HER 2 inhibition when more is better Teresa

HER 2 inhibition: when more is better? Teresa Gamucci Oncologia Medica ASL Frosinone

HER 2: Positive Predictive Marker Ø Trastuzumab is a HER 2 -targeted monoclonal antibody, that improves disease-free and overall survival when added to chemotherapy for treatment of early stage HER 2 -positive breast cancer; Ø Follow-up data from the NSABP B-31 and NCCTG 9831 trials and the BCIRG 006 trial 2 show overall survival rates of 83– 86% at 8– 10 years—a victory for a disease subtype previously associated with poor prognosis; Ø Despite these findings, up to a quarter of patients will have disease recurrence; Ø Various approaches have been tested to further improve outcome Perez EA et al. JCO 2014 Slamon DJ et al. SABCS 2015

Metastatic Breast Cancer

Trastuzumab prolongs overall survival in HER 2 -positive MBC Overall survival (%) 100 Chemotherapy (n = 234) Chemotherapy + trastuzumab (n = 235) 80 RR = 0. 80 (95% CI = 0. 64, 1. 00) 60 p = 0. 046 40 20 Median OS: 20. 3 months Median OS: 25. 1 months 0 0 5 15 25 Time (months after enrolment) 35 45 OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxel OS, overall survival; RR, relative risk of death Slamon DJ, et al. N Engl J Med 2001; 344: 783– 792.

Dual HER 2 receptor blockade

What have we learned from the metastatic setting? Presented By Carey Anders at 2017 ASCO Annual Meeting

CLEOPATRA trial n=406 Patients with HER 2 -positive MBC Placebo + trastuzumab PD Docetaxel ≥ 6 cycles recommended 1: 1 centrally confirmed (N=808) Pertuzumab + trastuzumab n=402 PD Docetaxel ≥ 6 cycles recommended Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Primary Endpoint: OS Swain SM, et al. N Engl J Med 2015.

CLEOPATRA trial: OS Median OS 56. 5 months vs 40. 8 months HR=0. 68 Improvement: 15. 7 months Swain SM, et al. N Engl J Med 2015.

CLEOPATRA trial: subgroup analysis of OS Swain SM, et al. N Engl J Med 2015.

TAn. DEM study

PERTAIN study Primary Endpoint: PFS Arpino G et al. SABCS 2016.

PERTAIN study: PFS Arpino G et al. SABCS 2016.

T-DM 1: Antibody Drug Conjugate HER 2 Cell membrane Intracellular emtansine release inhibition of microtubule polymerization

TDM 4450 g phase II study T-DM 1 vs Docetaxel and Trastuzumab 8 mg/kg loading dose; 6 mg/kg q 3 w IV HER 2 -positive, recurrent locally advanced breast cancer or MBC (N=137) + Docetaxel 75 or 100 mg/m 2 q 3 w (n=70) PDa Crossover to T-DM 1 (optional) T-DM 1 3. 6 mg/kg q 3 w IV PDa (n=67) Primary Endpoint: PFS Hurvitz SA et al. JCO, 2013

TDM 4450 g phase II stady: PFS Hurvitz SA et al. JCO, 2013

MARIANNE study: pertuzumab and T-DM 1 in first-line metastatic breast cancerc Pertuzumab + T-DM 1 HER 2 -positive, progressive or recurrent, locally advanced or untreated MBC (N = 1092) R Placebo + T-DM 1 Trastuzumab + taxane (docetaxel or paclitaxel) T-DM 1 ± pertuzumab: blinded, placebo-controlled Trastuzumab + taxane: open-label Primary Endpoint: PFS Perez EA et al. JCO 2017

MARIANNE study: PFS Perez EA et al. JCO 2017

MARIANNE study: analysis subgroup PFS Perez EA et al. JCO 2017

EGF 104900 study: Lapatinib plus Trastuzumab Blackwell KL et al. JCO 2012

EGF 104900 study: OS Blackwell KL et al. JCO 2012

Metastatic HER 2 + BC: more or less? The outcome of patients with HER 2 + breast cancer has significantly improved in the past two decades; The standard of care should consist of pertuzumab and trastuzumab along with docetaxel; For patients with only bone metastases could be considered treatment without Pertuzumab? Pertuzumab + Trastuzumab + IA is superior to Trastuzumab + IA in postmenopausal women HR + HER 2 + MBC Lapatinib + Trastuzumab is an option for pretreated patients (GIM 12? )

Neoadjuvant Breast Cancer

Neo. Sphere study Gianni L et al. Lancet Oncol 2012

Neo. Sphere study: p. CR Gianni L et al. Lancet Oncol 2012

Neo. Sphere study: 5 -years analysis Gianni L et al. Lancet Oncol 2016

KRISTINE/TRIO-021 study Hurwitz SA et al. ASCO 2016

KRISTINE/TRIO study: results Hurwitz SA et al. ASCO 2016

Neoadjuvant HER 2 + BC: more or less? ?

Adjuvant Breast Cancer

Trastuzumab and adjuvant CT: OS Study HR Median FU B 31/N 9831 0. 61 48 mos N 9831 AC-T vs AC-T-H vs AC-TH-H HERA 72 mos 0. 88 0. 78 0. 85 BCIRG 006 AC-T vs AC-TH-H AC-T vs TCH 0. 63 0. 77 Fin. HER 0. 55 48 mos 65 mos 62 mos

Duration of adjuvant Trastuzumab Trial Duration in months CT regimen No. of pts HERA 12 vs. 24 Center’s choice 3. 387 PHARE 6 vs. 12 Center’s choice 3. 400 PERSEPHONE 6 vs. 12 Center’s choice 4. 000 SHORTER 3 vs. 12 A+T vs. T+FEC 1. 500 SOLD 3 vs 12 T+FEC 3. 000

HERA trial results: 1 yr vs 2 yrs trastuzumab Goldhirsch A et al. Lancet 2013

PHARE trial: 6 mos vs 1 yr trastuzumab Pivot X et al. Lancet Oncol 2013

PHARE trial: results Pivot X et al. Lancet Oncol 2013

PHARE trial: DFS subgroup analysis Pivot X et al. Lancet Oncol 2013

SHORT-HER study Conte PF et al. ASCO 2017

SHORT-HER study: DFS Conte PF et al. ASCO 2017

SHORT-HER study: DFS subgroup analysis Conte PF et al. ASCO 2017

SHORT-HER study: OS Conte PF et al. ASCO 2017

LVEF change from baseline Presented By Pier Conte at 2017 ASCO Annual Meeting

Short. HER: Cardiac Adverse Events Presented By Carey Anders at 2017 ASCO Annual Meeting

Conclusions Presented By Pier Conte at 2017 ASCO Annual Meeting

Conclusions cont’ed Presented By Pier Conte at 2017 ASCO Annual Meeting

APHINITY: Study Design Presented By Carey Anders at 2017 ASCO Annual Meeting

APHINITY Primary Objective of invasive (i) DFS Presented By Carey Anders at 2017 ASCO Annual Meeting

Presented By Gunter Von Minckwitz at 2017 ASCO Annual Meeting

What were the cardiac and other “costs” of pertuzumab? Presented By Carey Anders at 2017 ASCO Annual Meeting

ALTTO study update

ALTTO study update: DFS Aspitia AM et al. ASCO 2017

ALTTO study update: DFS in HR +/- pts Aspitia AM et al. ASCO 2017

ALTTO study update: OS Aspitia AM et al. ASCO 2017

CONCLUSIONS Presented By Alvaro Moreno-Aspitia at 2017 ASCO Annual Meeting

What are the “costs” associated with ALTTO? Presented By Carey Anders at 2017 ASCO Annual Meeting

Exte. NET study Chan A et al. JCO 2016

How does this data compare to other Her 2 -targeted tyrosine kinase inhibitors? Presented By Carey Anders at 2017 ASCO Annual Meeting

BETH study

BETH study: results

KATHERIN study Ongoing www. clinicaltrials. gov

Which patients might benefit from more or less? < br />Practical Algorithm Presented By Carey Anders at 2017 ASCO Annual Meeting

Adjuvant HER 2 + BC: more or less? Anders CK et al. ASCO 2017

t. gamucci@libero. it