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Treatment Paradigms in the
Management of MBC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Kasr El-Aini School of Medicine
Cairo University
BGICC – Roche Symposium
Fairmont Hotel & Tower –Heliopolis
Thursday, 09/01/2014
Breast Cancer:
Basic Facts:
• Most frequently encountered cancer among females.
• Most common cause of cancer related deaths among
females.
• A national problem.
• Heterogeneous disease.
• HER2 +++ (20 – 25%)  Poor prognosis.
• Anti-HER2 Targeted Therapies  Changing the
landscape of disease.
Breast Cancer:
A Heterogeneous Disease:
Intrinsic Subtype Clinico-Pathologic Definition
Luminal A ER &/or PR +ve
HER2 –ve
Ki-67 (<20%)
Luminal B
(HER2 –ve)
ER &/or PR +ve
HER2 –ve
Ki-67 (>20%)
Luminal B
(HER2 +ve)
ER &/or PR +ve
HER2 +ve
Ki-67 (Any)
Erb-B2
Overexpression
ER & PR –ve
HER2 +ve
Basal Like
(Triple Negative)
ER & PR –ve
HER2 -ve
SurvivalProbability
Duration (months)
Sorlie et al PNAS 2001
Breast Cancer:
Major Criteria of Metastatic Disease:
Major Criteria of Metastases Clinical Implications
Heterogeneity between primary
tumor and metastatic disease:
 ER: 13%
 PR: 28%
 HER2: 5%
Ineffective therapy based on
primary tumor characteristics
Redundancy of mechanistic
pathways of growth
The need for combination therapy
Variable dormancy of malignant
cells
Delayed relapse
Contribution of cancer initiating
cells
Therapies targeting stem cells
Breast Cancer Metastases: Issues for the personalization of its prevention and treatment.
Mariano N. et al. The American Journal of Pathology, Vol. 183, No. 4, October 2013.
Breast Cancer:
HER2 Structure & Function:
PI3K MAPK Stat
Growth &
Proliferation
Angiogenesis
Invasion &
Metastases
Breast Cancer:
HER2 Directed Therapies Has Changed
The Landscape of Disease:
Dawood S, et al. J Clin Oncol. 2010;28(1):92-98.
12 60483624
0.2
0.8
0.6
0.4
1.0
Her2 +ve with Hereptin n=191
Her2 –ve n=1782
Her2 +ve no Herceptin n=191
Trastuzumab
Approval
(advanced
BC)
2004 2005 20061998 20032002 20082007
Her2+ Advanced Breast cancer:
Major clinical advances:
20102009
Phase 2
Randomized
trial
TDM1
Phase 3
Pertuzumab
Lapatinib
Approval
(advanced
BC)
Initial
studies for:
TDM1,
Pertuzumab,
Afatinib,
Neratinib
TDM1
Approval
2L mBC
Pertuzumab
approved
(advanced
BC)
Everolimus
Approval
(advanced
BC)
White = clinical study results prior to 2013.
Yellow = regulatory approvals prior to 2013.
2011 2012 2013
Adapted from Krop I. SABCS 2011, Abst ES1-3.
Breast Cancer:
Trastuzumab: 1 Agent & 4 Targets:
Breast Cancer:
Trastuzumab: 1 Agent & 4 Targets:
Breast Cancer:
Trastuzumab: 1 Agent & 4 Targets:
Breast Cancer:
Trastuzumab: 1 Agent & 4 Targets:
1. Previously unexposed.
2. Previously exposed:
a. > 6 months.
b. < 6 months.
3. 2nd line or later treatment.
Her2+ Advanced Breast cancer:
Clinical Scenarios:
1. Unexposed Patients:
• 469 MBC
• No ttt for
M-Stage.
• HER2 +ve
Chemotherapy +
Trastuzumab
Chemotherapy
(AC) +
Trastuzumab
(Paclitaxel) +
Trastuzumab
AC
Paclitaxel
Use of Chemotherapy plus Monoclonal Antibody
agents Against HER2 for MBC Overexpresses HER2.
Slamon et al, N Engl J. 2001;344-783-921
1. Unexposed Patients:
Use of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC
Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921
1. Unexposed Patients:
Use of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC
Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921
1. Unexposed Patients:
H0648g and M77001:Overall survival
with trastuzumab first-line therapy
* IHC 2+ tumours not confirmed by in situ hybridisation; subgroup analysis p value not reported.
† Statistically significant IHC 3+/FISH-positive.
1. Smith IE. Anticancer Drugs 2001; 12(Suppl. 4):S3–S10; 2. Slamon DJ, et al. N Engl J Med 2001; 344:783–792;
3. Marty M, et al. J Clin Oncol 2005; 23:4265–4274.
Survivalprobability
Time (months)
Trastuzumab + docetaxel (n = 92)
22.7 31.2
+37%
p = 0.0325†
Docetaxel (n = 94)
8.5 months
0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30 35 5040 45
M770013
H0648g*1,2
(IHC 3+ paclitaxel subgroup)
Time (months)
1.0
Survivalprobability
0.6
0.8
0.4
0.2
0.0
18 25
Trastuzumab + paclitaxel (n = 68)
Paclitaxel (n = 77)
0 5 15 20 25 30 35 40 45
7 months
10
Herceptin vs Lapatinib in 1LmBC:
COMPLETE STUDY (EGF 108919)
Primary end point:
PFS
Secondary end points:
OS & safety
Karen A. Gelmon ASCO 2012 LBA no. 671
• MBC Her 2+ve
(IHC 3+ and/or
FISH+)
• 1L MBC (no prior
chemo)
(n=636)
Taxane based Chemotherapy
+Lapatinib
(n=318)
Taxane based chemotherapy
+Herceptin
(n=318)
COMPLETE study (108919)
Progression Free Survival
Karen A. Gelmon ASCO 2012 LBA no. 671
PFS: intent to ttt population PFS: centrally confirmed HER 2+
COMPLETE STUDY (EGF108919)
Over all survival analysis
Karen A. Gelmon ASCO 2012 LBA no. 671
OS: intent to ttt population OS: centrally confirmed HER 2+
Unexposed Patients:
MBC, HER2 +ve  1L Treatment:
NCCN. Clinical practice guidelines in oncology: breast cancer. v.2.2013.
Trastuzumab
Chemotherapy:
• Taxanes.
• Venoralbine
• Capecitabine
• Gemcitabine
+/- Platinum
Pertuzumab and Trastuzumab have
complementary mechanisms of
action
1. Eigenbrot et al Proc Natl Acad Sci. 2010. 107: 15039–15044.
2. Cho et al. Nature 2003;421:756–760.
HER2
Pertuzumab1
Trastuzumab2
HER3
ShcGRb2Sos
RAF
MEK
MAPK
P
P
Akt
PI3K
P P
P
P PDK1
PP P
mTOR
Cyclin 01
GSK36
NF  B
BAD
p27
CLEOPATRA: Study design:
Baselga J, et al. N Engl J Med 2012; 366:109–119.
Randomisation:
Stratified by geographic region and prior treatment status
([neo]adjuvant chemotherapy received or not)
Dosing:
–Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance q3w
–Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance q3w
–Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated q3w
Patients with
HER2-positive
mBC
centrally
confirmed
(N = 808)
Placebo + trastuzumab
(n = 406)
1:1
Docetaxel*
≥6 cycles recommended
PD
Pertuzumab + trastuzumab
(n = 402)
Docetaxel*
≥6 cycles recommended
PD
*<6 cycles allowed for unacceptable toxicity or PD;
>6 cycles allowed at investigator discretion
PD, progressive disease
R
Primary endpoint:
Independently assessed PFS
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time (months)
Ptz + T + D: median 18.5 months
Pla + T + D: median 12.4 months
HR = 0.62
95% CI 0.51‒0.75
p<0.0001
∆ = 6.1 months
Progression-freesurvival(%)
Baselga et al. N Engl J Med 2011
CLEOPATRA: Patients receiving the
pertuzumab-based regimen had a
34% reduction in the risk of death
HR 0.66; 95% CI = 0.52–0.84
p = 0.0008
Placebo + trastuzumab + docetaxel 154 events; median 37.6 months
Pertuzumab + trastuzumab + docetaxel 113 events; median not reached
Overallsurvival(%)
Time (months)
10
20
30
40
50
60
70
80
90
0
100
10 20 300 5 15 25 35 5540 45 50
Swain SM, et al. Lancet Oncol 2013; 14:461–471.
Not reached
37.6 months
Independently assessed PFS by prior
Trastuzumab therapy in patients with
(neo)adjuvant therapy
Placebo
+ trastuzumab +
docetaxel
Median PFS, months
Pertuzumab
+ trastuzumab +
docetaxel
Median PFS, months
Hazard
ratio
(CI)
Prior (neo)adjuvant
trastuzumab treatment
(n = 88)
10.4 16.9
0.62
(0.35‒1.07)
No prior (neo)adjuvant
trastuzumab treatment
(n = 288)
12.6 21.6
0.60
(0.43‒0.83)
Baselga et al. N Engl J Med 2011
Unexposed Patients:
MBC, HER2 +ve, 1L Treatment:
• Trastuzumab + Pertuzumab + Chemotherapy.
• Trastuzumab + Chemotherapy.
Exposed Patients:
MBC, HER2 +ve, 2L Treatment:
Trastuzumab +
Chemotherapy
Disease
Progression Trastuzumab +
Pertuzumab
Chemotherapy
Disease
Progression
• Switch CTh.
• Lapatinib.
• Investigational.
Exposed Patients:
MBC, HER2 +ve, 2L Treatment:
Ado-Trastuzumab Emtansine (T-DM1):
Approved in 2013
Ado-Trastuzumab Emtansine:
T-DM1:
Lewis Phillips GD, et al.
Cancer Res.
2008; 68:9280–9290.
Primary endpoints:
PFS by INV, safety
Key Secondary endpoints:
ORR, clinical benefit, OS, QOL, symptom control
TDM4450 Study Design
Randomized, phase II, international,
open-label study
1:1
HER2-positive,
recurrent locally
advanced BC or
MBC (n=137)
T-DM1
3.6 mg/kg Q3W until PD
Trastuzumab
8 mg/kg dose; 6 mg/kg Q3W
+ Docetaxel
75 or 100 mg/m2 Q3W
Crossover
T-DM1PD
Perez EA, et al. Abstr LBA3. ESMO 2010
Time (months)
BO21976 (TDM4450g): PFS by investigator
Randomised patients
Hurvitz SA, et al.
J Clin Oncol 2013; 31:1157–1163.
Progression-freesurvival(proportion)
Hazard ratio and log-rank p-value were from stratified analysis
Trastuzumab
+ docetaxel (n = 70)
T-DM1 (n = 67)
Median
PFS, mo
Hazard
ratio 95% CI
Log-rank
P value
9.2
14.2
0.59 0.36– 0.97 0.035
CI, confidence interval; INV, investigator; PD, progressive disease; PFS, progression-free survival.
1.0
0.8
0.6
0.4
0.2
0.0
0 2 4 6 8 10 12 14 16 18 20
Due to
TDM-1
Cross
over
EMILIA Study Design:
Primary End Points:
PFS by independent review, OS, and safety
Key Secondary End Points:
PFS by investigator, ORR, duration of response, time to symptom progression
1:1
HER2+ (central) LABC
or MBC (N=980)
• Prior taxane and
trastuzumab
• Progression on
metastatic tx or
within 6 mos of
adjuvant tx
T-DM1
3.6 mg/kg q3w IV
Capecitabine
1000 mg/m2 orally bid, days 1–14,
q3w
+
Lapatinib 1250 mg/day orally qd
PD
PD
EMILIA: Progression-Free Survival
by Independent Review
Median (mos) No. events
Cap + Lap 6.4 304
T-DM1 9.6 265
Stratified HR=0.650 (95% CI, 0.55, 0.77)
P<0.0001
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Proportionprogression-free
Time (mos)
Unstratified HR=0.66 (P<0.0001).
EMILIA: Overall Survival:
Interim Analysis
Time (mos)
Proportionsurviving
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
77.0% 65.4%
47.5%
84.7%
Median (mos) No. events
Cap + Lap 23.3 129
T-DM1 NR 94
Stratified HR=0.621 (95% CI, 0.48, 0.81)
P=0.0005
Efficacy stopping boundary P=0.0003 or
HR=0.617
Unstratified HR=0.63 (P=0.0005).
NR=not reached.
TH3RESA Study design:
HER2-positive (central)
advanced BC
(N=600)
≥2 prior HER2-directed
therapies for advanced BC
Prior treatment with
trastuzumab, lapatinib,
and a taxane
T-DM1
3.6 mg/kg q3w IV
(n=400)
Treatment of
physician’s choice
(TPC)a
(n=200)
PD
PD
T-DM1c
(optional
crossover)
1
2
Co-primary endpoints:
PFS by investigator and OS
Key secondary endpoints:
ORR by investigator and safety
A: TPC single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed
therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy.
Wildiers, et al. ESMO 2013
TPC* Treatment Category
TPC* treatment category
TPC
(n=184a)
Combination with HER2-directed agent, % 83.2
Chemotherapyb + trastuzumab 68.5
Lapatinib + trastuzumab 10.3
Hormonal therapy + trastuzumab 1.6
Chemotherapyb + lapatinib 2.7
Single-agent chemotherapy b
16.8
T-containing
80.4
a Includes patients who received study treatment.
b The most common chemotherapy agents used were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel.
* Treatment of physicians choice
Wildiers, et al. ESMO 2013
PFS by Investigator Assessment
Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.
Unstratified HR=0.521 (P<0.0001).
* TPC: Treatment of physicians choice
Wildiers, et al. ESMO 2013
PFS for Patients Treated With Trastuzumab-
Containing Regimens
Unstratified HR=0.54 (P<0.0001).
* TPC: Treatment of physicians choice
Wildiers, et al. ESMO 2013
First Interim OS Analysis
44 patients in the TPC arm received crossover T-DM1 treatment after documented
progression.
Unstratified HR=0.57 (P=0.004).
* TPC: Treatment of physicians choice Wildiers, et al. ESMO 2013
ORR in Patients With Measurable Disease
By Investigator Assessment
Wildiers, et al. ESMO 2013
* TPC: Treatment of physicians choice
Overview of AEs
TPC
(n=184a)
T-DM1
(n=403a)
All-grade AEs, % 88.6 93.5
Grade ≥3 AEs b % 43.5 32.3
AEs leading to treatment
discontinuation,c % 10.9 6.7
AEs leading to dose
reduction, % 19.6 9.4
LVEF <50% & ≥15%
decrease from baselined % 1.1 1.5
a One patient randomized to the TPC arm received 2 cycles of T-DM1 by mistake; this patient was included in the T-DM1 group
for safety analyses. b Grade 5 AEs: TPC, 1.6% (n=3); T-DM1, 1.2% (n=5). Three were considered related to T-DM1: hepatic
encephalopathy, subarachnoid hemorrhage, and pneumonitis. One was considered related to TPC: noncardiogenic pulmonary
edema. c For any study drug. d No patient experienced an LVEF <40%. LVEF, left ventricular ejection fraction
Wildiers, et al. ESMO 2013
Summary: HER2+ MBC
• 1st Line: Pertuzumab/trastuzumab/taxane
• 2nd/3rd line: T-DM1
• Other options after progression:
– Trastuzumab/lapatinib
– Lapatinib/capecitabine
– Trastuzumab/other chemo
– Trastuzumab or Lapatinib + AI
– ??everolimus-based therapy

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Treatment paradigms in the management of mbc bgicc 2014

  • 1. Treatment Paradigms in the Management of MBC Mohamed Abdulla M.D. Prof. of Clinical Oncology Kasr El-Aini School of Medicine Cairo University BGICC – Roche Symposium Fairmont Hotel & Tower –Heliopolis Thursday, 09/01/2014
  • 2. Breast Cancer: Basic Facts: • Most frequently encountered cancer among females. • Most common cause of cancer related deaths among females. • A national problem. • Heterogeneous disease. • HER2 +++ (20 – 25%)  Poor prognosis. • Anti-HER2 Targeted Therapies  Changing the landscape of disease.
  • 3. Breast Cancer: A Heterogeneous Disease: Intrinsic Subtype Clinico-Pathologic Definition Luminal A ER &/or PR +ve HER2 –ve Ki-67 (<20%) Luminal B (HER2 –ve) ER &/or PR +ve HER2 –ve Ki-67 (>20%) Luminal B (HER2 +ve) ER &/or PR +ve HER2 +ve Ki-67 (Any) Erb-B2 Overexpression ER & PR –ve HER2 +ve Basal Like (Triple Negative) ER & PR –ve HER2 -ve SurvivalProbability Duration (months) Sorlie et al PNAS 2001
  • 4. Breast Cancer: Major Criteria of Metastatic Disease: Major Criteria of Metastases Clinical Implications Heterogeneity between primary tumor and metastatic disease:  ER: 13%  PR: 28%  HER2: 5% Ineffective therapy based on primary tumor characteristics Redundancy of mechanistic pathways of growth The need for combination therapy Variable dormancy of malignant cells Delayed relapse Contribution of cancer initiating cells Therapies targeting stem cells Breast Cancer Metastases: Issues for the personalization of its prevention and treatment. Mariano N. et al. The American Journal of Pathology, Vol. 183, No. 4, October 2013.
  • 5. Breast Cancer: HER2 Structure & Function: PI3K MAPK Stat Growth & Proliferation Angiogenesis Invasion & Metastases
  • 6. Breast Cancer: HER2 Directed Therapies Has Changed The Landscape of Disease: Dawood S, et al. J Clin Oncol. 2010;28(1):92-98. 12 60483624 0.2 0.8 0.6 0.4 1.0 Her2 +ve with Hereptin n=191 Her2 –ve n=1782 Her2 +ve no Herceptin n=191
  • 7. Trastuzumab Approval (advanced BC) 2004 2005 20061998 20032002 20082007 Her2+ Advanced Breast cancer: Major clinical advances: 20102009 Phase 2 Randomized trial TDM1 Phase 3 Pertuzumab Lapatinib Approval (advanced BC) Initial studies for: TDM1, Pertuzumab, Afatinib, Neratinib TDM1 Approval 2L mBC Pertuzumab approved (advanced BC) Everolimus Approval (advanced BC) White = clinical study results prior to 2013. Yellow = regulatory approvals prior to 2013. 2011 2012 2013 Adapted from Krop I. SABCS 2011, Abst ES1-3.
  • 8. Breast Cancer: Trastuzumab: 1 Agent & 4 Targets:
  • 9. Breast Cancer: Trastuzumab: 1 Agent & 4 Targets:
  • 10. Breast Cancer: Trastuzumab: 1 Agent & 4 Targets:
  • 11. Breast Cancer: Trastuzumab: 1 Agent & 4 Targets:
  • 12. 1. Previously unexposed. 2. Previously exposed: a. > 6 months. b. < 6 months. 3. 2nd line or later treatment. Her2+ Advanced Breast cancer: Clinical Scenarios:
  • 13. 1. Unexposed Patients: • 469 MBC • No ttt for M-Stage. • HER2 +ve Chemotherapy + Trastuzumab Chemotherapy (AC) + Trastuzumab (Paclitaxel) + Trastuzumab AC Paclitaxel Use of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921
  • 14. 1. Unexposed Patients: Use of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921
  • 15. 1. Unexposed Patients: Use of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921
  • 16. 1. Unexposed Patients: H0648g and M77001:Overall survival with trastuzumab first-line therapy * IHC 2+ tumours not confirmed by in situ hybridisation; subgroup analysis p value not reported. † Statistically significant IHC 3+/FISH-positive. 1. Smith IE. Anticancer Drugs 2001; 12(Suppl. 4):S3–S10; 2. Slamon DJ, et al. N Engl J Med 2001; 344:783–792; 3. Marty M, et al. J Clin Oncol 2005; 23:4265–4274. Survivalprobability Time (months) Trastuzumab + docetaxel (n = 92) 22.7 31.2 +37% p = 0.0325† Docetaxel (n = 94) 8.5 months 0 0.2 0.4 0.6 0.8 1.0 0 5 10 15 20 25 30 35 5040 45 M770013 H0648g*1,2 (IHC 3+ paclitaxel subgroup) Time (months) 1.0 Survivalprobability 0.6 0.8 0.4 0.2 0.0 18 25 Trastuzumab + paclitaxel (n = 68) Paclitaxel (n = 77) 0 5 15 20 25 30 35 40 45 7 months 10
  • 17. Herceptin vs Lapatinib in 1LmBC: COMPLETE STUDY (EGF 108919) Primary end point: PFS Secondary end points: OS & safety Karen A. Gelmon ASCO 2012 LBA no. 671 • MBC Her 2+ve (IHC 3+ and/or FISH+) • 1L MBC (no prior chemo) (n=636) Taxane based Chemotherapy +Lapatinib (n=318) Taxane based chemotherapy +Herceptin (n=318)
  • 18. COMPLETE study (108919) Progression Free Survival Karen A. Gelmon ASCO 2012 LBA no. 671 PFS: intent to ttt population PFS: centrally confirmed HER 2+
  • 19. COMPLETE STUDY (EGF108919) Over all survival analysis Karen A. Gelmon ASCO 2012 LBA no. 671 OS: intent to ttt population OS: centrally confirmed HER 2+
  • 20. Unexposed Patients: MBC, HER2 +ve  1L Treatment: NCCN. Clinical practice guidelines in oncology: breast cancer. v.2.2013. Trastuzumab Chemotherapy: • Taxanes. • Venoralbine • Capecitabine • Gemcitabine +/- Platinum
  • 21. Pertuzumab and Trastuzumab have complementary mechanisms of action 1. Eigenbrot et al Proc Natl Acad Sci. 2010. 107: 15039–15044. 2. Cho et al. Nature 2003;421:756–760. HER2 Pertuzumab1 Trastuzumab2 HER3 ShcGRb2Sos RAF MEK MAPK P P Akt PI3K P P P P PDK1 PP P mTOR Cyclin 01 GSK36 NF  B BAD p27
  • 22. CLEOPATRA: Study design: Baselga J, et al. N Engl J Med 2012; 366:109–119. Randomisation: Stratified by geographic region and prior treatment status ([neo]adjuvant chemotherapy received or not) Dosing: –Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance q3w –Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance q3w –Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated q3w Patients with HER2-positive mBC centrally confirmed (N = 808) Placebo + trastuzumab (n = 406) 1:1 Docetaxel* ≥6 cycles recommended PD Pertuzumab + trastuzumab (n = 402) Docetaxel* ≥6 cycles recommended PD *<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion PD, progressive disease R
  • 23. Primary endpoint: Independently assessed PFS D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab 0 5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80 90 100 Time (months) Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months HR = 0.62 95% CI 0.51‒0.75 p<0.0001 ∆ = 6.1 months Progression-freesurvival(%) Baselga et al. N Engl J Med 2011
  • 24. CLEOPATRA: Patients receiving the pertuzumab-based regimen had a 34% reduction in the risk of death HR 0.66; 95% CI = 0.52–0.84 p = 0.0008 Placebo + trastuzumab + docetaxel 154 events; median 37.6 months Pertuzumab + trastuzumab + docetaxel 113 events; median not reached Overallsurvival(%) Time (months) 10 20 30 40 50 60 70 80 90 0 100 10 20 300 5 15 25 35 5540 45 50 Swain SM, et al. Lancet Oncol 2013; 14:461–471. Not reached 37.6 months
  • 25. Independently assessed PFS by prior Trastuzumab therapy in patients with (neo)adjuvant therapy Placebo + trastuzumab + docetaxel Median PFS, months Pertuzumab + trastuzumab + docetaxel Median PFS, months Hazard ratio (CI) Prior (neo)adjuvant trastuzumab treatment (n = 88) 10.4 16.9 0.62 (0.35‒1.07) No prior (neo)adjuvant trastuzumab treatment (n = 288) 12.6 21.6 0.60 (0.43‒0.83) Baselga et al. N Engl J Med 2011
  • 26. Unexposed Patients: MBC, HER2 +ve, 1L Treatment: • Trastuzumab + Pertuzumab + Chemotherapy. • Trastuzumab + Chemotherapy.
  • 27. Exposed Patients: MBC, HER2 +ve, 2L Treatment: Trastuzumab + Chemotherapy Disease Progression Trastuzumab + Pertuzumab Chemotherapy Disease Progression • Switch CTh. • Lapatinib. • Investigational.
  • 28. Exposed Patients: MBC, HER2 +ve, 2L Treatment: Ado-Trastuzumab Emtansine (T-DM1): Approved in 2013
  • 29. Ado-Trastuzumab Emtansine: T-DM1: Lewis Phillips GD, et al. Cancer Res. 2008; 68:9280–9290.
  • 30. Primary endpoints: PFS by INV, safety Key Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control TDM4450 Study Design Randomized, phase II, international, open-label study 1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137) T-DM1 3.6 mg/kg Q3W until PD Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m2 Q3W Crossover T-DM1PD Perez EA, et al. Abstr LBA3. ESMO 2010
  • 31. Time (months) BO21976 (TDM4450g): PFS by investigator Randomised patients Hurvitz SA, et al. J Clin Oncol 2013; 31:1157–1163. Progression-freesurvival(proportion) Hazard ratio and log-rank p-value were from stratified analysis Trastuzumab + docetaxel (n = 70) T-DM1 (n = 67) Median PFS, mo Hazard ratio 95% CI Log-rank P value 9.2 14.2 0.59 0.36– 0.97 0.035 CI, confidence interval; INV, investigator; PD, progressive disease; PFS, progression-free survival. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 Due to TDM-1 Cross over
  • 32. EMILIA Study Design: Primary End Points: PFS by independent review, OS, and safety Key Secondary End Points: PFS by investigator, ORR, duration of response, time to symptom progression 1:1 HER2+ (central) LABC or MBC (N=980) • Prior taxane and trastuzumab • Progression on metastatic tx or within 6 mos of adjuvant tx T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w + Lapatinib 1250 mg/day orally qd PD PD
  • 33. EMILIA: Progression-Free Survival by Independent Review Median (mos) No. events Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.650 (95% CI, 0.55, 0.77) P<0.0001 0.0 0.2 0.4 0.6 0.8 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Proportionprogression-free Time (mos) Unstratified HR=0.66 (P<0.0001).
  • 34. EMILIA: Overall Survival: Interim Analysis Time (mos) Proportionsurviving 0.0 0.2 0.4 0.6 0.8 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 77.0% 65.4% 47.5% 84.7% Median (mos) No. events Cap + Lap 23.3 129 T-DM1 NR 94 Stratified HR=0.621 (95% CI, 0.48, 0.81) P=0.0005 Efficacy stopping boundary P=0.0003 or HR=0.617 Unstratified HR=0.63 (P=0.0005). NR=not reached.
  • 35. TH3RESA Study design: HER2-positive (central) advanced BC (N=600) ≥2 prior HER2-directed therapies for advanced BC Prior treatment with trastuzumab, lapatinib, and a taxane T-DM1 3.6 mg/kg q3w IV (n=400) Treatment of physician’s choice (TPC)a (n=200) PD PD T-DM1c (optional crossover) 1 2 Co-primary endpoints: PFS by investigator and OS Key secondary endpoints: ORR by investigator and safety A: TPC single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy. Wildiers, et al. ESMO 2013
  • 36. TPC* Treatment Category TPC* treatment category TPC (n=184a) Combination with HER2-directed agent, % 83.2 Chemotherapyb + trastuzumab 68.5 Lapatinib + trastuzumab 10.3 Hormonal therapy + trastuzumab 1.6 Chemotherapyb + lapatinib 2.7 Single-agent chemotherapy b 16.8 T-containing 80.4 a Includes patients who received study treatment. b The most common chemotherapy agents used were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel. * Treatment of physicians choice Wildiers, et al. ESMO 2013
  • 37. PFS by Investigator Assessment Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months. Unstratified HR=0.521 (P<0.0001). * TPC: Treatment of physicians choice Wildiers, et al. ESMO 2013
  • 38. PFS for Patients Treated With Trastuzumab- Containing Regimens Unstratified HR=0.54 (P<0.0001). * TPC: Treatment of physicians choice Wildiers, et al. ESMO 2013
  • 39. First Interim OS Analysis 44 patients in the TPC arm received crossover T-DM1 treatment after documented progression. Unstratified HR=0.57 (P=0.004). * TPC: Treatment of physicians choice Wildiers, et al. ESMO 2013
  • 40. ORR in Patients With Measurable Disease By Investigator Assessment Wildiers, et al. ESMO 2013 * TPC: Treatment of physicians choice
  • 41. Overview of AEs TPC (n=184a) T-DM1 (n=403a) All-grade AEs, % 88.6 93.5 Grade ≥3 AEs b % 43.5 32.3 AEs leading to treatment discontinuation,c % 10.9 6.7 AEs leading to dose reduction, % 19.6 9.4 LVEF <50% & ≥15% decrease from baselined % 1.1 1.5 a One patient randomized to the TPC arm received 2 cycles of T-DM1 by mistake; this patient was included in the T-DM1 group for safety analyses. b Grade 5 AEs: TPC, 1.6% (n=3); T-DM1, 1.2% (n=5). Three were considered related to T-DM1: hepatic encephalopathy, subarachnoid hemorrhage, and pneumonitis. One was considered related to TPC: noncardiogenic pulmonary edema. c For any study drug. d No patient experienced an LVEF <40%. LVEF, left ventricular ejection fraction Wildiers, et al. ESMO 2013
  • 42. Summary: HER2+ MBC • 1st Line: Pertuzumab/trastuzumab/taxane • 2nd/3rd line: T-DM1 • Other options after progression: – Trastuzumab/lapatinib – Lapatinib/capecitabine – Trastuzumab/other chemo – Trastuzumab or Lapatinib + AI – ??everolimus-based therapy