1. HER2 inhibition: when more is better?
Teresa Gamucci
Oncologia Medica
ASL Frosinone

2. 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

3. Metastatic Breast Cancer

4. Trastuzumab prolongs overall survival in HER2-positive MBC20 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: months
Median OS: 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.

5. Dual HER2 receptor blockade

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

7. 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.

8. 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.

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

10. TAnDEM study

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

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

15. T-DM1: Antibody Drug Conjugate
HER2
HER2
Cell membrane
Intracellular emtansine release  inhibition of microtubule polymerization 17 17

16. 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

17. TDM4450 g phase II stady: PFS
Hurvitz SA et al. JCO, 2013

18. 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: (Accessed November 2012).
T-DM1 ± pertuzumab: blinded, placebo-controlled
Trastuzumab + taxane: open-label
Primary Endpoint: PFS
Perez EA et al. JCO 2017

19. MARIANNE study: PFS
Perez EA et al. JCO 2017

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

21. EGF104900 study: Lapatinib plus Trastuzumab
Blackwell KL et al. JCO 2012

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

23. 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?)

24. Neoadjuvant Breast Cancer

25. NeoSphere study
Gianni L et al. Lancet Oncol 2012

26. NeoSphere study: pCR
Gianni L et al. Lancet Oncol 2012

27. NeoSphere study: 5-years analysis
Gianni L et al. Lancet Oncol 2016

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

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

30. Neoadjuvant HER2 + BC: more or less?

31. Adjuvant Breast Cancer

32. 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

33. 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

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

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

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

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

38. SHORT-HER study
Conte PF et al. ASCO 2017

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

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

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

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

43. ShortHER: Cardiac Adverse Events
Presented By Carey Anders at 2017 ASCO Annual Meeting

44. Presented By Pier Conte at 2017 ASCO Annual Meeting
Conclusions
Presented By Pier Conte at 2017 ASCO Annual Meeting

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

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

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

48. Presented By Gunter Von Minckwitz at 2017 ASCO Annual Meeting

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

50. ALTTO study update

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

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

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

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

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

56. ExteNET study
Chan A et al. JCO 2016

57. 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

58. BETH study

59. BETH study: results

60. KATHERIN study
Ongoing

61. 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

62. Adjuvant HER2 + BC: more or less?
Anders CK et al. ASCO 2017