MAPK Under investigation Everolimus ERK *Not approved in all countries Cell differentiation Nucleus Transcription factors Angiogenesis Cell proliferation Cell survival (apoptosis inhibition) Cell adhesion/ penetration/metastasis Perez et al. Cancer 2012; Hernandez-Aya & Gonzalez-Angulo Oncologist 2011

38 Pertuzumab: A HER2 dimerization inhibitor Pertuzumab is the first in a new class of targeted anticancer therapeutic agents HER2 dimerization inhibitors (HDI) By blocking HER2 dimerization, pertuzumab inhibits key HER signaling pathways that mediate cancer cell proliferation and survival Pertuzumab prevents the formation of HER2:HER3 receptor pairs the most active HER complex regarding transformation potential HER1,3,4 Pertuzumab HER2 Pertuzumab binds to the dimerisation domain Franklin et al. Cancer Cell 2004;5: Agus et al. Cancer Cell 2002;2:

39 HER2-containing dimers induce potent mitogenic signalling resulting in cell survival and proliferation Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER Signalling activity Most common and most potent oncogenic dimer in HER2-positive breast cancer HER2 is therefore a rational target for anti-cancer therapy Tzahar E, et al. Mol Cell Biol 1996; 16: ; Citri A, et al. Exp Cell Res 2003; 284:54 65.

40 HER2 is activated in two different ways Overexpression: o o Arising from gene amplification, which results in constitutive activation of HER2 (ligand independent) Antagonized by trastuzumab Co-receptor: o o For other HER family members especially HER3 (ligand dependent) Antagonized by pertuzumab

41 Hypotheses HER2-positive breast cancers are driven by both ligand-independent and ligand-dependent HER2-HER3 complexes Dual blockade of these complexes with trastuzumab and pertuzumab should result in greater clinical activity than treatment with trastuzumab alone

42 Pertuzumab and trastuzumab bind to different domains on HER2 and have complementary MoAs HER1, 3, 4 Pertuzumab HER2 Trastuzumab Pertuzumab binds to subdomain II and inhibits ligand-dependent signalling 1 Trastuzumab binds to subdomain IV and inhibits ligand-independent intracellular signalling 2 The pertuzumab trastuzumab combination offers a more comprehensive HER2 blockade 3,4 1. Franklin MC, et al. Cancer Cell 2004; 5: ; 2. Junttila TT, et al. Cancer Cell 2010; 15: ; 3. Nahta R, et al. Cancer Res 2004; 64: ; 4. Scheuer W, et al. Cancer Res 2009; 69:

43 CLEOPATRA: Pivotal study of pertuzumab in first-line HER2-positive mbc Placebo + trastuzumab (n = 406) PD Patients with previously untreated HER2-positive mbc centrally confirmed (N = 808) R 1:1 Docetaxel* 6 cycles recommended * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion Pertuzumab + trastuzumab (n = 402) PD Docetaxel* 6 cycles recommended Randomization stratified by geographic region and neo/adjuvant chemotherapy Study dosing q3w: Pertuzumab/placebo: 840 mg loading 420 mg maintenance Trastuzumab: 8 mg/kg loading 6 mg/kg maintenance Docetaxel: 75 mg/m mg/m 2 escalation if tolerated Primary endpoint PFS (independently assessed) PD, progressive disease. Baselga J, et al. N Engl J Med 2012; 366:

44 OS (%) Final OS Analysis Median follow-up 50 months (range 0 70 months) Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = n at risk Ptz + T + D Pla + T + D Time (months) ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab. ESMO2014

45 OS (%) Final OS Analysis Median follow-up 50 months (range 0 70 months) Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = months Δ months months n at risk Ptz + T + D Pla + T + D Time (months) ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab.

46 PFS (%) Updated PFS Investigator-Assessed Ptz + T + D: median 18.7 months Pla + T + D: median 12.4 months Δ 6.3 months Time (months) HR % CI = 0.58, 0.80 p < n at risk Ptz + T + D Pla + T + D ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.

47 Patients with 1 episode (%) CLEOPATRA: No episodes of febrile neutropenia after discontinuation of docetaxel Febrile neutropenia (grade 3) by cycle of treatment Most events of febrile neutropenia occurred during the first cycles of the pertuzumab-based regimen and with trastuzumab and docetaxel 1 Docetaxel was administered for a median of 8 cycles in both treatment arms Patients were to receive a minimum of 6 cycles of docetaxel No episodes of febrile neutropenia were reported after discontinuation of docetaxel, with either the pertuzumab-based regimen or trastuzumab and docetaxel alone 1, Pertuzumab, trastuzumab and docetaxel (n = 408) Placebo, trastuzumab and docetaxel (n = 396) Cycle 1. Swain S, et al. SABCS 2012; Poster P ; 2. Swain S, et al. Lancet Oncol 2013; 14:

48 (mo nth s) Impact of HER2-targeted therapies on overall survival in the first-line mbc setting Trastuzumab + taxane 3, months Trastuzumab + taxane + carboplatin 5 ~37 months Pertuzumab + trastuzumab + taxane 4 (median OS 56.5months) Anthracycline or taxane 1 ~15 months Taxane alone 2 ~18 months AC 2 ~21 months Single-agent chemotherapy 2 chemotherapies HER2-targeted agent + chemotherapy Two HER2-targeted agents + chemotherapy Disclaimer: This figure is for illustrative purposes only and is not intended for formal cross-trial comparison AC, anthracycline + cyclophosphamide 1. Chan S, et al. J Clin Oncol 1999; 17: ; 2. Slamon DJ, et al. N Engl J Med 2001; 344: ; 3. Marty M, et al. J Clin Oncol 2005; 23: ; 4. Swain SM, et al. Lancet Oncol 2013; 14: ; 5. Valero V, et al. J Clin Oncol 2011; 29:

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50 NeoSphere

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53 T-DM1 MOA: Binding of T-DM1 The trastuzumab component of T-DM1 binds to HER2 receptors on the tumour cell surface Leads to downstream signalling inhibition/blockade MOA, mode of action. Lewis Phillips GD, et al. Cancer Res 2008; 68:

54 T-DM1 MOA: Endocytosis & Lysosomal degradation HER2 receptor T-DM1 complex is internalised into the tumour cell via endocytosis Once endocytosis is complete, trastuzumab and the HER2 receptor are degraded and a cytotoxic metabolite* is released * Lysine-bound emtansine plus linker MOA, mode of action. Erickson HK, et al. Cancer Res 2006; 66:

55 T-DM1 MOA: Inhibition of microtubule polymerisation & Cell cycle arrest and cell death Inside the tumour cell, DM1 binds to microtubules and inhibits their polymerisation The inhibition of microtubule polymerisation results in cell cycle arrest and cell death DM1, derivative of maytansine, a microtubule polymerisation inhibitor; MOA, mode of action. Lewis Phillips GD, et al. Cancer Res 2008; 68:

56 EMILIA (BO21977): Study design HER2-positive LABC or MBC (N = 991) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 PO bid, days 1 14, q3w + Lapatinib 1250 mg/day PO qd PD PD Stratification factors: world region, number of prior chemotherapy regimens for MBC or unresectable LABC, presence of visceral disease Primary endpoints: PFS by independent review, OS and safety Key secondary endpoints: PFS by investigator, ORR, DoR Statistical considerations: hierarchical statistical analysis was performed in pre-specified sequential order: PFS by independent review OS secondary endpoints PFS analysis: 90% power to detect HR = 0.75; 2-sided alpha 5% OS analysis: 80% power to detect HR = 0.80; 2-sided alpha 5% DoR, duration of response; HR, hazard ratio; IV, intravenous; LABC, locally advanced breast cancer; MBC, metastatic breast cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; q3w, 3-weekly dosing; qd, daily. Verma S, et al. N Engl J Med 2012; 367:

57 EMILIA (BO21977): Drug exposure Cap (n = 487) Lap (n = 488) T-DM1 (n = 490) Median dose intensity, % Pts with dose reduction, n (%) 260 (53.4) 133 (27.3) 80 (16.3) T-DM1 decreased to 3.0 mg/kg, n (%) 58 (11.8) T-DM1 decreased to 2.4 mg/kg, n (%) 22 (4.5) Verma S, et al. N Engl J Med 2012; 367: (supplementary material available with the publication online); Blackwell KL, et al. ASCO 2012 (Abstract LBA1; oral presentation)

58 Proportion progression-free EMILIA (BO21977): PFS survival by IRF 1.0 Median (months) No. events 0.8 Cap + lap T-DM Stratified HR = (95% CI = ) p < No. at risk by IRF: Time (months) Cap + lap T-DM Unstratified HR = 0.66 (p <0.0001). CI, confidence interval; HR, hazard ratio; IRF, independent review facility; PFS, progression-free survival. Verma S, et al. N Engl J Med 2012; 367: (supplementary material available with the publication online); Blackwell KL, et al. ASCO 2012 (Abstract LBA1; oral presentation).

59 Proportion surviving EMILIA (BO21977): Overall survival Confirmatory analysis Median (mo) No. events Cap + lap % T-DM Stratified HR = (95% CI = ); p = % Efficacy stopping boundary p = or HR = % 64.7% No. at risk: Data cut-off July 31, 2012; Unstratified HR = 0.70 (p = ). Time (months) Cap + lap T-DM CI, confidence interval; HR, hazard ratio. Verma S, et al. N Engl J Med 2012; 367: (supplementary material available with the publication online); Verma S, et al. ESMO 2012 (Abstract LBA12; oral presentation).

60 Patients (%) Proportion progression-free EMILIA (BO21977): ORR and DoR in patients with measurable disease ORR Difference: 12.7% (95% CI = ) p = DoR Median, months (95% CI),50 Series % 1.0 Cap + lap 6.5 ( ) T-DM ( ) 0.8, % 0.6,30 0.4,20 0.2,10,0 120/389 Cap + lap 173/397 T-DM Time (months) No. at risk Cap + lap T-DM CI, confidence interval; DoR, duration of response; ORR, objective response rate. Verma S, et al. N Engl J Med 2012; 367: (supplementary material available with the publication online); Blackwell KL, et al. ASCO 2012 (Abstract LBA1; oral presentation).

61 EMILIA (BO21977): Overview of AEs Cap + lap (n = 488) T-DM1 (n = 490) All-grade AE, n (%) 477 (97.7) 470 (95.9) Grade 3 AE, n (%) 278 (57.0) 200 (40.8) AEs leading to treatment discontinuation (for any study drug), n (%) 52 (10.7) 29 (5.9) AEs leading to death within 30 days of last dose of study drug, n (%)* 4 (0.8) 1 (0.2) *Cap + lap: coronary artery disease, multi-organ failure, coma and hydrocephalus; T-DM1: metabolic encephalopathy AE, adverse event. Verma S, et al. N Engl J Med 2012; 367: (supplementary material available with the publication online); Verma S, et al. ESMO 2012 (Abstract LBA12; oral presentation).

62 EMILIA (BO21977): Non-haematological AEs Grade 3 AEs with incidence 2% Cap + lap (n = 488) T-DM1 (n = 490) AE, % All grades Grade 3 All grades Grade 3 Diarrhoea Hand-foot syndrome Vomiting Hypokalaemia Fatigue Nausea Mucosal inflammation Increased AST Increased ALT AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Verma S, et al. N Engl J Med 2012; 367:

63 EMILIA (BO21977): Haematological AEs Cap + lap (n = 488) T-DM1 (n = 490) AE, % All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Neutropenia Febrile neutropenia Anaemia Thrombocytopenia AE, adverse event. Verma S, et al. N Engl J Med 2012; 367: (supplementary material available with the publication online); Blackwell KL, et al. ASCO 2012 (Abstract LBA1; oral presentation)

64 EMILIA (BO21977): Cardiac dysfunction Cap + lap T-DM1 Cardiac dysfunction AEs,* n (%) All grades Grade 3 (n = 488) 15 (3.1) 2 (0.4) (n = 490) 9 (1.8) 1 (0.2) Lowest post-baseline LVEF value, n (%) 45% 40 to <45% <40% (n = 461) 454 (98.5) 4 (0.9) 3 (0.7) (n = 482) 476 (98.8) 3 (0.6) 3 (0.6) LVEF <50% and 15-point decrease from baseline, n (%) (n = 445) 7 (1.6) (n = 481) 8 (1.7) * Includes preferred terms decreased ejection fraction and left ventricular dysfunction ; does not include cardiac AEs (e.g. myocardial infarction, atrial fibrillation) AE, adverse event; LVEF, left ventricular ejection fraction. Verma S, et al. N Engl J Med 2012; 367: (supplementary material available with the publication online); Verma S, et al. ESMO 2012 (Abstract LBA12; oral presentation)

65 TH3RESA (BO25734): T-DM1 versus treatment of physician s choice (3 rd line) HER2-positive (central) advanced BC* (N = 600) 2 T-DM1 3.6 mg/kg q3w IV (n = 404) PD 2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib and a taxane 1 Treatment of physician s choice (TPC) (n = 198) PD T-DM1 (optional crossover) Stratification factors: world region, number of prior regimens for MBC, presence of visceral disease Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR, DoR, landmark survival rate, safety *Advanced BC includes MBC and unresectable locally advanced/recurrent BC. TPC could have been single-agent chemotherapy, hormonal therapy or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. First patient in: Sep Study amended Sep 2012 (following EMILIA 2 nd interim OS results) to allow patients in the TPC arm to receive T-DM1 after documented PD. Excluding single-agent hormonal therapy. BC, breast cancer; DoR, duration of response; IV, intravenous; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; q3w, every 3 weeks. Wildiers H, et al. ECC 2013 (Abstract 15; oral presentation). Krop IE, et al. Lancet Oncol 2014; 15:

66 Proportion progression-free TH3RESA (BO25734): PFS by investigator assessment Median (95% CI), months TPC (n = 198) T-DM1 (n = 404) 3.3 ( ) 6.2 ( ) No. of events Stratified HR = (95% CI = ) p < No. at risk: Time (months) Median TPC follow-up: 198 TPC, 6.5 months; T-DM1, months. Unstratified 62 HR* = (95% 28 CI = ) p < * Provided as a sensitivity analysis. T-DM CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; TPC, treatment of physician s choice. Krop IE, et al. Lancet Oncol 2014; 15:

67 Proportion surviving TH3RESA (BO25734): First interim OS analysis* 1.0 Observed 21% of targeted events TPC (n = 198) T-DM1 (n = 404) Median (months) 14.9 (11.27 NE) NE No. of events Stratified HR = (95% CI = ); p = Efficacy stopping boundary HR or p < No. at risk: Time (months) 16 TPC * 1 st interim OS analysis (prespecified to occur with final PFS analysis) Number of observed events: 105. Efficacy crossing boundary HR < 0.363; p < T-DM Forty-four patients in the TPC arm received crossover T-DM1 treatment after documented progression. Unstratified HR = 0.57 (p = 0.004). Clinical data cut-off: 11 February CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival; TPC, treatment of physician s choice. 1. Krop IE, et al. Lancet Oncol 2014; 15: Wildiers H, et al. ECC 2013 (Abstract 15; oral presentation).

68 TH3RESA (BO25734): Overview of AEs Adverse events, n (%) TPC (n = 184*) T-DM1 (n = 403*) All-grade AEs 163 (88.6) 377 (93.5) Grade 3 AEs 80 (43.5) 130 (32.3) Serious adverse event 38 (20.7) 74 (18.4) AEs leading to treatment discontinuation 20 (10.9) 27 (6.7) AEs leading to dose reduction 36 (19.6) 38 (9.4) LVEF <50% and 15% decrease from baseline 2 (1.1) 6 (1.5) * One patient randomised to the TPC arm received two cycles of T-DM1 by mistake; this patient was included in the T-DM1 group for safety analyses. Grade 5 AEs: TPC, 1.6% (n = 3); T-DM1, 1.2% (n = 5). Three were considered related to T-DM1: hepatic encephalopathy, subarachnoid haemorrhage and pneumonitis. One was considered related to TPC: non-cardiogenic pulmonary oedema 2. For any study drug 2. No patient experienced an LVEF <40%. AE, adverse event; LVEF, left ventricular ejection fraction; TPC, treatment of physician s choice. 1. Krop IE, et al. Lancet Oncol 2014; 15: Wildiers H, et al. ECC 2013 (Abstract 15; oral presentation).

69 ΣΑΣ ΕΥΧΑΡΙΣΤΩ ΓΙΑ ΤΗΝ ΠΡΟΣΟΧΗ ΣΑΣ! 69