Targeted adjuvant systemic therapy: Current status and future directions of Trastuzumab May 25 th 2007 “Highlights in the Management of Breast Cancer” Mediterranean School of Rome Giuseppe Tonini University Campus Bio-Medico of Rome

Background Breast cancer is an heterogeneous disease with different tumor subtypes and different natural histories Overexpression of HER2/neu defines one of these subtypes The HER2/neu gene belongs to a family of genes which encode for transmembrane receptors and includes HER1-4 Slamon DJ et al: Science. 1987; 235.

HER2/neu gene is a proto-oncogene located on 17q21 HER2/neu is a transmembrane glycoprotein The extracellular domain interacts with other HER proteins allowing the facilitation of signal transduction after ligand binding The intracellular domain has an intrinsic Tyrosine Kinase (TK) activity that regulates various important aspects of the growth and differentiation of cells There is no known ligand for HER2 itself Background Slamon DJ et al: Science. 1987; 235

The EGFR/HER Family Valabrega G et al: Ann Oncol 2007

Amplification of HER2 occurs in about 20-25% of invasive breast cancers It has been shown to be associated with poorly differentiated cancers, high rates of cell proliferation and lymph node involvement Most clinical studies have shown that patients with HER2 positive tumors have a poorer prognosis The prognostic value is strongest in patients with node positive disease while there is no consensus in its value in node negative patients The prognostic impact appears to be related only to the first 3-4 years after surgery as indicated by the peak of early recurrences HER2 as a prognostic factor Menard et al; Oncogene. 2003; 22, 6570

HER2 as a prognostic factor Nodes negative Nodes positive

HER2 as a predictive factor Anthracycline based chemotherapy appears to be particularly beneficial HER2 overexpression may be associated with resistance to alkylator based therapy The influence of HER2 on response to taxanes is unclear HER2 may also predict response to endocrine therapy Roughly 50% of HER2 amplified tumors are hormone receptor positive (typically lower levels than HER2 negative tumors) A prospective neoadjuvant study showed that in the HER2 positive patients the RR to letrozole were 88% VS 21% for the tamoxifen arm Ellis et al; JCO 2006; 24 (19):

Trastuzumab: Humanized Anti-HER2 Antibody

Mechanisms of Trastuzumab action and resistance Valabrega G et al: Ann Oncol 2007

Adjuvant Trastuzumab The beneficial effects on morbidity and/or mortality are seen in patients with HER2-positive breast cancer with HER2 overexpression at the 3+ level (IHC analysis) and/or HER2 gene amplification (FISH- CISH-positive). Phase III trials in early breast cancer HER-2 +: the addition of Trastuzumab in adjuvant therapy significantly improves DFS Plosker GL and Keam SJ: Drugs 2006

Randomized Phase III Trials Adjuvant Trastuzumab Trial HERA NSABP B-31 NCCTG N9831 BCIRG 006 FinHer No. patients a Reference Piccart-Gebhart et al 2005 Smith et al 2007 Romond et al 2005 Slamon et al 2006 Joensuu et al 2006 a HER2-positive subgroup

HER2 positive (IHC 3+ / FISH+) Invasive breast cancer resected by lumpectomy/mastectomy Nodal status –node positive (NSABP B-31) –node positive or high-risk node negative (NCCTG N9831, HERA, BCIRG 006) Known hormone receptor status (ER / PgR or ER alone) No previous or current cardiac disease Pivotal adjuvant Herceptin trials: patient characteristics

Randomized Phase III Trials

Romond et al:N Engl J Med 2005; 353: Combined analysis of B31 and N9831

Romond et al:N Engl J Med 2005; 353: Combined analysis of B31 and N9831

Romond et al:N Engl J Med 2005; 353: Adding trastuzumab significantly improves DFS !!! P<0.0001

Romond et al:N Engl J Med 2005; 353: Adding trastuzumab significantly improves OS!!! P=0.015

Romond et al:N Engl J Med 2005; 353: Combined analysis of B31 and N9831

Romond et al:N Engl J Med 2005; 353: Sequential trastuzumab does not add nothing !!!

Romond et al:N Engl J Med 2005; 353: Early trastuzumab is better than sequential trastuzumab !!!

Cardiac Safety 31.4% of patients receiving trastuzumab discontinued radiotherapy before 52 weeks for cardiac events NSABP-31 N9831 Control Group 0.8% Grade III-IV events Trastuzumab Group 4.1% Control Group 0% Trastuzumab Group 2.9% Romond et al:N Engl J Med 2005; 353:

Randomized Phase III Trials

Piccart et al:N Engl J Med 2005; 353: Design of the HERA Trial

HERA Trial: patient characteristics (%) well balanced arms Piccart et al:N Engl J Med 2005; 353:

HERA Trial: tumor characteristics (%) well balanced arms Piccart et al:N Engl J Med 2005; 353:

HERA trial: recent developments Median follow-up more than 2 years Smith et al, 2007

HERA Trial: Disease–Free Survival year Herceptin Observation No. at risk Events HR 0.64 p value < year DFS % CI, confidence interval; HR, hazard ratio Months from randomisation Patients (%) % CI 0.54, 0.76 Smith et al, 2007 Absolute DFS benefit favoring trastuzumab of 6.3%

HERA Trial: Overall Survival Smith et al, % Months from randomisation Patients (%) year Herceptin Observation No. at risk Deaths HR 0.66 p value year OS % CI 0.47, 0.91 Absolute OS benefit favoring trastuzumab of 2.7%

HERA trial: DFS subgroup analysis summary No evidence of any subgroup in which there is less efficacy (similar efficacy in each subgroup) No substantial influence of any baseline characteristic on the DFS benefit for Herceptin

Summary of Cardiac Toxicity in Three Studies P <0.002

Slamon D., SABCS x AC 60/600 mg/m 2 4 x Docetaxel 100 mg/m 2 6 x Docetaxel and Carboplatin 75 mg/m2 AUC 6 1 Year Trastuzumab N=3,222 1 Year Trastuzumab AC  T AC  TH TCH Her2+ (Central FISH) N+ or high risk N- 4 x AC 60/600 mg/m2 4 x Docetaxel 100 mg/m2 Stratified by Nodes and Hormonal Receptor Status BCIRG 006: study design

Slamon D, SABCS 2006 BCIRG 006: Endpoints Primary Disease-free Survival Secondary Overall Survival Toxicity Pathologic & Molecular Markers Slamon D., SABCS 2006

Patient characteristics well balanced arms Randomized (n=3,222) AC-T n=1,073 AC-TH n=1,074 TCH n=1,075 %% Age < 50 years52 54 KPS = Mastectomy Radiotherapy Hormonotherapy5051 Enrollment: April 2001 to March 2004 Slamon D., SABCS 2006

Tumor Characteristics well balanced arms Randomized (n=3,222) AC-T n=1,073 AC-TH n=1,074 TCH n=1,075 Number of nodes +%% – – > Tumor Size (cm)%%  2 > 2 and  > ER and/or PR +54 Slamon D., SABCS 2006

Recent developments Median follow-up more than 3 years Slamon D., SABCS 2006

Disease Free Survival (1st interim analysis) Median follow-up time = 23 months Year from randomization Slamon D., SABCS 2006

Disease Free Survival (2nd Interim Analysis) Median follow-up time = 36 months Absolute DFS benefits (from years 2 to 4): AC  TH vs AC  T: 6% TCH vs AC  T: 5% % Disease Free Patients Events 81% 87% 86% 77% 83% 82% 87% 93% 92% AC->T AC->TH TCH HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P< HR (TCH vs AC->T) = 0.67 [0.54;0.83] P= Year from randomization Slamon D., SABCS 2006 Significant difference between trastuzumab arms and non trastuzumab arm

Overall Survival ( 2nd Interim Analysis) Median follow-up time = 36 months Year from randomization Slamon D., SABCS 2006 % Survival HR (AC->TH vs AC->T) = 0.59 [0.42;0.85] P=0.004 HR (TCH vs AC->T) = 0.66 [0.47;0.93] P= Patients Events AC->T AC->TH TCH 97% 99% 98% 93% 97% 95% 92% 91% 86% Significant difference between trastuzumab arms and non trastuzumab arm

Grade 3/4 Non-Hematological toxicity AC-T n=1,050 % AC-TH n=1,068 % TCH n=1,056 % Arthralgia Myalgia Fatigue Hand-foot syndrome Stomatitis Diarrhea Nausea Vomiting Irregular menses * * * * * Yellow = numerically less events AC-TH or TCH *Statistically significant AC-TH or TCH Slamon D., SABCS 2006

Grade 3/4 Hematological Toxicity AC-T n=1,050 % AC-TH n=1,068 % TCH n=1,056 % Neutropenia Leucopenia Febrile neutropenia Neutropenic infection Anemia Thrombocytopenia Leukemia (%)3 pts (0.3)1 pt (0.1)0 pts * * * * Yellow = numerically less events AC-TH or TCH *Statistically significant AC-TH or TCH Slamon D., SABCS 2006

AC-T n=1,050 AC-TH n=1,068 TCH n=1,056 Cardiac related death 0 / 0 Cardiac left ventricular function (CHF) Grade 3 / 4 3 / 417 / 20 4 / 4 first interim analysis second interim analysis P = Slamon D., SABCS 2006 Safety analysis population: cardiotoxicity Statistically significant increase in cardiac events in the AC-TH arm

TOPO IIa Amplification as a Predictor of Anthracycline Response in Breast Cancer StudyYrN Park et al Tanner et al Knoop at al Park et al Coon et al Di Leo et al Since 2002, at least 6 studies have been published demonstrating the association between topo II alpha amplification and improved anthracyline response.

Year from randomization % Disease Free Patients EventsTopo II % 88% 82% 84% 78% Co-Amplified Non Co-amplified HR (Co-Amp vs Non Co-Amp) = 1.44 [1.16;1.78] P<0.001 Co-Amplified Non Co-amplified DFS Topo II Co-Amplified vs.... Non Co-Amplified (2nd Interim Analysis) Slamon D., SABCS 2006

DFS Co-Amplified Topo II by Arm (2nd Interim Analysis) Year from randomization % Disease Free Patients Events 32842AC->T 35735AC->TH 35942TCH 92% 95% 94% 87% 89% 87% 85% 83% P=0.336 P=0.648 Slamon D., SABCS 2006 In co-amplified Topo II patients trastuzumab does not add nothing in term of DFS to anthracycline based therapy

Year from randomization % Disease Free Patients Events AC->T 64387AC->TH 61892TCH 83% 91% 90% 78% 85% 84% 71% 83% 81% P<0.001 DFS Non Co-Amplified Topo II by Arm (2nd Interim Analysis) Slamon D., SABCS 2006 In NOT co-amplified Topo II patients trastuzumab INCREASES DFS compared to anthracycline based therapy

Adjuvant Herceptin trials: summary of DFS data to date Romond et al 2005; Joensuu et al 2006; Slamon et al 2006; Smith et al 2007 a Relapse-free survival; V, vinorelbine 0 HERA (n=5090) 2 years Combined analysis (n=3351) 2 years Median follow-up BCIRG 006 DCarboH (n=1075) 3 years BCIRG 006 AC  DH (n=1074) FinHer VH / DH a (n=232) 3 years 12 Favours Herceptin Favours no Herceptin HR

St. Gallen guidelines: update on adjuvant treatments for Early Breast Cancer Herceptin provides substantial benefit to patients with HER2-positive tumours at high risk of early recurrence Herceptin should be added either with or after chemotherapy for HER2-positive patients, irrespective of endocrine responsiveness and nodal status Goldhirsch et al 2006

Adjuvant Herceptin: answering some key questions Optimal duration of Herceptin treatment? - HERA (1 year versus 2 years Herceptin) Effect of delayed switching to Herceptin? - HERA Is concurrent or sequential Herceptin administration optimal? - NCCTG N9831

Future directions 1) EGFR family inhibitors associated with trastuzumab Because HER2 and EGFR coexpression occurs in 30% of breast cancers, blockage of both receptors is a rational strategy which may improve RR to trastuzumab. Such combination may also be considered for trastuzumab-resistant tumours, in which compensatory signalling by EGFR may inhibit the response to trastuzumab. - Lapatinib, Gefitinib, Pertuzumab Valabrega G et al: Ann Oncol 2007

Future directions 2) Association with agents targeting other pathways and modified anti-HER2 antibodies It is under early clinical investigation for breast cancer after promising results in a preclinical setting. - inhibitors of mTOR (kinase located downstream the PI3K-AKT pathway): CCI-779 and RAD001 - trastuzumab + bevacizumab (NCI-sponsored phase I/II trial ongoing in HER2-overexpressing metastatic breast cancer patients) - recombinant molecules in which the antibody-combining site is fused directly to the toxin have been developed and show strong selectivity for HER2 binding Valabrega G et al: Ann Oncol 2007

Ongoing large clinical phase III trials: 1) The TEACH trial (3,000 patients) - it compares lapatinib and placebo after completion of any chemotherapy (anthracycline, taxane or CMF regimen) 2) ALTTO (Adjuvant lapatinib and/or trastuzumab treatment optimization) (to begin): -it will investigates the benefit of trastuzumab 1 year vs lapatinib 1 year vs trastuzumab 12 ws  lapatinib 34 ws vs combination trastuzumab+lapatinib 1 year (after chemotherapy) -it expects an ultimate enrollment of 8,000 patients Lapatinib (Tykerb) in early stage HER2-overexpressing breast cancer Ito Y et al: Breast Cancer 2007

Co-amplification of c-myc and HER2: benefit of trastuzumab C-MYC/HER2Regimen PatientsEventsHR2p Non co-amplifiedAC T AC TH ,630,007 Co-amplifiedAC T AC TH ,240,0001 Relationship between amplification of HER2 and c-myc in NSABP-B31 trial Kim et al Breast Cancer Research Treat 2005

Co-amplification of c-myc and HER2: benefit of trastuzumab Patients with co-amplification of c-myc and HER2 have worse outcome when treated with chemotherapy alone, whereas the addition of Trastuzumab reverses this trend Patients treated with trastuzumab achieved recurrence-free survival of over 90% HER2 amplification could represent an antiapoptotic signal for the pro-apoptotic function of c-Myc Trastuzumab could promote the apoptotic function of c-myc Kim et al Breast Cancer Research Treat 2005

Results from four major randomised trials provide level 1 evidence for OS benefit of adjuvant Herceptin Adjuvant Herceptin greatly increases the chance of Survival for patients with HER2-positive Early Breast Cancer Adjuvant Herceptin should be considered for all patients with HER2-positive breast cancer Close cardiac monitoring is mandatory Sequential vs.... concurrent vs.... chemotherapy regimen? Role of Topo II α testing? Role of c-myc testing? Take-Home Messages

Adjuvant Herceptin approval Chile Columbia Dominican Republic Ecuador Norway USA Guatemala Iceland India Israel Bosnia- Herzegovina Mexico New Zealand Nicaragua Pakistan Philippines Russia South Korea Switzerland Australia EU