treatment paradigms in the management of mbc bgicc 2014
TRANSCRIPT
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 SymposiumFairmont Hotel & Tower –HeliopolisThursday, 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 +veHER2 –ve
Ki-67 (<20%)
Luminal B (HER2 –ve)
ER &/or PR +veHER2 –ve
Ki-67 (>20%)
Luminal B (HER2 +ve)
ER &/or PR +veHER2 +ve
Ki-67 (Any)
Erb-B2 Overexpression
ER & PR –veHER2 +ve
Basal Like (Triple Negative)
ER & PR –veHER2 -ve
Surv
ival
Pro
bab
ility
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
AngiogenesisInvasion & 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
1.0Her2 +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
PaclitaxelUse 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.
Su
rviv
al p
rob
ab
ilit
y
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
M770013H0648g*1,2
(IHC 3+ paclitaxel subgroup)
Time (months)
1.0
Su
rviv
al p
rob
ab
ilit
y
0.6
0.8
0.4
0.2
0.018 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
Trastuzumab2HER3
ShcGRb2Sos
RAF
MEK
MAPKP
P
Akt
PI3KP P
PP 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 withHER2-positive
mBCcentrally
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 discretionPD, 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 monthsPla + T + D: median 12.4 months
HR = 0.6295% CI 0.51‒0.75p<0.0001
∆ = 6.1 months
Pro
gres
sio
n-f
ree
surv
ival
(%
)
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 = 0.52–0.84p = 0.0008
Placebo + trastuzumab + docetaxel 154 events; median 37.6 months
Pertuzumab + trastuzumab + docetaxel 113 events; median not reached
Ove
rall
surv
ival
(%)
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 +
docetaxelMedian PFS, months
Pertuzumab+ trastuzumab +
docetaxelMedian 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
Dis
eas
e P
rogr
essi
on
Trastuzumab + Pertuzumab
Chemotherapy
Dis
eas
e P
rogr
essi
on
• 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 DesignRandomized, phase II, international, open-label study
1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137)
T-DM13.6 mg/kg Q3W until PD
Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W
+ Docetaxel 75 or 100 mg/m2 Q3W
CrossoverT-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.
Pro
gre
ss
ion
-fre
e s
urv
iva
l (p
rop
ort
ion
)
Hazard ratio and log-rank p-value were from stratified analysis
Trastuzumab
+ docetaxel (n = 70)
T-DM1 (n = 67)
Median
PFS, moHazard
ratio 95% CI
Log-rank
P value
9.2
14.20.59 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
Pro
po
rtio
n p
rogr
ess
ion
-fre
e
Time (mos)
Unstratified HR=0.66 (P<0.0001).
EMILIA: Overall Survival:Interim Analysis
Time (mos)
Pro
po
rtio
n s
urv
ivin
g
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=0.0005Efficacy 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-directedtherapies for advanced BCPrior treatment withtrastuzumab, lapatinib,and a taxane
T-DM13.6 mg/kg q3w IV(n=400)
Treatment ofphysician’s choice(TPC)a
(n=200)
PD
PDT-DM1c
(optionalcrossover)
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 categoryTPC
(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-containing80.4
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 DiseaseBy Investigator Assessment
Wildiers, et al. ESMO 2013
* TPC: Treatment of physicians choice
Overview of AEsTPC
(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