HER2 inhibition: when more is better? Teresa Gamucci Oncologia Medica ASL Frosinone
HER2: Positive Predictive Marker Trastuzumab is a HER2-targeted monoclonal antibody, that improves disease-free and overall survival when added to chemotherapy for treatment of early stage HER2-positive breast cancer; Follow-up data from the NSABP B-31 and NCCTG 9831 trials and the BCIRG 006 trial2 show overall survival rates of 83–86% at 8–10 years—a victory for a disease subtype previously associated with poor prognosis; Despite these findings, up to a quarter of patients will have disease recurrence; 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 HER2-positive MBC 20 40 60 80 100 5 15 25 35 45 Chemotherapy (n = 234) Chemotherapy + trastuzumab (n = 235) RR = 0.80 (95% CI = 0.64,1.00) p = 0.046 Overall survival (%) First-line trastuzumab in combination with chemotherapy improved median survival in this high-risk population of patients with metastatic breast cancer (MBC).1 There was a significant increase in median overall survival (OS) resulting from the addition of trastuzumab to chemotherapy compared with chemotherapy alone (25.1 vs 20.3 months; p = 0.046). This study included only patients whose tumours were either immunohistochemisty (IHC) 2+ or IHC 3+: as such they were considered to be at high risk of disease progression. For important safety information, see the full Prescribing Information.2 References Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer. N Engl J Med 2001; 344:783–792. Herceptin® (trastuzumab) Prescribing Information. October 2010. Median OS: 20.3 months Median OS: 25.1 months Time (months after enrolment) 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 HER2 receptor blockade
What have we learned from the metastatic setting? Presented By Carey Anders at 2017 ASCO Annual Meeting
CLEOPATRA trial n=406 1:1 n=402 Placebo + trastuzumab PD Docetaxel ≥6 cycles recommended Patients with HER2-positive MBC centrally confirmed (N=808) 1:1 Pertuzumab + trastuzumab PD n=402 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.
TAnDEM study
PERTAIN study Primary Endpoint: PFS Arpino G et al. SABCS 2016.
PERTAIN study: PFS Arpino G et al. SABCS 2016.
T-DM1: Antibody Drug Conjugate HER2 HER2 Cell membrane Intracellular emtansine release inhibition of microtubule polymerization 17 17
TDM4450g phase II study T-DM1 vs Docetaxel and Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV + Docetaxel 75 or 100 mg/m2 q3w (n=70) Crossover to T-DM1 (optional) PDa HER2-positive, recurrent locally advanced breast cancer or MBC (N=137) T-DM1 3.6 mg/kg q3w IV (n=67) PDa TDM4450g study design Patient population : MBC patients with no prior 1st line treatment Patients were HER2+ by local testing but central HER2 testing was not required for enrollment Prospectively-designed central HER2 testing was performed for 61 patients in the trastuzumab + docetaxel arm and 61 patients in the T-DM1 arm. Straight forward study design to test the hypothesis of the ADC vs standard of care first line therapy with docetaxel and trastuzumab For the control arm, the investigators were given a choice of whether to use 75 mg/m2 docetaxel or 100 mg/m2 docetaxel (approximately 75% used 75 mg/2). Once assigned, no intrasubject dose escalation was allowed. Cross-over to T-DM1 was optional (27 patients crossed over from the trastuzumab + docetaxel group to receive T-DM1 as second line treatment) Patients continued on therapy until either PD or toxicity requiring change of therapy, as deemed necessary by investigator or per study guidelines Primary endpoint: PFS by investigator and Secondary Endpoints: OS, ORR, DOR, CBR and QOL by Fact B and TOI; OS and QOL data will not be presented here (OS data cut will be available early 2012; QOL data to be presented at a future congress) CBR, clinical benefit rate; DOR, duration of response; MBC, metastatic breast cancer; ORR; overall response rate; OS, overall survival; PFS, progression-free survival; q3w, every 3 weeks; QOL, quality of life. Primary Endpoint: PFS Hurvitz SA et al. JCO, 2013 18
TDM4450 g phase II stady: PFS Hurvitz SA et al. JCO, 2013
Trastuzumab + taxane (docetaxel or paclitaxel) MARIANNE study: pertuzumab and T-DM1 in first-line metastatic breast cancerc HER2-positive, progressive or recurrent, locally advanced or untreated MBC (N = 1092) Pertuzumab + T-DM1 Trastuzumab + taxane (docetaxel or paclitaxel) R Placebo + T-DM1 MARIANNE/TDM4788g/BO22589: Randomised, three-arm, multi-centre, Phase III study evaluating the efficacy and safety of trastuzumab emtansine (T-DM1) with pertuzumab or trastuzumab emtansine (T-DM1) with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab (Herceptin) plus taxane (docetaxel or paclitaxel) in patients with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer. Arm 1: Trastuzumab emtansine (T-DM1): 3.6 mg/kg iv q3w Pertuzumab: 840 mg iv on Day 1 of Cycle 1 followed by 420 mg iv q3w Arm 2: Pertuzumab-placebo: 840 mg iv on Day 1 of Cycle 1 followed by 420 mg iv q3w Arm 3: Trastuzumab: when administered with docetaxel: 8 mg/kg iv on Day 1 ofCycle 1 followed by 6 mg/kg q3w or when administered with paclitaxel: 4 mg/kg iv on Day 1 of Cycle 1 followed by 2 mg/kg q1w starting on Day 8 of Cycle 1. Docetaxel: 75 mg/m2 or 100 mg/m2 iv every 3 weeks for a minimum of 6 cycles. OR Paclitaxel: 80 mg/m2 iv weekly for a minimum of 18 weeks. Reference ClinicalTrials.gov. A study of trastuzumab emtansine (T-DM1) plus pertuzumab/pertuzumab placebo versus trastuzumab [Herceptin] plus a taxane in patients with metastatic breast cancer (MARIANNE). Available at: http://clinicaltrials.gov/ct2/show/NCT01120184 (Accessed November 2012). T-DM1 ± 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
EGF104900 study: Lapatinib plus Trastuzumab Blackwell KL et al. JCO 2012
EGF104900 study: OS Blackwell KL et al. JCO 2012
Metastatic HER2 + BC: more or less? The outcome of patients with HER2 + 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 + HER2 + MBC Lapatinib + Trastuzumab is an option for pretreated patients (GIM 12?)
Neoadjuvant Breast Cancer
NeoSphere study Gianni L et al. Lancet Oncol 2012
NeoSphere study: pCR Gianni L et al. Lancet Oncol 2012
NeoSphere 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 HER2 + BC: more or less?
Adjuvant Breast Cancer
Trastuzumab and adjuvant CT: OS Study HR Median FU B31/N9831 0.61 48 mos N9831 AC-T vs AC-T-H AC-T-H vs AC-TH-H 0.88 0.78 72 mos HERA 0.85 BCIRG006 AC-T vs AC-TH-H AC-T vs TCH 0.63 0.77 65 mos FinHER 0.55 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 3.400 PERSEPHONE 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
ShortHER: Cardiac Adverse Events Presented By Carey Anders at 2017 ASCO Annual Meeting
Presented By Pier Conte at 2017 ASCO Annual Meeting Conclusions Presented By Pier Conte at 2017 ASCO Annual Meeting
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
Presented By Alvaro Moreno-Aspitia at 2017 ASCO Annual Meeting 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
ExteNET study Chan A et al. JCO 2016
Presented By Carey Anders at 2017 ASCO Annual Meeting How does this data compare to other Her2-targeted tyrosine kinase inhibitors? Presented By Carey Anders at 2017 ASCO Annual Meeting
BETH study
BETH study: results
KATHERIN study Ongoing www.clinicaltrials.gov
Presented By Carey Anders at 2017 ASCO Annual Meeting Which patients might benefit from more or less?<br />Practical Algorithm<br /><br /><br /> Presented By Carey Anders at 2017 ASCO Annual Meeting
Adjuvant HER2 + BC: more or less? Anders CK et al. ASCO 2017
t.gamucci@libero.it