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