Download - 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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