Nuevos Fármacos (II): Práctica Clínica Erlotinib ... Antonio Diaz-Gonzalez.pdf · Nuevos...
Transcript of Nuevos Fármacos (II): Práctica Clínica Erlotinib ... Antonio Diaz-Gonzalez.pdf · Nuevos...
Nuevos Fármacos (II): Práctica ClínicaNuevos Fármacos (II): Práctica Clínica
Erlotinib, GefitinibDasatinib
Juan A. Díaz-González
Clínica UniversitariaUniversidad de Navarra
GefitinibGefitinibErlotinibErlotinibLapatinibLapatinib
erbBerbB--TKTK
DasatinibDasatinibABLABL--TKTKSRCSRC--TKTK
MoleculeMolecule TargetTarget
SmallSmall--moleculemolecule TirosineTirosine KinaseKinase inhibitorsinhibitors
EGF
TGFααααAmphiregulin
ββββ-cellulinHB-EGF Heregulins
NRG2
NRG3
Heregulins
ββββ-cellulin
Cysteine - rich
domains
Tyrosine - kinase
domain
erbB-1
HER1
EGFR
erbB-2
HER2
neu
erbB-3
HER3
erbB-4
HER4
erbBerbB family family TirosineTirosine KinaseKinase
C-Terminus
100
100
100
44
82
33
36
59
24
48
79
28
EGFR Signal Transduction PathwaysEGFR Signal Transduction Pathways
Nyati MK et al. Nature Rev Cancer 2006
ClinicalClinical AntiAnti--EGF Receptor EGF Receptor TherapiesTherapies
TyrosineTyrosine kinase kinase inhibitorsinhibitors
Monoclonal Monoclonal antibodiesantibodies
Signal Transduction
R R
K K
Ligands
Cetuximab (C225)Panitumumab (ABX-EGF)
Matuzumab (EMD72000)ICR62, MDX447...
Gefitinib (ZD1839, Iressa)Erlotinib (OSI 774, Tarceva)Lapatinib (GW572016, Tykerb)
Gefitinib (ZD1839, Iressa)
• Selective inhibitor of EGFR-TK (did not inhibit: ErbB2, KDR and Flt1, MAPK)
• Competitive inhibitor of ATP binding. Reversible.
• Orally bioavailable
• t1/2 48h
• Antitumor activity: lung, prostate, breast, colon, ovarian
• Chemo and Radiation enhancement
• Phase I:
• 250 mg po qd as minimum dose for clinical response
• 500 mg po qd as MTD for prolonged use
• Acne-like rash & diarrhea (mild)
Iressa Development Strategy NSCLC
IDEAL trialsIDEAL trialsRandomized, 2-dose
(250 vs 500) monotherapystudies in refractory NSCLC
Striking activityin pre-clinical models
well-tolerated
Broad Phase I programdose finding
10% responses in refractory NSCLC
INTACT trialsINTACT trialsRandomized, controlled
combination chemo studies in first combination chemo studies in first lineline (250 vs 500 vs placebo)
1998
2000
39.620.4Rash >grade 1, %
8.0
2.8
37
19
500 mg/d(n=106)
2.7mPFS, months
7.6mOS, months
40.3*SymptomImprovement, %
18.4RR, %
250 mg/d(n=103)
¹ Fukuoka M, et al. J Clin Oncol 2003² Kris MG, et al. JAMA 2003
IDEAL 1IDEAL 1¹¹
•• Randomized Phase IIRandomized Phase II
•• Japan & EuropeJapan & Europe
•• platinum, 1 or 2 prior platinum, 1 or 2 prior regimensregimens
•• Objective Objective tumourtumour response response raterate
•• SafetySafety
IDEAL 2IDEAL 2²²
•• Randomized Phase II.Randomized Phase II.
•• USAUSA
•• platinum and platinum and docetaxeldocetaxel, 2 or , 2 or more prior regimensmore prior regimens
•• Objective Objective tumourtumour response response raterate
•• Symptom improvement rateSymptom improvement rate
7562Rash, %
6
24
35
9
500 mg/d(n=114)
271-year Survival, %
7mOS, months
43*SymptomImprovement, %
12RR, %
250 mg/d(n=102)
* Median time 2 weeks
IDEAL Trials: IDEAL Trials: IressaIressa((N = 416)N = 416)
•• IDEAL IIDEAL I
–– Overall response rate 19%Overall response rate 19%
•• IDEAL IIIDEAL II
–– Overall response rate 10.6% Overall response rate 10.6%
•• Higher rates in Higher rates in females, never females, never smokers, smokers, adenocarcinomaadenocarcinomahistology, and Asianshistology, and Asians
•• No differences between dosesNo differences between dosesin efficacyin efficacy
•• Greater number of adverse Greater number of adverse events at 500events at 500--mg dose mg dose
•• Highly acceptable safety profile Highly acceptable safety profile at at 250250--mg dosemg dose
0.0
0.2
0.4
0.6
0.8
1.0
Time from randomization, mo
0 2 4 6 8 10 12 14 16 18 20 22
250 mg500 mg
Probability of survival
Survival in IDEAL I & II
1. Giaccone G, et al. J Clin Oncol 20042. Herbst RS, et al.. J Clin Oncol 2004
INTACT 1INTACT 1
•• Phase III randomized, doublePhase III randomized, double--blind, placeboblind, placebo--controlled, in chemotherapy controlled, in chemotherapy naive patients with advanced NSCLC.naive patients with advanced NSCLC.¹¹
•• Chemo (Chemo (CDDPCDDP--GemcitabineGemcitabine) + ) + GefitinibGefitinib 500 mg/d, 500 mg/d, GefitinibGefitinib 250 mg/d, or 250 mg/d, or placebo. placebo.
INTACT 2INTACT 2
•• Phase III randomized, doublePhase III randomized, double--blind, placeboblind, placebo--controlled, in chemotherapy controlled, in chemotherapy naive patients with advanced NSCLC.naive patients with advanced NSCLC.22
•• Chemo: (Chemo: (PaclitaxelPaclitaxel--CarboplatinCarboplatin) + ) + GefitinibGefitinib 500 mg/d, 500 mg/d, GefitinibGefitinib 250 mg/d, or 250 mg/d, or placebo. placebo.
48.11.4
66.44.7
79.214.6
Acne-like rash, %
grade 3 or 4, %
9.9
5.0
28.7
QT + placebo
(n=363)
9.88.7mOS, months
5.3
30.4
QT + ZD1839, 250 mg/d (n=365)
4.6mTTP, months
30.0RR, %
QT + ZD1839, 500 mg/d (n=365)
N=1037
48.11.4
66.44.7
79.214.6
Acne-like rash, %
grade 3 or 4, %
9.9
5.0
28.7
QT + placebo
(n=363)
9.88.7mOS, months
5.3
30.4
QT + ZD1839, 250 mg/d (n=365)
4.6mTTP, months
30.0RR, %
QT + ZD1839, 500 mg/d (n=365)
N=1037
48.11.4
66.44.7
79.214.6
Acne-like rash, %
grade 3 or 4, %
9.9
5.0
28.7
QT + placebo
(n=363)
9.88.7mOS, months
5.3
30.4
QT + ZD1839, 250 mg/d (n=365)
4.6mTTP, months
30.0RR, %
QT + ZD1839, 500 mg/d (n=365)
N=1037
48.11.4
66.44.7
79.214.6
Acne-like rash, %
grade 3 or 4, %
9.9
5.0
28.7
QT + placebo
(n=363)
9.88.7mOS, months
5.3
30.4
QT + ZD1839, 250 mg/d (n=365)
4.6mTTP, months
30.0RR, %
QT + ZD1839, 500 mg/d (n=365)
N=1037
INTACT 1 INTACT 2
21.4
1.1
44.5
3.6
56.7
12.6
Acne-like rash, %
grade 3 or 4, %
10.9
6.0
44.8
QT + placebo
(n=363)
9.99.9mOS, months
5.8
50.3
QT + ZD1839, 250 mg/d (n=365)
5.5mTTP, months
49.7RR, %
QT + ZD1839, 500 mg/d (n=365)
N=1093
21.4
1.1
44.5
3.6
56.7
12.6
Acne-like rash, %
grade 3 or 4, %
10.9
6.0
44.8
QT + placebo
(n=363)
9.99.9mOS, months
5.8
50.3
QT + ZD1839, 250 mg/d (n=365)
5.5mTTP, months
49.7RR, %
QT + ZD1839, 500 mg/d (n=365)
N=1093
Erlotinib (OSI 774, Tarceva)
• Small-molecule inhibitor of HER1/EGFR TK (ATP-competitive). Reversible
• Chemical class: quinazoline
• Orally available. 25 mg, 100 mg & 150 mg.
• t1/2= 36h
• G1 arrest, reduces RB phosporilation, increases p27 expression, induces apoptosis
• Other TKs inhibition (dose dependent)
O
O
O
O
N
N
HN
HCI
+
+
HER3
+++BT-20
+++++MDA468
HER2HER1100
80
60
40
20
0
1 10 100 1,000 10,000
Tarceva™ concentration (nM)
Activation (%)
468/P-HER1/EGFR
468/P-MAPK
BT-20/P-HER1/EGFR
BT-20/P-MAPK
+
+
HER3
+++BT-20
+++++MDA468
HER2HER1
+
+
HER3
+++BT-20
+++++MDA468
HER2HER1100
80
60
40
20
0
1 10 100 1,000 10,000
Tarceva™ concentration (nM)
Activation (%)
468/P-HER1/EGFR
468/P-MAPK
BT-20/P-HER1/EGFR
BT-20/P-MAPK
100
80
60
40
20
0
1 10 100 1,000 10,000
Tarceva™ concentration (nM)
Activation (%)
468/P-HER1/EGFR
468/P-MAPK
BT-20/P-HER1/EGFR
BT-20/P-MAPK
Akita R, et al. Proc AACR 2002; #4973
Erlotinib (OSI 774, Tarceva)
Dose: 150 mg po qd (1h before or 2h later food intake)
Dose adjustment: 50 mg reduction
Toxicity
• acneiform rash 65%
• Diarrhea 50%. Loperamida
• Intersticial lung disease 0.8%
Phase I (Hidalgo M. JCO 2001)
Dose-limiting toxicity: diarrhea at 200mg/day po qd
Skin rash observed at all doses, max. moderate at 150mg/day po qd
Placebo 150mg daily
BR.21 study design
RANDOM I zE
Erlotinib* 150mg daily
Previously treated NSCLC
Stratified by:
Centre
Performance status 0/1 vs 2/3
Response to prior Rx
(CR/PR:SD:PD)
Prior regimens
(1 vs 2)
Prior platinum
(yes vs no) *2:1randomization
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease
0 6 12 18 24 30
HR=0.70 (0.58–0.85) Stratified log-rank p<0.001
100
80
60
40
20
0
Percentage
ErlotinibPlacebo
Time (months)0 6 12 18 24 30
HR=0.70 (0.58–0.85) Stratified log-rank p<0.001
100
80
60
40
20
0
Percentage
ErlotinibPlacebo
Time (months)
HR=0.70 (0.58–0.85) Stratified log-rank p<0.001
100
80
60
40
20
0
Percentage
ErlotinibPlacebo
Time (months)
BR.21 Survival
Shepherd F et al. N Engl J Med 2005
TALENT & TRIBUTE trials
• Tarceva™: 150mg/day p.o.
• TRIBUTE: carboplatin and paclitaxel (n=1,079)
• TALENT: gemcitabine and cisplatin (n=1,137)
Patients with HER1/EGFR-positive or -negative, stage IIIB/IV NSCLC
Randomization
Daily oral Tarceva™ +6 cycles of chemotherapy
Placebo + 6 cycles of chemotherapy
Daily oral Tarceva™alone Placebo
Until disease progression Until disease progression
All-patients Never-smokers
TRIBUTE trial
Herbst RS, et al. J Clin Oncol 2005
PA.3: Erlotinib phase III trial pancreatic cancer
Until disease progression or
unacceptable toxicity
Until disease progression or
unacceptable toxicity
Daily oral TarcevaTM + gemcitabine
Daily oral placebo +gemcitabine
Patients with unresectable, locally advanced or metastaticpancreatic cancerRandomization
n=569
Median OS: 6.37 m Median OS: 5.91 mp= 0.034
Moore MJ. ASCO 2005
US Food and Drug Administration
¹ Fukuoka M, et al. J Clin Oncol 2003 ¹ Kris MG, et al. JAMA 2003
² Shepherd FA, et al. N Engl J Med 2005² Moore MJ. Proc Am Soc Clin Oncol 2005
Erlotinib²
Advanced NSCLC after failure of both platinum-based and docetaxel chemotherapy
Gefitinib¹
• Advanced NSCLC after failure of one or more prior chemotherapy regimens
• In combination with gemcitabine for thetreatment of locally advanced, inoperable ormetastatic pancreatic cancer in patients whohave not received previous chemotherapy.
Pao W & Miller VA. JCO 2005
7p12
EGFR mutations and response to EGFR TKI
Nyati MK et al. Nature Rev Cancer 2006
EGFR mutations and response to EGFR TKI
1+1 2+2 1+2
Downstream signaling cascade
Rusnak et al. Mol Cancer Ther 2001Xia et al. Oncogene 2002
Konecny et al. Cancer Res. 2006
Binds to intracellular ATP binding site of EGFR (ErbB-1)and HER2 (ErbB-2)
Blocks downstream signaling through homodimers and heterodimers of EGFR
Mechanism of ActionMechanism of Action
Lapatinib (GW572016, Tykerb)
Lapatinib Dual EGFR/ErbB2 TKI
TyrosineKinase
Lapatinib
IC 50 (nM)
Gefitinib
IC 50 (nM)
Erlotinib
IC 50 (nM)
ErbB1 10.8 16.2 33.1
ErbB2 9.20 646 1010
ErbB4 371 1050 2770
E. Wood et al., Proc AACR 2003, 44 #6187
Lapatanib and Capecitabine vs Cabecitabine in Advanced or Metastatic Breast Cancer
Patients on treatment until progression or unacceptable toxicity, then followed for survival
• Progressive, HER2+ MBC or LABC
• Previously treated with anthracycline, taxane and trastuzumab*
• No prior capecitabine
Lapatinib 1250 mg po qdcontinuously +
Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk
Capecitabine 2500 mg/m2/d podays 1-14 q 3 wk
Stratification:
• Disease sites
• Stage of disease
RANDOMIZE
*Trastuzumab must have been administered for metastatic disease
N=528
Geyer et al, ASCO 2006
Time to Progression
Progression-Free Survival 70
10
20
30
40
50
60
70
80
90
0
100
10 20 30 40 50 600Time (weeks)
Capecitabine
Lapatinib +
Capecitabine
0.00016P-value (log-rank, 1-sided)
69 (43%)45 (28%)Progressed or died*
19.736.9Median TTP, wk
161160No. of pts
0.51 (0.35, 0.74)Hazard ratio (95% CI)
% of patients free from progression
Time (weeks)0 10 20 30 40 50 60 70
Cumulative Progression-Free Survival, %
0
10
20
30
40
50
60
70
80
90
100
0.000045P-value (log-rank, 1-sided)
73 (45%)45 (28%)Progressed or died
0.48 (0.33, 0.70)Hazard ratio (95% CI)
17.936.9Median PFS, wk
161160No. of pts
CapecitabineLapatinib +capecitabine
Geyer et al, ASCO 2006
Lapatanib and Capecitabinevs Cabecitabine Breast cancer
Lapatinib monotherapy is clinically active in heavily pre- treated IBC patients
Lapatinib is well tolerated
• Generally grade 1/2 GI and skin toxicity• Very low cardiac toxicity
• Correlation of ErbB2 (IHC3+ or FISH+) with response
• 62% response rate in ErbB2 overexpressors (1250 mg po qd)
• Clinical activity against HER2+ brain metastases (750 mg po BID)
Preliminary biomarker analysis suggests
Spector et al. ASCO 2006, #502
Lin et al, ASCO 2006, #503
Perez E., ASCO 2006, #583
Incidence of Rash and Other Dermatologic Adverse Events
NA
30
NA
27
62
47
Gefitinib (phase II)
250 mg/d (n=102) NSCLC
250 mg/d (n=103) NSCLC
8
13
15
21
7
10
15
26
45
57
54
67
Gefitinib (phase III)
250 mg/d + cis/gem (n=362) NSCLC
500 mg/d + cis/gem (n=358) NSCLC
250 mg/d + carbo/paclitaxel (n=342) NSCLC
500 mg/d + carbo/paclitaxel (n=342) NSCLC
Agent
Adverse Event (% of patients)
NA
NA
NA
NA
81
66
Erlotinib (phase III)
150 mg/d + carbo/placlitaxel (n=417) NSCLC
150 mg/d + cis/gem (n=580) NSCLC
20
35
29
29
35
26
79
67
68
Erlotinib (phase II)
150 mg/d (n=115) HNSCC
150 mg/d (n=57) NSCLC
150 mg/d (n=34) Ovarian
PruritusDry SkinRash
Manifestacionesclínicas
• Rash folicular con distribución
acneiforme (cara, cuero cabelludo,
pecho y parte alta de espalda)
• Pequeñas pústulas y pápulas
(inflamatorio) eritematosas
confinadas a folículos pilosos
distribuidas en cara, tronco y brazos.
– No comedones ni lesiones quísticas.
– No forman escaras.
– durante las primeras 2 semanas
Manifestacionesclínicas
• Xerosis y prurito: entre las
zonas de erupción folicular. Manos
y dedos.
• Perionixis y paroniquia: eritema
con descamación en los laterales
de los dedos, con fisuras. Lesiones
pustulosas periungueales. Primera
quincena de tratamiento
• Tricomegalia y alteraciones en
el crecimiento del cabello:
Meses de tratamiento
Lesiones no inflamatorias
Pápulas-pústulas
Inflamatorias-exudativas
Distribución
Sí: Sí: comedoscomedos
Sí
Propionibacteriaium acnes
Cara
No
Sí
SíSí
Cara,tronco
Sí: pápulas
Sí (monomorfas 2-3 mm)
No (firmes)No (firmes)
TroncoTronco
AcnéAcné--esteroidesesteroides AcnéAcné--TKITKIAcné vulgarAcné vulgar
Pérez-Soler RJ. Oncologist 2005
DiagnósticoDiagnóstico clínicoclínico y y diferencialdiferencial
ManejoManejo clínicoclínico rashrash--TKITKI
Lavado: jabón antiséptico (x2)Geles de baño avena/aceitesCrema corporal emoliente
RashRash
Crema de corticoides (prednicarbato)
Gel eritromicina tópica
PruritoPrurito
Antihistamínico (hidroxicina 25-50mg/8h)
PerionixisPerionixis--paroniquiaparoniquia
Sol. Acuosa de nitrato de Ag 1/200
(fisuras)
Mupirocina tópica
Gentamicina-corticoide
Prevención:Prevención:
Mupirocina intranasal(Bactroban nasal)
Erupción folicular 2-3:Tetraciclinas orales (2ª cotrimoxazol)
TratamientoTratamientoCultivoMuporicina tópicaATB po amplio espectro
Recomendaciones generales Sobreinfección
No usarNo usarRetinoides
Benzoyl peróxido
EGFR & EGFR & RadioresistanceRadioresistance…and coming back…and coming back
EGFR activationEGFR activation
Chemo and RT resistanceChemo and RT resistance
EGFR inhibitionEGFR inhibition
Radiation enhancementRadiation enhancement
Wosikowski K. Clin Cancer Res 1997Ang KK. Cancer Res 2002
Huang SM. Cancer Res 1997Milas L. Clin Cancer Res 2000
Bianco C. Clin Cancer Res 2002
Schmidt-Ulrich RK. Oncogene 1997Dent P. Mol Biol Cell 1999
Dittmann K. J Biol Chem 2005Chinnaiyan P. Cancer Res 2005
RadiationRadiation
TGF?p-EGFR
DNA repair• Rad51• DNA-PK
ProliferationSurvival
AcceleratedAccelerated repopulationrepopulation
RadiationRadiation
TGF?p-EGFR
DNA repair• Rad51• DNA-PK
TGFαp-EGFR
DNA repair• Rad51• DNA-PK
ProliferationSurvival
AcceleratedAccelerated repopulationrepopulation
Coming back:Coming back:
EGFREGFR--TKI & RadiotherapyTKI & Radiotherapy
TKI G1RT G2
Reduction S-phase fraction
Apoptosis: supra-additive effect
In vivo response enhancement
DecreaseProliferation
p-EGFRRad51 & DNA-PK
Chinnaiyan P. Cancer Res 2005
DasatinibDasatinib (BMS(BMS--354825, 354825, SprycelSprycel))
Orally-bioavailable inhibitor of several oncogenic TK:
AblAbl & & ArgArg kinaseskinasesSrcSrc--family family c-KIT & c-FMS (CSF-1R), EphA2 PDGFR1β
Tokarski J. S. 2006
BCRBCR--ABLABL is the oncogenic tyrosine kinase expressed by Philadelphia chromosome-positive (Ph+) stem cells, directlyinvolved in the pathogenesis of chronic myeloid leukemia
TheThe PhiladelphiaPhiladelphia chromosomechromosome
Translocation 9,22fuses the c-ABL gene with the breakpoint cluster (BCR) geneBCR-ABL fusion protein is a constitutively active TKcauses cell transformation and chronic myeloid leukemia.
Sawyers C. N. 1999
DasatinibDasatinib BCRBCR--ABL ABL inhibitioninhibition activityactivity
300-fold more potent againstBCR-ABL than imatinib in vitro
(Copland, 2006)
Inhibits 18 of the 19 BCR-ABL mutations that are resistantto imatinib (Shah, 2006)
The T315I mutant clone isresistant to both imatinib anddasatinib (Burgess, 2004)
The median reduction in BCR-ABL transcript was 32% after 4 weeks of therapy
(Shah, 2004)
DasatinibDasatinib BCRBCR--ABL ABL inhibitioninhibition activityactivity
Talpaz et al. NEJM 2006
FDA FDA ApprovedApproved IndicationsIndications (START (START phasephase II II studiesstudies, 2005), 2005)
1) Acute lymphoid leukemiaPhiladelphia chromosome-positive, resistant or intolerant to prior therapy
2) Chronic myeloid leukemia, accelerated phase, blast crisis or chronic phaseResistant or intolerant to imatinib
Dose
• 70 mg po BID with or without food: may be escalated to 100 mg BID (90mg BID
CML cf) in patients who do not achieve a hematologic or cytogenetic response
• continue until disease progression or intolerance
PharmacologyMetabolismLiver cytochrome P450 CYP3A4 to an active metabolite (5% of AUC).
ExcretionRenal Excretion (4% recovered in the urine )Feces (85%)
t1/2= 1.3 to 5 hours (Sawyers et al, 2005; Evans et al, 2005)
HematologicalHematological toxicitiestoxicitiesNeutropenia andthrombocytopenia 48-83%Anemia in 18-70%.
OtherOther commoncommon grade 3/4 grade 3/4 eventsevents::Bleeding (10%)Fluid retention (9%)Dyspnea (6%)Pyrexia (5%)Pleural effusion (5%),Diarrhea (5%)CNS hemorrhage 1%
DasatinibDasatinib -- toxicitytoxicity
(START Studies: Ottmann, Guilhot, Talpaz, Hoschhaus, 2005)
GastrointestinalDiarrheaNauseaAbdominal painVomiting
ConstitutionalPyrexiaHeadacheFatigueAstheniaAnorexia
Fluid retention 50% superficial edema (36%)pleural effusion (22%)
Bleeding 40%14%gastrointestinal bleeding.
Grade 3-4 adverse events
Adapter and structural proteins
Src
GF
MEK2
ERK
Raf
PI3K
Akt
Migration/morphogenesisMigration/morphogenesisSurvivalSurvivalCellular Cellular
transformationtransformation MitogenesisMitogenesis
Growth factors(EGF, PDGF, HGF)
Ras
Rac Rho
Grb2
Gab1
SOS
GF
Integrins
FAK
CasSrc
Actin cytoskeleton
p190RhoGAP
Translocation tocytoskeleton
Extracellular matrix
MEK1
PLCg
RTKs (EGFR,PDGFR, c-Met)
PYPYPY
PYPYPY
P
Shc
Shp2
P
PP
STAT3
C-Myc
Src
SRC SRC inhibitioninhibition by by DasatinibDasatinib led to decreased migration and invasion, cell morphology changes, and apoptosis (Johnson et al, 2005).
SRCSRC--family family kinaseskinases in signal transductionin signal transduction
Juan A. Díaz-GonzálezClínica UniversitariaUniversidad de Navarra