Key Issues in the Management of Metastatic Breast Cancer

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



First-Line Chemotherapy for HER2-Positive MBC

Results


Progression-Free Survival




Cardiac Dysfunction



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


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


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


ORR = overall response rateDR = duration of responseTTP = time to progression OS = overall survival


M77001: Toxicity


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*


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


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.


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



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



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


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


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


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


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)



CR = complete responsePR = partial responseSD = stable disease

HR = hazard ratioPFS = progression-free survivalORR = overall response rateCI = confidence interval

Toxicity



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

Documents

Key Issues in the Management of Metastatic Breast Cancer