key issues in the management of metastatic breast cancer
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Key Issues in the Management of
Metastatic Breast Cancer
Case 2 (HER2 positive), v5 - July 3, 2009 - to Abraxis Medical
First-Line Treatment of HER2-Positive ER-Negative Metastatic Breast Cancer
Case
Case: History
• 47-year-old woman with invasive ductal carcinoma– 2.0 cm– Node negative– ER negative– HER2 positive
• Treated with lumpectomy, adjuvant chemotherapy with AC x 4, and radiation
• Treatment completed in June 2004
Case: Clinical Presentation
• In 2007, presents with nausea and RUQ pain
• CT abdomen: diffuse liver metastases; marker lesion 5.5 cm
• CT chest: multiple pulmonary lung nodules all <1.0 cm
• Lytic bony metastases through thoracic and lumbar spine
• Mildly elevated transaminases, normal bilirubin
• ECOG PS = 1RUQ = right upper quadrantECOG = Eastern Cooperative Oncology GroupPS = performance status
Case: What Are the Treatment Options?
1. Taxane + trastuzumab
2. Vinorelbine + trastuzumab
3. Capecitabine + trastuzumab
4. Taxane + carboplatin + trastuzumab (TCH)
5. Other
Case: Evidence-Based Treatment Options
• Randomized data: with trastuzumab– Paclitaxel and doxorubicin/cyclophosphamide– Docetaxel – Taxane and platinum
• Phase II data: multiple agents + trastuzumab– Vinorelbine– Capecitabine– Gemcitabine– nab-paclitaxel
Chemotherapy + Trastuzumab for MBC that Overexpresses HER2
Slamon DJ et al. N Engl J Med 2001;344:783-92.
CT = chemotherapyKPS = Karnofsky performance status
Slamon et al. N Engl J Med 2001
* Doxorubicin or epirubicin
• MBC• HER2 overexpression• No prior CT for MBC• Measurable disease• KPS >60%• n = 469
No previous anthracyclines
Previous anthracyclines
Trastuzumab + anthracycline* +
cyclophosphamide(n = 143)
Anthracycline* + cyclophosphamide
(n = 138)
Trastuzumab + paclitaxel(n = 92)
Paclitaxel (n = 96)
RANDOMIZATION
Chemotherapy Alone
(n = 234)
Chemotherapy +Trastuzumab
(n = 235)P
Median survival (months) 20.3 25.1 0.046
1-year survival (%) 67 78 0.008
Median TTP (months) 4.6 7.4 <0.001
RR (%) 32 50 <0.001
TTP = time to progressionRR = response rate
Slamon DJ et al. N Engl J Med 2001;344:783-92.
Slamon et al. N Engl J Med 2001
First-Line Chemotherapy for HER2-Positive MBC
Results
First-Line Chemotherapy for HER2-Positive MBC
Progression-Free Survival
Slamon DJ et al. N Engl J Med 2001;344:783-92.
Slamon et al. N Engl J Med 2001
First-Line Chemotherapy for HER2-Positive MBC
Cardiac Dysfunction
Slamon DJ et al. N Engl J Med 2001;344:783-92.
Slamon et al. N Engl J Med 2001
Anthracycline + Cyclophosphamide +
Trastuzumab(n = 143)
Anthracycline + Cyclophosphamide
Alone(n = 135)
Paclitaxel + Trastuzumab
(n = 91)
Paclitaxel Alone(n = 95)
Cardiac dysfunction,symptomatic or not (n, %)
39 (27) 11 (8) 12 (13) 1 (1)
Cardiac dysfunction,NYHA class III or IV (%) 16 3 2 1
Death due to cardiac dysfunction (n) 1 1 0 0
NYHA = New York Heart Association
First-Line Chemotherapy for HER2-Positive MBC
M77001: Design
Marty M et al. J Clin Oncol 2005;23:4265-74.
LVEF = left ventricular ejection fraction
• MBC• HER2 positive• No prior CT for MBC• No prior taxanes• Baseline LVEF >50%• n = 186
Trastuzumab 4 mg/kg loading dose then 2 mg/kg q wk
until disease progression+ docetaxel 100 mg/m2
q 3 wk 6 cycles(n = 92)
Docetaxel 100 mg/m2 q 3 wk 6 cycles
(n = 94)
RANDOMIZATION
First-Line Chemotherapy for HER2-Positive MBC
M77001: Results
* Kaplan-Meier estimate Intent-to-treat population
Trastuzumab + Docetaxel
(n = 92)
Docetaxel Alone
(n = 94)P
ORR (%) 61 34 0.0002
Median DR (months) 11.7 5.7 0.009
Median TTP (months) 11.7 6.1 0.0001
Median OS* (months) 31.2 22.7 0.0325
Marty M et al. J Clin Oncol 2005;23:4265-74.
ORR = overall response rateDR = duration of responseTTP = time to progression OS = overall survival
First-Line Chemotherapy for HER2-Positive MBC
M77001: Toxicity
Marty M et al. J Clin Oncol 2005;23:4265-74.
Trastuzumab + Docetaxel
(n = 92)
Docetaxel Alone
(n = 94)
Grade 3/4 leukopenia (%) 20 15
Grade 3/4 neutropenia (%) 32 22
Febrile neutropenia/ neutropenic sepsis (%) 23 17
Asymptomatic decrease in LVEF ≥15% (%) 17 8
Symptomatic CHF (n) 2 0
LVEF = left ventricular ejection fractionCHF = congestive heart failure
• Stratification:– Prior chemotherapyo Adjuvant/neoadjuvant
– Centre• Primary efficacy end point: TTP
8 TH
8 TCH
Docetaxel 100 mg/m2 q 3 wk
Docetaxel 75 mg/m2 q 3 wkCarboplatin AUC: 6 mg/mL/min
Trastuzumab*
Trastuzumab*
First-Line Chemotherapy for HER2-Positive MBC
BCIRG 007: Taxane and Platinum
Forbes JF et al. ASCO 2006:LBA516.Pieńkowski T et al. ESMO 2006:148PD.
FISH = fluorescent in situ hybridizationAUC = area under the curveTTP = time to progression
HER2 positive by FISHn = 263
* 4 mg/kg IV, day 1, cycle 1; 2 mg/kg IV weekly starting day 8; 6 mg/kg IV q 3 wk starting 3 wk after last chemotherapy
First-Line Chemotherapy for HER2-Positive MBC
BCIRG 007: Results
TH(n = 131)
TCH(n = 132)
Best overall response (n, %)
CR 24 (18) 23 (17)
PR 71 (54) 73 (55)
SD/NC 24 (18) 20 (15)
PD 11 (8.4) 11 (8.3)
NE 1 (0.8) 5 (3.8)
RR (CR + PR) (%)72.5
(64.0–80)72.7
(64.3–80.1)
Clinical benefit rate (%)CR, PR, or SD for >24 wk 67.2 66.7
CR = complete responsePR = partial responseSD = stable diseaseNC = no change PD = progressive diseaseNE = not evaluableRR = response rate
Forbes JF et al. ASCO 2006:LBA516.
First-Line Chemotherapy for HER2-Positive MBC
BCIRG 007: Time to Progression
Pieńkowski T et al. ESMO 2006:148PD. Intent-to-treat population
Randomized Trials: Trastuzumab Added to Chemotherapy in First-Line MBC
Chemotherapy nRR (%) TTP (months)
Chemo-therapy
Chemo-therapy +
TrastuzumabChemo-therapy
Chemo-therapy +
Trastuzumab
Docetaxel1 186 34 61 6.1 11.7
Paclitaxel2 188 17 41 3.0 6.9
Paclitaxel3 124 57 75 6.8 10.0
Doxorubicin or epirubicin +
cyclophosphamide2
281 42 56 6.1 7.8
1. Marty M et al. J Clin Oncol 2005;23:4265-74. 2. Slamon DJ et al. N Engl J Med 2001; 344:783-92. 3. Gasparini G et al. Breast Cancer Res Treat 2007;101:355-65.
RR = response rateTTP = time to progression
Phase II Trials
1. Vinorelbine + trastuzumab
2. Capecitabine + trastuzumab
3. Gemcitabine + trastuzumab
4. nab-paclitaxel and trastuzumab
Phase II Trials: Trastuzumab Added to Chemotherapy in MBC
ChemotherapyLine of
Therapy n RR (%) TTP (months)
Vinorelbine1 First 54 68 5.6
Vinorelbine2 Various 40 75 7.9 (first line)3.7 (second/third line)
Vinorelbine3 First 40 78 17Capecitabine4 First 43 63 Not reachedGemcitabine5 Third 64 38 5.8
nab-paclitaxel6 First 17 64.7 NR1. Burstein HJ et al. J Clin Oncol 2003;21:2889-95. 2. Burstein HJ et al. J Clin Oncol 2001;19:2722-30. 3. Jahanzeb M et al. Oncologist 2002;7:410-7. 4. Xu L et al. SABCS 2006:2065.
RR = response rateTTP = time to progressionNR = not reported
5. O’Shaughnessy JA et al. Clin Breast Cancer 2004;5:142-7.
6. Mirtsching B et al. ASCO 2008:1118.
Case: What Are the Treatment Options?
1. Taxane + trastuzumab
2. Vinorelbine + trastuzumab
3. Capecitabine + trastuzumab
4. Taxane + carboplatin + trastuzumab (TCH)
Case: Treatment
• Docetaxel 100 mg/m2
• Trastuzumab– 4 mg/kg loading dose over 90 min; 2 mg/kg weekly
maintenance dose over 30 min
• After 2 cycles:– Liver enzymes normalize– Patient feels better
Case: Duration of Chemotherapy Treatment + Trastuzumab
• Options:– Continue chemotherapy until patient has dose-
limiting toxicities?– Continue chemotherapy until 2 cycles past best
response?– Continue chemotherapy for 6 cycles total?– Other?
Case: Progress
• Treated with 4 cycles of docetaxel then dose reduced by 20% due to neutropenia– Total of 6 cycles– Dose-limiting sensory neuropathy and peripheral edema– CT abdomen: marker liver lesion reduced from 5.5 to 2.0 cm
• Continued on single-agent trastuzumab 5 months
• Increasing liver enzymes
• CT abdomen: progressive liver metastases
Case: Treatment Options
1. Stop trastuzumab and start vinorelbine
2. Stop trastuzumab and start capecitabine
3. Continue trastuzumab and start capecitabine
4. Initiate lapatinib + capecitabine
von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S
Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/ Breast International Group 03-05 study
von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.
GBG-26: First Randomized Phase III Study to Investigate Continuation of Trastuzumab
• Primary end point: TTP• Study closed early (IDMC)
TTP = time to progressionIDMC = independent data-monitoring committee* First-line treatment for MBC: n = 111; adjuvant treatment: n = 3
Progression under taxane + trastuzumab (n = 114*) or trastuzumab monotherapy/ trastuzumab + nontaxane (n = 42)
Capecitabine 2500 mg/m2 bid days 1–14 q 21 days
+ continuation of trastuzumab 6 mg/kg q 3 wk
(n = 78)
Capecitabine 2500 mg/m2 bid days 1–14 q 21 days
(n = 78)
RANDOMIZATION
von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.
GBG-26: Continuation of Trastuzumab Significantly Improves Response Rate
OR = odds ratioCR = complete responsePR = partial responseSD = stable diseasePD = progressive disease
Population that received at least one cycle of allocated treatmentResponse to treatment not assessed: combination arm, 2.6%; capecitabine arm, 8.1%
OR: 2.50P = 0.0115
von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.
GBG-26: Progression-Free Survival
Median TTPCapecitabine (X): 5.64 months (4.16–6.30)Capecitabine + trastuzumab (H): 8.16 months (7.25–11.21)
Unadjusted HR*: 0.685 (0.482–0.974)P = 0.0338 (2-sided log rank)
* Intent-to-treat population
von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.
GBG-26: Overall Survival
Median Overall SurvivalCapecitabine (X): 20.39 months (17.77–24.66)Capecitabine + trastuzumab (H): 25.48 months (19.02–30.69)
Unadjusted HR*: 0.763 (0.477–1.220)P = 0.2570 (2-sided log rank)
* Intent-to-treat population
von Minckwitz G et al. J Clin Oncol 2009;27:1999-2006.
Lapatinib: Mechanism of Action
Image: GlaxoSmithKline
MAPKMAPKAktAkt
SosSos
PI3KPI3K
ShcShc RasRas
RafRaf
MAPKMAPK
Grb2Grb2ATPATP
PPAktAkt
Proliferationpathway
Survivalpathway
Normal activation by ATP Activation blocked by lapatinib
Survivalpathway
Proliferationpathway
ErbB1 ErbB2 ErbB1 ErbB2
Lapatinib
Phase III Trial of Capecitabine ± Lapatinib in Advanced or MBC
• Primary end point: TTP• Secondary end points: PFS, OS, ORR,
rate of clinical benefit, and safety
Geyer CE et al. N Engl J Med 2006;355:2733-43.
Geyer et al. N Engl J Med 2006
IHC = immunohistochemistryFISH = fluorescent in situ hybridizationTTP = time to progressionPFS = progression-free survivalOS = overall survivalORR = overall response rate
• Stage IIIB or IIIC with T4 lesion, or MBC that has progressed
• HER2 positive (IHC 3+ or 2+ with FISH)• Unlimited prior therapies, but no prior
capecitabine• Prior therapies must include:
– Trastuzumab in metastatic setting– Anthracycline and taxane in either
metastatic or adjuvant setting
Lapatinib 1250 mg/day poCapecitabine 2000 mg/m2/day, days 1–14 q 21 days(n = 163)
Median trastuzumab-discontinuation time = 5.3 wk
Capecitabine 2500 mg/m2/day, days 1–14 q 21 days(n = 161)
Median trastuzumab-discontinuation time = 6.0 wk
RANDOMIZATION
Phase III Trial of Capecitabine ± Lapatinib in Advanced or MBC: TTP
Cameron D et al. Breast Cancer Res Treat 2008;112:533-43.
Cameron et al. Breast Cancer Res Treat 2008
Weeks
Cum
ulat
ive
prog
ress
ion
free
(%
)
Intention-to-treat population
HR = hazard ratioCI = confidence intervalTTP = time to progression
(n = 198)(n = 201)
Phase III Trial of Capecitabine ± Lapatinib in Advanced or MBC: Overall Efficacy
Independent assessment, intent-to-treat population* End points based on evaluation by the independent review committee under blinded conditions† Calculated with log-rank test‡ Calculated with Fisher’s exact test
End Point
Lapatinib + Capecitabine
(n = 198)
Capecitabine Alone
(n = 201)
HR(95% CI)
P
Median TTP (months) 6.2 4.30.57
(0.43–0.77)<0.00013*
PFS0.55
(0.4–0.74)<0.001†
ORR (%) (95% CI)23.7
(18.0–30.3)13.9
(9.5–19.5)0.017‡
Clinical benefit (%)(CR + PR + SD ≥6 months)
29.3 17.4 0.008‡
Death (n) (%) 55 (28) 64 (32)
Cameron D et al. Breast Cancer Res Treat 2008;112:533-43.
Cameron et al. Breast Cancer Res Treat 2008
CR = complete responsePR = partial responseSD = stable disease
HR = hazard ratioPFS = progression-free survivalORR = overall response rateCI = confidence interval
Toxicity
Cameron D et al. Breast Cancer Res Treat 2008;112:533-43.
Cameron et al. Breast Cancer Res Treat 2008
Pat
ient
s (%
)
L = lapatinibC = capecitabinePPE = palmar plantar erythrodysesthesia
Summary
• Suppressing HER2 upon progression appears to continue to benefit– Either continue trastuzumab with a change in
chemotherapy or switch to lapatinib
Case: Progress
• Continued trastuzumab– 4 mg/kg loading dose over 90 min; 2 mg/kg weekly
maintenance dose over 30 min
• Started capecitabine 2000 mg/m2 bid
• Tolerated therapy well
• PR after 2 cyclesPR = partial response
Challenges for Physicians in Canada
• Treatment with trastuzumab beyond progression is not funded in many provinces
• Lapatinib is an oral drug; coverage is not yet certain*
• Capecitabine is an oral drug and is not covered in some provinces for patients <65 years without a drug plan
* As of June 2009
HER2-Positive MBC Treatment Summary
• For women with HER2-positive MBC, trastuzumab + chemotherapy should be the treatment of choice– Choice of chemotherapy should be individualized based on
clinical presentation
• Treatment options for patients who progress on trastuzumab:– Continuation of trastuzumab + other chemotherapeutic agents
(phase II data)– Continuation of trastuzumab + capecitabine (phase III data)– Lapatinib + capecitabine (phase III data)– Chemotherapy alone
Treatment Summary
• No gold-standard treatment for MBC• Individualize treatment based on tumour
burden and patient characteristics• Goals of treatment:
– Prolong survival– Relieve symptoms with minimal treatment-related
toxicities (integral part of overall care)
• Discuss clinical trials when appropriate
Key Issues in the Management of
Metastatic Breast Cancer
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