lapatinib in breast cancer

Lapatinib in Breast CancerProf. Shad Salim Akhtar

MBBS, MD, MRCP(UK), FRCP(Edin), FACP(USA)Member ASCO, ESMO, UICC, AUICC FellowsMember Global Community Against Cancer UICC

Consultant Medical OncologistChairman Board of DirectorsHakim Sanaullah Cancer CentreSopore, Kashmir, J & K

38 years female mother of 3 children Mastectomy, Axillary node dissection Tumor characteristics

2.5 cms, 3/14 nodes involved No lymphovascular invasion, ER/PR -ve, Her-2/neu +ve (FISH),

Adjuvant therapy AC X 4 Paclitaxel X12 weeks Trastazumab X 5 months

Right upper quadrant painSevere headacheCT scan abdomen

Liver lesions consistent with metastasis 3 Liver biopsy

Adenocarcinoma high grade, ER/PR -ve, Her-2/neu 3+(IHC)

MRI brainFive lesions consistent with metastasis

throughout brainWBRT givenWhat next?

Metastatic Breast Cancer Metastatic breast cancer

6% of all newly diagnosed cases 30% during the course of illness

Brain metastasis Case series

10-16% Autopsy series

20-30% Population based estimates

5.1 % (Barnholtz-Sloan et al: JCO 2004; 22: 2865-72)

Pestalozzi BC et al: Ann Oncol 2008;17:935-44

Survival & Site of Relapse

Site of relapse Median surv (mons)Local alone UndefinedContra-lateral breast 30.2Regional and local 20.6Bone only 21.8Visceral (excluding liver) 13.1Liver only 5.4Central nervous system 4.0

Goldhirsch A et al: J Clin Oncol 1988;6:89

Brain Metastasis Risk FactorsYounger age at presentationHormone receptor negative diseaseVisceral metastasis at relapse

Lung Metastasis free interval <24 monthsPremenopausal at diagnosis

Gori S et al: The Oncologist 2007; 12:766 Silmane K et al: Ann Oncol 2004; 15:1640

ErB2 Over-expression / Amplification & Brain Metastasis

Amplified or over-expressed 25% patients

Metastasis and Primary concordance Near 97% FISH more accurate than IHC

3 fold increased risk of metastasis to viscera (Kallioniemi OP et al:1991)

Lear-Kaul KC et al:Arch Pathol Lab Med 2003; 127:1451-7

Receptor status Brain BreastHer-2/neu +ve 13 13Her-2/neu -ve 16 15Fuchs IB et al J Clin Oncol 2002; 20:4130-3

Brain Metastasis Risk Factors Total number reviewed 9524

Node negative 42% No anthracyclines, taxanes or trastuzumab

Time period 1978-99 Median follow up 13 years Incidence of CNS relapse 5.2% As first site of recurrence 1.3% Pts with lung mets at relapse 16.4%

Pestalozzi BC et al: Ann Oncol 2008;17:935-44

Factors Predicting CNS As First Recurrence

Factor Incidence (10 yrs incidence)

Her-2/neu positive disease 2.7%ER-ve Node positive disease 2.6%ER negative 2.3%Age <35 years 2.2%Node positive (>3 n) disease 2.2%Grade III tumor 2.2%Tumor size >2 cms 1.7%

Pestalozzi BC et al: Ann Oncol 2008;17:935-44

Brain Metastasis Risk Factors

Gabos Z et al: J Clin Oncol 2006; 24:5658

664 patients not treated with trastuzumab; med foll up 3.9 yrs

Incidence of Brain Metastasis Trastuzumab Treated Pts

Melisko ME et al: Nature Clin Pract Oncol 2009; 6:25:33

Abbott NJ et al. (2006) Astrocyte–endothelial interactions at the blood–brain barrierNat. Rev. Neuro. 7: 41–53 doi:10.1038/nrn1824

Figure 3 Pathways across the blood–brain barrier.

Trastuzumab is a large molecule (145 Kda)

Why Do Pts with Trastuzumab Therapy Have Higher Incidence of Brain Mets?

Selection bias Increased survival

Increased follow up time

Therapy Brain Met Incidence

Per 100 person-years of observation

TZ+Ct 9.3-9.8% 16.1CT 7% 15.7

Burstein HJ et al: Ann Oncol 2005; 16:1772-7

This is a view of Indian Administered Kashmir

Brain Metastasis Therapy

Multiple large volumeWBRT Median survival 4.5-6 months

Longer than 1 yr survivalCognitive impairment

No impact on systemic diseaseNieder C et al: Am J Clin Oncol 1999; 22;573-79

Brain Metastasis-TherapyIsolated or low volume

Surgical resectionStereotactic surgery

May follow WBRT Improved local control and may be

survival Survival ? 1year

Gerosa M et al: J Neurosurgery 2000; 97:515-24

Do we have a drug which works in Her-2/neu +ve breast cancer with cerebral metastasis after failure of trastuzumab?

LA

PA

TI

NI

B

Paul B et al: Am J Health-Syst Pharm 2008; 65:1703-10

Lapatinib Orally active small molecule Dual TK inhibitor, reversible

ErbB ErbB2

Phase I studies 7% ORR in heavily pretreated MBC Manageable side effects Effective dose 175-1800 mg/day

Case reports Shrinkage of CNS metastasis

Stein SH et al: Eur J Cancer Suppl 3; 2005:78 (Abst#277)Spector NL et al: J Clin Oncol 2005:23:2502-12

Lapatinib Activity in Breast Cancer

Cameron DA et al: Nature Clin Pract Oncol 2008:5:512-20

Similar to early trastuzumab trials

ORR independent assess 1.4%Clinical benefit –6%

31% Clinical benefit

Phase II Trial Outcome Modest clinical activity

Her-2/neu+ve disease progressing after TZ No clinical activity in chemo refractory

her-2/neu negative disease Time to response 12 weeks Duration of response 28.4 weeks Major side effects (grade 1-2)

Diarrhea Skin rash

Cameron DA et al: Nature Clin Pract Oncol 2008:5:512-20

Lapatinib -Phase II Trial Brain MetastasisSafety and efficacy in Her-2/neu +ve breast

cancer new or progressive brain metastasis Min 1 measurable lesion (1.0 cm dia)

Lapatinib 750 mg BIDAssessment

MRI every 8 wks & FDG-PET wk 1 & 8Primary

Obj resp (CR+PR) in brain by RECISTSecondary

Safety, QOL, PET changes

Lin NU et al: J Clin Oncol 2008; 26:1993-9

Efficacy of Lapatinib CNS Mets39 patients Age 31-76 (52) yrs

All developed brain mets on trastuzumab37 progresses after prior radiation

Median TTP was 3.0 months (95% CI, 2.3 to 3.7 months).For the patient with CNS objective response, TTP was 11.3 months.

Lin NU et al: J Clin Oncol 2008; 26:1993-9

Lapatinib Overall ActivityClinical Category Response

Number %CNS Overall response 1 2.6Complete response 0 0Partial response 1 2.6Stable disease* 6 15.4Non CNSMeasurable disease 16Overall response 4 25Complete response 0 0Partial response 4 25Non measurable disease 23Lin NU et al: J Clin Oncol 2008; 26:1993-9

* Stable disease at both CNS and Non CNS sites >16wks

Volumetric Changes in CNS Lesions

Lin NU et al: J Clin Oncol 2008; 26:1993-9

PR10-30% reduction

>=30% reduction

34/39 pts in the study were analyzed

TTP better if reduction >=10%

EGF105084: Phase II study of lapatinib for brain metastases in ErbB2+ breast cancer

Lapatinib 750 mg b.i.d.

Eligibility criteria:• Stage IV patients with ≥ 1

measurable lesion in the brain

• Unequivocal evidence of new and/or progressive brain metastasis after WBRT or STS

• IHC3+ or FISH gene amplification

• Prior trastuzumab therapy

Two Cohorts:1.ECOG PS 0 or 1

and 1 or 2 trastuzumab-containing regimens

2.ECOG PS 2 or > 2 prior trastuzumab-containing regimens

(Open label phase II study n = 220)

Primary endpoint: CNS objective RR using volumetric MRISecondary endpoints: Safety tolerability, neurological signs and symptoms, progression free and overall survival

Lin NU et al: Clin Cancer Res 2009; 15:1452-9

EGF105084: extension arms

Stratification: PS and number of prior trastuzumab-containing regimens

Lapatinib Monotherapy750 mg BID

PDExtension

arms

Lin NU et al: Clin Cancer Res 2009; 15:1452-9

CT + Lap extra CNS PD with SD in CNSAfter 2006 Cap for CNS progression

Efficacy of Lapatinib MonotherapyCohort A (94) Cohort B (143) Total (237)

Complete response 0 0 0Partial response 6 (6) 9 (6) 15 (6)Stable disease 41 (44) 47 (33) 88 (37)Progressive disease

39 (41) 69 (48) 108 (46)

Unknown 6 (6) 9 (6) 15 (6)Median PFS * 2.73 2.07 2.40Median survival * 9.56 5.49 6.37

Lin NU et al: Clin Cancer Res 2009; 15:1452-9

* Months

Lin NU et al: Clin Cancer Res 2009; 15:1452-9

19 patients 8% 50 (21%) patients

Duration of CNS response in Lap+Cap extension phase pts with >=20% reduction in tumor volume

Lin NU et al: Clin Cancer Res 2009; 15:1452-9

Med PFS 18.4 wks

Volumetric Reduction in CNS Mets

>20% reduction >50% reduction Yes No Yes No

Number* 50 186 19 217Med PFS 3.61 1.87 3.38 2.07Number# 20 30 11 39Med PFS 4.60 1.89 6.21 3.12

* Lapatinib monotherapy #Lapatinib and capecitabine

Lin NU et al: Clin Cancer Res 2009; 15:1452-9

A volumetric reduction of 20% indicates improvement in PFS

19.7% patients in ext arm PFS >6 months

Brain MRIBaseline Week 8

Subject 000133Lin et al, Abs. 1012, ASCO 2007

Here rests the greatest human being ever to walk on the earth: The Prophet Mohammed (PBUH)

He brought hope for humanity

Lapatinib in Advanced Breast Cancer•324 women Her-2/neu +ve LABC/ MBC

•Previous therapy •>= 4 cycles of chemotherapy +trastuzumab

•Randomization •Lap 1250 mg od + /- Cap 2000 mg/m2 in 2 doses

Geyer CE et al: N Eng J Med 2006; 355:2733-43

Lapatinib Efficacy End Points

Geyer CE et al: N Eng J Med 2006; 355:2733-43

CNS as the first event Monotherapy group 11Combination group 4

Trastuzumab Wash Out

Geyer CE et al: N Eng J Med 2006; 355:2733-43

First Line MBC

Leo DA et al: J Clin Oncol 2008:26:1-12

Her-2/neu Positive 86All patients 579

Inflammatory Breast Cancer

Cristonfanilli M et al: SABC 2006; Dec 14-17 (Abst#1)

Lapatinib with HT 1286 post menop HR positive MBC 212 international centres No previous therapy Letrozole + Lap (1500 mg) or placebo Her-2 +ve pts (219)

Median PFS 8.2 VS 3.0 months This may be the first line therapy in future

Fricker J: Lancet Oncology: 2009; 10:20

Data from Stephen Johnson, UK

Toxicity we fear

Lapatinib Toxicity

Lin NU et al: J Clin Oncol 2008; 26:1993-9

Adverse events

Vomiting Anorexia

3

15

9

Rash

<1% G3

Gr 3Gr 2

Gr 4

Gr 1

Patie

nts

%

10

20

30

40

50

60

70

0Diarrhea

27

25

13

1

21

6

FatigueNausea

13

74

1

<1

LVEF

3

811

3

48

1% G2

Lin et al, Abs. 1012, ASCO 2007EGF105084

Lin NU et al: Clin Cancer Res 2009; 15:1452-9

Results of an analysis of rash in nine TYKERB clinical trials

Skin events were primarily grade 1/2 (53%) Grade 3 skin events were 6% Grade 4 Nil. Most skin events developed early (Days 1–14) and

were self-limiting Med duration of skin events 25 days 87% skin events did not require dose adjustment

or treatment interruption. 1% resulted in therapy discontinuation Incidence of rash with TYKERB was less than that

seen with other ErbB1 inhibitors

Cardiotoxicity Cardiac muscle cells contain a range of

cellular receptors including ErbB2

Inhibition of the ErbB2 pathway blocks the normal repair-and survival-signaling pathways, reversibly impairing cardiac maintenance without inducing direct cell death

Tykerb appears to be less cardiotoxic

Common Terminology Criteria for Adverse Events v3.0 (CTCAE)

Adverse event

Short name Grade

1 2 3 4 5

L V systolic dysfunc

tion

Left ventricular

systolic dysfunction

Asymptomatic; resting ejection

fraction (EF) <50–60%, shortening

fraction (SF) <24–30%

Asymptomatic; resting EF <50–

40%; SF <24–15%

Symptomatic CHF

responsive to

treatment;

resting EF <40–

20%; SF

<15%

Refractory CHF or poorly

controlled; EF<20%;

intervention such as

ventricular assist device or ventricular

reduction surgery or

heart transplant indicated

Death

Hudis C: N Engl J Med 2007; 357:39-51

Effect of lapatinib on the heart

Patients, n (%)

*Patients presented with dyspnea, palpitations, and signs of CHF, and responded promptly to standard therapy with furosemide, corticosteroids and diuretics, or diuretics and nitroglycerin.†12 patients remain blinded and are assumed to have received lapatinib for analysis purposes.

7 (0.2)51 (1.4)58 (1.6)†Total(N = 3,558)

4 (0.2)34 (1.5)38 (1.7)Neither A nor T(n = 2,201)

1 (0.1)12 (1.6)13 (1.7)

Trastuzumab (with chemotherapy or after A) (n = 759)

2 (0.3)5 (0.8)7 (1.2)Anthracyclines (n = 598)

Symptomatic LVEF decrease*

Asymptomatic LVEF decrease

Decreased LVEFPrior therapy

Perez et al. Annals Oncol 17(suppl. 9) Abstract 1420. Presented at ESMO 2006

2.1% asymptomatic decline in LVEF. Med time to onset 83 days. Resolves completely in almost all

Ongoing Lapatinib Trials

Cameron DA et al: Nature Clin Pract Oncol 2008; 5:512-20

Cameron DA et al: Nature Clin Pract Oncol 2008; 5:512-20

Ongoing Lapatinib Trials

Women with centrally

determined HER2-

positive invasive breast cancer

(N = 8000 planned)

Trastuzumab 8 mg/kg IV (loading dose)* 6 mg/kg every 3 wks for 1 yr

Paclitaxel 80 mg/m2 IV once wkly x 12

Trastuzumab 8 mg/kg (loading dose) 6 mg/kg every 3 wks for 1 yr

Lapatinib 1000 mg orally once daily x 51 wks Paclitaxel 80 mg/m2 IV once wkly x 12

Lapatinib1500 mg orally once daily x

34 wks

Lapatinib 1500 mg/kg orally once daily x 51 wks Paclitaxel 80 mg/m2 IV once wkly x 12

Trastuzumab 4 mg/kg IV (loading dose) 2 mg/kg

once wkly x 11 Paclitaxel 80 mg/m2 IV

once wkly x 12

Surgery, neoadjuvant

anthracycline-based

therapy for 4 cycles;

LVEF ≥ 50

6-week wash-out

ALLTO Trial Design

*For concomitant dosing with paclitaxel, trastuzumab will be given on a weekly schedule (4 mg/kg IV loading dose followed by 2 mg/kg IV weekly). Trastuzumab will revert to the 3-weekly schedule (6 mg/kg without loading dose).

ALTTO endpointsPrimary

Disease-free survivalSecondary (Efficacy)

Overall survival Time to recurrence Time to distant recurrence Incidence of CNS as first site of recurrence

Secondary (Other) Safety and tolerability Translational research Pharmacogenetics research

EGF Pathway EGFR: transmembrane protein

Extracellular Domain

Transmembrane Domain

Intracellular Domain

Tyrosine Kinase Domain

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

EGF Pathway

Shc

PI3K

RafMEKK-1

MEKMKK-7

JNKERK

Ras

mTOR

Grb2

AKT

Sos-1

EGFR activation EGFR activation mediates multiple mediates multiple processesprocesses

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

O’Shaughnessy J, et al. J Clin Oncol ASCO Annual Meeting Proceedings 2008; 26(Suppl.): Abstract 1015 and oral presentation

ErbB1–ErbB1

ErbB1–p95

ErbB1–ErbB3ErbB2–ErbB2

ErbB2–ErbB4

ErbB1–ErbB4

PTENPTEN

Cell proliferationCell survival

Cell mobility and invasiveness

PI3K

Akt

MUC4

PI3K

Akt

SOS

RAS

RAF

MEKMAPK

Transcription

ErbB2–ErbB3

Masking of Her-2 by mucin-4

Increased signaling from other HER receptors

Loss of PTEN (phosphatase and tensin homolog)

Mutation in PI3K gene

Increased IGF-receptor signaling

Loss or absence of external domain of the receptor leading to truncated form of the receptor p95

Toamsello G et al:Expert Rev Anticancer Therapy 2008;12:1883

Lapatinib

Her -2/neu +ve 78 pts Trastuzumab therapy

38 before CNS relapse 29 after CNS relapse

Park IH et al: Ann Oncol 2009; 20:56-62

Trastuzumab Beyond Progression Her-2/neu + progressing on trastuzumab

78 pts in each arm

Trastuzumab + C

Capecitabine

TTP 8.2 m 5.6 mORR 48% 27%

Von Minckwitz G et al: J Clin Oncol 2009; 1999-2006

291 pts Lapatinib Lap+TrastuzumabPFS 8.1 wks 12 wks

Jehanzeb M: J Clin Oncol 2009; 27:1935O’Shaughnessy J et al: J Clin Oncol 2008: 26:44s

Lapatinib CYP34A effect on AUC

Inducers Decrease by 72% Inhibitors Increase by 3-4 fold

Fat content in food (per 500 cals) Low (5%) 3 fold increase High (50%) 4 fold increase

Lower dose may decrease diarrhea

Reddy N et al:Clin Pharm Ther 2007; 81:s16-7

Lapatinib Dose Finding Study LABC or MBC

Untreated in mets setting ErbB2-amplified

Lapatinib doses 1500 once daily 500 mg BID

138 patients randomized

Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

Lapatinib Dose Overall response rate

24% Clinical benefit (CR, PR, SD for 24 weeks)

31% Median time to response

7.9 weeks PFS

4 months 63% 6 months 43%

Adverse events (primarily grade1,2) Diarrhea, rash, pruritis and nausea

Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

Lapatinib Dose VS Response

Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

Lapatinib Dose

“There were no significant differences in clinical activity or the AE profile between the dosing schedules"

Gomez Hl et al: J Clin Oncol 2008; 26:18:2999-3005

Tale of Lapatinib Dose Diarrhea dose related Phase I trials

175-1800 mg/ day OD or BID

Dose in Phase III trial (Geyer trial) 1250 mg/day From phase I (Chu S et al)

Published 9 months after Geyer trial Cost per month 2900 US$

Seruga B et al: J Clin Oncol 2008; 26:18:2940-2

South Asia Income

Country < 1$/day < 2$/dayIndia 44.2% 86.2%Bangladesh 29.1% 77.*%Pakistan 31.0% 84.7%

Kurkure AP et al: UICC Strategies for South Asia 2006: 26

Private Institutions-the conflict?

Patient autonomyPatient autonomy

Profit

What Dose Lapatinib?

250 mg BD with food5 250 mg tablets fastingDecrease the cost by 40%

1700 US$

Ratain MJ et al: J Clin Oncol 2007:25:3397-8 Ciccarese M et al: J Clin Oncol 2008; DOI:10.1200

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