Adjuvant therapy of HER2 positive early breast cancer The Evidences Antonio Frassoldati Oncologia Clinica - Ferrara

Evidences on adjuvant trastuzumab are based on randomized trials in over 14,000 women TrialPt. N.Trastuz.DurationMedian FUPublished results B31/N C+S1 y48 mosY N S or C+S1 y72 mosY* HERA5090S1 or 2 y48 mosY BCIRG C+S1 y65 mosY FinHER232C3 m62 mosY PACS-04528S1y47 mosY S= sequential; C= concomitant * Early release after second interim analysis (arm A, B) and first interim analysis (arm B,C)

Main trial designs of adjuvant Trastuzumab NSABP B-31 Node positive N9831 Node pos/neg HR Paclitaxel q3w x 4 Paclitaxel x 4, H qw x 52 AC q3w x 4 H qw x 52 Paclitaxel qw x 12 Paclitaxel qw x 12, H qw x 52 AC q3w x 4 BCIRG 006 Node pos/neg HR Docetaxel q3w x 4 AC q3w x 4 H qw x 12, q3w † x 14 Docetaxel q3w x 4 Carboplatin + Docetaxel q3w † x 6 H qw x 18, q3w x 12 HERA Chemotherapy (any) Node pos/neg HR Chemotherapy (any)  H qw x 52 Chemotherapy (any)  H qw x 104

Main research questions in trials of adjuvant trastuzumab Does trastuzumab reduce the rate of recurrence (and death)? (All) Does the schedule of trastuzumab administration matter? (N9831, BCIRG006) Does the duration of trastuzumab matter? (HERA) Does the chemotherapy regimen influence the activity and safety of trastuzumab? (BCIRG006)

Cross-comparison among the trials of adjuvant trastuzuamb TrialPt. N.Primary endpoint Crossover B31/N DFS15% N DFSY HERA°5090DFS52% BCIRG DFS2.1% FinHER232DFSN PACS04528DFSN ° Pts in HERA trial were randomized after the end of adjuvant therapy

B31/N9831 Efficacy results Perez, JCO 2011 Relapse HR 0.52 ( )

B31/N9831 Efficacy results Perez, JCO 2011 Death HR 0.61 ( )

No. of deaths H 1 year vs. observation 012 Favours trastuzumab Favours no trastuzumab HR OS benefit 29 vs. 37 p= year (0%) 59 vs. 90 p= vs. 213 p= Median follow-up (% follow-up time after selective crossover) years (4.1%) years (30.9%) year (0%) Median follow-up (% follow-up time after selective crossover) years (4.3%) years (33.8%) No. of DFS events H 1 year vs. observation 127 vs. 220 p< vs. 321 p< vs. 458 p< Favours trastuzumab Favours no trastuzumab HR DFS benefit 1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011 HERA: DFS and overall survival over time

HERA - Observation patients by status on 16 May patients originally randomised to observation 1354 patients alive and disease free 16 May patients DFS event or lost to follow-up 198 alive post DFS event 469 patients remained on observation 344 patients ineligible for crossover Gianni, Lancet Oncol patients crossed over to trastuzumab

HERA - DFS (landmark analysis): selective crossover and no crossover Months from randomisation No. at risk Patients alive and disease free (%) Selective crossover* No crossover HR 0.68 ( ) p= Gianni, Lancet Oncol 2011 * Median time to start trastuzumab: 22.8 mos ( )

N9831 Efficacy results Sequential vs Concomitant + sequential Perez, JCO 2011

BCIRG006 Efficacy results Slamon, NEJM 2011 DFS HR AC-TH vs AC-T 0.64 TCH vs AC- T 0.75

FinHER Efficacy results Joensuu, JCO 2009

Efficacy of adjuvant trastuzuamb on Survival Trial HRMedian FU B31/N mos N9831 AC-T vs AC-T-H AC-T-H vs AC-TH-H mos HERA° mos BCIRG006 AC-T vs AC-TH-H AC-T vs TCH mos FinHER mos ° ITT, not adjusted for selective crossover

Efficacy in subgroups ER and Nodal status Slamon, NEJM 2011 AC-TH-H TCH

Time-dependent Hazard Rate for recurrence by hormone receptor status ER positive ER negative Untch, Ann Oncol 2008 HERA trial

Efficacy in subgroups Small tumors Gonzalez-Angulo, JCO 2009 MDACC 965 pT1a-b N0 Hazard Ratio for recurrence % 86.4%

Efficacy in subgroups Small tumors Slamon, NEJM 2011 BCIRG006

Efficacy in subgroups Topo2A status Slamon, NEJM 2011 With Topo2A coamplification Without Topo2A coamplification

Cardiac safety TrialNot starting trastuzuamb Trastuz. Discontin. Cardiac dysfunction° CHF B31/N %17.3% 320/ % N9831 (C+S)2.8%19%9.1% 87/ % HERA--5.2%3.7%0.8% BCIRG006 AC-TH 2.1%n.r. AC-TH 18.6% TCH 9.4% AC-TH 2.0% TCH 0.4% FinHER--4-7% of doses 3.9%*0.9% * ° >10 points relative reduction in LVEF *after CT

0.00 Suter et al 2007 a Median follow-up 12 months; DFS, disease-free survival Obs; any cardiac end point H; any cardiac end point Obs; DFS events H; DFS events Months a Probability No. at risk Observation Trastuzumab HERA: risk-benefit ratio with adjuvant trastuzumab a

Cardiac outcomes after any type of cardiac endpoint Trastuzumab patients who have any type of CE (n=73) Trastuzumab patients who reached acute recovery after any type of CE (n=59) Trastuzumab patients who had a further LVEF drop to <50% (n=59) 19.2% 80.8% 71.2% 28.8% 35.3% 64.7%

Duration of Trastuzumab TrialDuration in months CT regimenNo. of pts HERA (BIG) 12 vs. 24Center’s choice 3,387 PHARE (France) 6 vs. 12Center’s choice 3,400 PERSEPHONE (UK) 6 vs. 12Center’s choice 4,000 SHORTER (Italy) 3 vs.12A+T vs. T+FEC 1,500 SOLD (Finland & BCG) 3 vs 12T+FEC3,000

Adjuvant HER2- directed Therapy Questions to be solved: – Indication for the better regimen for combination with trastuzumab (Anthracycline/taxane or docetaxel/carboplatin) – Role of shorter trastuzumab regimens – Treatment of triple-positive tumor migth avoid chemotherapy, particularly on small tumors (T1a,b N0) – Prediction of response to individual HER2-directed agents – Role of dual HER2 inhibition

Double inhibition of HER2

Trastuzumab clearly changed the prognosis of HER2 breast cancer patients. Several new ways for further improvements can now to be explored HER2 street