LUNG CANCER MOLECULAR THERAPY
Prof. Dr. Can ÖZTÜRK
Gazi University School of Medicine Department of Pulmonology
Crude Rate* ASR (World)
LungLung 37.337.3 47.747.7
StomachStomach 9.69.6 12.212.2
BladderBladder 8.68.6 11.011.0
ColorectalColorectal 7.4 7.4
9.1 9.1
LarinxLarinx 6.46.4 8.08.0
ProstateProstate 6.16.1 8.08.0
LeukemiaLeukemia 5.15.1 5.85.8
Brain,CNS Brain,CNS
3.93.9 4.54.5
NHLNHL 3.33.3 3.8 3.8
Oral cavityOral cavity 2.62.6 3.23.2
Total(exceTotal(except skin)pt skin)
110.3110.3 137.3137.3
Turkey - Male (All ages)
*per 100.000
Crude Rate* ASR (World)
BreastBreast 19.919.9 22.022.0
Colorectal Colorectal
7.67.6 8.58.5
StomachStomach 5.75.7 6.46.4
OvariumOvarium 4.84.8 5.45.4
LungLung 4.64.6 5.35.3
LeukemiaLeukemia 4.44.4 4.74.7
Corpus-Corpus-UterusUterus
4.14.1 4.84.8
Cervix- Cervix- UterusUterus
4.04.0 4.54.5
Brain, CNS Brain, CNS 3.53.5 3.83.8
Non-Non-Hodgkin Hodgkin lenfoma lenfoma
2.92.9 3.13.1
Total(excepTotal(except skin) t skin)
82.082.0 91.291.2
Turkey - Female (All Ages)
*per 100.000
UNTREATED NSCLC- PROGNOSISUNTREATED NSCLC- PROGNOSIS
STAGESTAGE MS(Mts)MS(Mts) 1yr. Sur.(%)1yr. Sur.(%) 2yr. Sur.(%) 2yr. Sur.(%)
c I, IIc I, II 1313 5656 88
c IIIc III 4-94-9 16-3016-30 0-40-4
c IVc IV 33 -- --
UNTREATED SCLC- PROGNOSISUNTREATED SCLC- PROGNOSIS
STAGESTAGE MEDIAN SUR.MEDIAN SUR. 1 YR. SURVIVAL1 YR. SURVIVAL
LIMITEDLIMITED
++
Supportive CareSupportive Care
12 weeks12 weeks
18 weeks18 weeks % 7% 7
EXTENSIVEEXTENSIVE
++
Supportive CareSupportive Care
5 weeks5 weeks
8 weeks8 weeks
TreatmentTreatment- Prognosis- Prognosis
Status of treatment is dismalStatus of treatment is dismal
Five year survival Five year survival approx.approx. 15% 15%– 61% for Colon61% for Colon– 86% for Breast86% for Breast– 96% for Prostate96% for Prostate
NSCLC – Survival based on stagesNSCLC – Survival based on stages
Greene et al, eds. AJCC Cancer Staging Manual. 6th ed. 2002.
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5
Years following diagnosis
% S
urv
ival
Stage IStage IIStage IIIStage IV
5 year survival - TARGETS5 year survival - TARGETS
NSCLC CURRENT TARGETNSCLC CURRENT TARGET
STAGE STAGE % % % %
IAIA 70-85 85-95 70-85 85-95
IBIB 60-70 70-85 60-70 70-85
IIAIIA 35-45 45-60 35-45 45-60
IIB 25-35 35-45IIB 25-35 35-45
IIIA 5-20 20-30IIIA 5-20 20-30
IIIB 3-7 10-20IIIB 3-7 10-20
IV <1 2-5IV <1 2-5
SCLC CURRENT TARGETSCLC CURRENT TARGET
STAGE STAGE % % % %
LTD 15-25 25-30LTD 15-25 25-30
EXT <1 2-5EXT <1 2-5
Langer CJ, Fox Chase Cancer Center-2006
NSCLC- Systemic TherapyNSCLC- Systemic Therapy
Uptodate standart therapiesUptodate standart therapiesEpidermal Epidermal GrowthGrowth Fa Faccttoor Rer Recceptor (EGFR) eptor (EGFR) InhibitorsInhibitors– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)
Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodiesbodies– Cetuximab (Erbitux)Cetuximab (Erbitux)
Anti-Anti-VasVascucullaar Endotr Endothheleliial al GrowthGrowth Fa Faccttoor (VEGF) r (VEGF) MonoMonocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)
2-drug platinum-based combinations2-drug platinum-based combinations
Schiller JH. NEJM 2002; 346:92-98
Systemic TherapySystemic Therapy – – First LineFirst Line
2 drug platinum based regimens
Results- First LineResults- First Line
Medan survival8 months
Survival
TTP
Schiller JH. NEJM 2002; 346:92-98
MedianTTP3.7 months
Response rate%19
Second Line TherapiesSecond Line Therapies
Docetaxel Docetaxel is superior than best supportive is superior than best supportive carecare
Response rateResponse rate % % 77 MedMedian survivalian survival 7.0 vs 4.6 7.0 vs 4.6 monthsmonths* * MedMediian TTP 10.6 vs. 6.7 an TTP 10.6 vs. 6.7 weeksweeks**
Pemetrexed (Alimta) Pemetrexed (Alimta) is effective as is effective as docetaxeldocetaxel, , but less toxicity profilebut less toxicity profile
Shepherd et al. JCO 2000;18:2095-2103Hanna et al. JCO 2004; 22:1589-97
Targeted Therapies in Lung CancerTargeted Therapies in Lung Cancer
GeneGeneralral SpesifiSpesificc
AngiogenesisAngiogenesis VEGFVEGFVEGFRVEGFRFGFFGFIntegrinIntegrin
EGFR EGFR familyfamily EGFREGFRHER2HER2
SiSignalgnal RasRasRaf kinazRaf kinazMEKMEKmTORmTORPKCPKC
GeneGeneralral SpesifiSpesificc
Cell CycleCell Cycle cdkscdks
ApoptoApoptosissis Bcl-2Bcl-2SurvivinSurvivinXIAPXIAPP53P53clusterinclusterin
OthersOthers DNA MTaseDNA MTaseHDACHDACproteproteoosomsom
ExtracellularExtracellular MMPMMP
ReReceptors/ceptors/kinaseskinases
C-kitC-kitPDGFRPDGFRablabl
Targeted TherapiesTargeted Therapies
EGFR EGFR IInhibitornhibitorss– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)
Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodybody– Cetuximab (Erbitux)Cetuximab (Erbitux)
Anti-Anti-VEGF MonoVEGF Monocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)
Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor (EGFR) (EGFR) && Human Cancer Human Cancer
EGFR critically regulates tumor cell division,EGFR critically regulates tumor cell division, proliferation, proliferation, repair repair
EGFR may play a critical role in EGFR may play a critical role in metastasismetastasis, angiogenesis, , angiogenesis, invasioninvasion
Binding of specific ligands to EGFR (eg, EGF, TGF-Binding of specific ligands to EGFR (eg, EGF, TGF-) activates ) activates the receptor and triggers signal transduction cascades that the receptor and triggers signal transduction cascades that affect cell proliferationaffect cell proliferation
EGFR is expressed in a significant percentage of human tumors EGFR is expressed in a significant percentage of human tumors and is correlated with poor prognosis, decreased survival, and is correlated with poor prognosis, decreased survival, and/or increased metastasisand/or increased metastasis
Inhibition of EGFR on tumor cells may inhibit the growth or Inhibition of EGFR on tumor cells may inhibit the growth or progression of EGFR-expressing tumorsprogression of EGFR-expressing tumors
TK Intracellular area
Transmembranous area
Extracellular area
EGFR structure
Tumors showing high EGFR expression
High expression generallyassociated with
EGFR expression in human tumorsEGFR expression in human tumors
NSCLCNSCLC 40-80%40-80%
ProstateProstate 40-80%40-80%
GastricGastric 33-74%33-74%
BreastBreast 14-91%14-91%
ColorectalColorectal 25-77%25-77%
PancreaticPancreatic 30-50%30-50%
OvarianOvarian 35-70%35-70%
InvasionInvasion
Metastasis Metastasis
Late-stage diseaseLate-stage disease
Chemotherapy resistanceChemotherapy resistance
Hormone-therapy resistanceHormone-therapy resistance
Poor outcomePoor outcome
NSCLC-NSCLC- EGFR & HER2 EGFR & HER2
86
35
25
85
30
60
10
66
0
10
20
30
40
50
60
70
80
90
100
Sq (n=36) Ad (n=73) LC (n=16) BAC (n=10)
Histology
Frequency (
%)
EGFR HER2
F. Hirsch et al. Semin Oncol, 2002F. Hirsch et al. Semin Oncol, 2002
Lung Cancer-EGFR expression
NSCLC-NSCLC- EGFR & HER2 EGFR & HER2SurvivalSurvival
Relationship of HER1 & HER2 to Survival in NSCLC
J. Brabender et al. Clin Cancer Res, 2001J. Brabender et al. Clin Cancer Res, 2001
EGFR Targeted TherapiesEGFR Targeted Therapies
Inhibition of EGFR signalling with either the monoclonal Inhibition of EGFR signalling with either the monoclonal Ab or the tyrosine kinase inhibitors(TKI) reduces Ab or the tyrosine kinase inhibitors(TKI) reduces proliferation in a variety of epithelial tumor cells and blocks proliferation in a variety of epithelial tumor cells and blocks cell cycle progression in the G1 phasecell cycle progression in the G1 phase
Inhibition of cell cycle progression is an effective Inhibition of cell cycle progression is an effective mechanism for modulating the growth of tumorsmechanism for modulating the growth of tumors
EGFR inhibition, using TKI; induce apoptosis (in human EGFR inhibition, using TKI; induce apoptosis (in human tumor cells and vascular endothelial cells)tumor cells and vascular endothelial cells)
Ongoing trials are evaluating the clinical utility of EGFR Ongoing trials are evaluating the clinical utility of EGFR inhibitors for the treatment of EGFR-expressing cancersinhibitors for the treatment of EGFR-expressing cancers
Acquired spesifications of Cancer CellsAcquired spesifications of Cancer Cells
SpesificationsSpesifications
Autocrine growth signalAutocrine growth signal YesYes Yes Yes
Insensitivity to anti-growth signalsInsensitivity to anti-growth signals Yes Yes Yes YesAwareness of cell deathAwareness of cell death Yes Yes Yes YesUncontrolled proliferationUncontrolled proliferation Yes Yes Yes YesContinious angiogenesisContinious angiogenesis Yes Yes Yes YesTissue invasion and MetastasisTissue invasion and Metastasis YesYes Yes Yes
Decrease by EGFR Inhibition
Hanahan ve Weinberg, Cell, 2000Hanahan ve Weinberg, Cell, 2000
Increase by EGFR activation
TKI
Proliferation
Invasion
MetastasisAngiogenesis
Apoptosis
Adhesion
Sensitivity to chemotherapy
TKI-Small moleculesTKI-Small molecules: mechanism of : mechanism of actionaction
Etessami A, et al. Drugs Fut 2000;25:895–9Moyer J, et al. Cancer Res 1997;57:4838–48
Harari PM, et al. Semin Radiat Oncol 2002;12(Suppl. 2):21–6
Gene Transcription
G0G1
Priming
S
G2
M
Cell CycleCell Cycle
Growth Factor
++
Growth Factors & Cell Cycle
Receptors
Targeted TherapiesTargeted Therapies
EGFR EGFR IInhibitornhibitorss– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)
Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodybody– Cetuximab (Erbitux)Cetuximab (Erbitux)
Anti-Anti-VEGF MonoVEGF Monocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)
Untreated advanced NSCLC*
Stratification:Weight loss in last 6
months(%5 vs >%5)
PS: 0 - 1 vs 2
*Evre IIIB/IV KHDAK†INTACT = IRESSA NSCLC Trial Assessing Combination Therapy; INTACT 1 (N=1093) gemcitabin (1250 mg/m2)/cisplatin (80 mg/m2); INTACT 2 (N=1037) paclitaxel (225 mg/m2)/carboplatin (AUC=6).
Chemo† x 6 cycles + 250 mg gefitinib
Chemo† x 6 cycles + 500 mg gefitinib
Chemoi† x 6 cycles + Placebo
Gefitinib / Placebo until progression
Randomise
Gefitinib-Gefitinib- with Chemotherapy with ChemotherapyFirst Line-Phase IIIFirst Line-Phase III
INTACT 1 & 2
Gefitinib-Gefitinib- with Chemotherapy with ChemotherapyFirst Line-Phase IIIFirst Line-Phase III
Med. survival
~10 months
~10 months
Gefitinib – Gefitinib – Second & Third LineSecond & Third Line--Phase II Phase II
Patient no. Response Rate (%)Median
survival (Mts)
IDEAL-1Japan, Europe, Australia, S. Africa
208% 18.4 (total)% 27.5 (Japan)% 10.4 (Non-Japan)
7.6
IDEAL-2United States 216 12 % 7
250mg ve 500mg doses- no difference in efficacyAdverse effects- acceptable (rash and diarrhea) – more frequent in 500 mg group
IDEAL-1: M. Fukuoka et al. JCO 2003; 21:2237-2246
IDEAL-2: MG Kris et al. JAMA 2003; 2149-2158
(250mg vs. 500mg)
Inclusion Criteria• Stage IIIB veya IV NSCLC• Treated with platinum
based CT( 1 or 2 times)• PS 0-3
Gefitinib – Gefitinib – Second & Third LineSecond & Third Line--Phase III Phase III ISEL: Iressa Survival Evaluation in Lung CancerISEL: Iressa Survival Evaluation in Lung Cancer
Gefitinib 250 mg/gün
Placebo
RANDOMİZE
N=1692
Thatcher et al. Lancet 2005
Thatcher et al. Lancet 2005
Gefitinib – Gefitinib – Second & Third LineSecond & Third Line--Phase III Phase III ISEL - SISEL - Survivalurvival
1.0
0.6
0.8
0.2
0.0
0.4
0 162 144 10 1286
Pro
bab
ility
Months
(n=1129)Placebo(n=563)
Median survival (mts)
1-year survival (%)
5.6 5.1
27
HR=0.89 (95% CI, 0.78-1.03)* P<0.11*
22
Gefitinib
Gefitinib
Placebo
Targeted TherapiesTargeted Therapies
EGFR EGFR IInhibitornhibitorss– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)
Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodybody– Cetuximab (Erbitux)Cetuximab (Erbitux)
Anti-Anti-VEGF MonoVEGF Monocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)
Erlotinib-Erlotinib-With ChemotherapyWith Chemotherapy--First Line - Phase IIIFirst Line - Phase III
TALENT TALENT studystudy - Cisplatin/gemcitabin - Cisplatin/gemcitabinee + + (tarceva (tarceva oror pla placcebo) ebo)
1172 1172 ptspts, , chchemo-naiveemo-naive
TarcevaTarceva PlaPlacceboebo
Med. sMed. survivalurvival ((daysdays))
301301 309309
TTP (TTP (daysdays)) 167167 179179
Gatzemeier U. ASCO 2004 Abstract
Erlotinib-Erlotinib-with chemotherapywith chemotherapy--First Line-Phase IIIFirst Line-Phase III
TRIBUTE TRIBUTE studystudy - - CCarboplatin/paclitaxel + arboplatin/paclitaxel + (tarceva (tarceva or placeboor placebo))
1059 1059 ptspts, , chchemo-naiveemo-naive
TarcevaTarceva PlaceboPlacebo
Med. Med. survivalsurvival ((mtsmts))
10.810.8 10.610.6
RR (%)RR (%) 21.521.5 19.319.3
TTP (TTP (mtsmts)) 5.15.1 4.94.9
Herbst R. J Clin Oncol 2005
Erlotinib-Erlotinib-with chemotherapywith chemotherapy--First Line-Phase IIIFirst Line-Phase III
TRIBUTE TRIBUTE studystudy – – Subgroup analysisSubgroup analysis::
NonsmokersNonsmokers
tarceva vs platarceva vs placcebo:ebo:
MedMediian san survivalurvival = 23 = 23 mtsmts v vs.s. 10 10 mtsmts
Miller VA et al. ASCO 2004 Abstract
Why are TALENT and TRIBUTE negative Why are TALENT and TRIBUTE negative
studies? Possible explanationsstudies? Possible explanations
Concurrent use may be antagonisticConcurrent use may be antagonistic
– in vitro evidence of antagonism with combination chemotherapy in vitro evidence of antagonism with combination chemotherapy regimensregimens
Remarkable benefit in the non-smoker subset:Remarkable benefit in the non-smoker subset:
– smoking potentially reduces exposure to Tarceva via induction of smoking potentially reduces exposure to Tarceva via induction of metabolising enzymesmetabolising enzymes11
Triplets are redundant doublets; Tarceva kills the same Triplets are redundant doublets; Tarceva kills the same tumour cell population?tumour cell population?
1Hamilton M, et al. Proc Am Assoc Cancer Res 2005;43 (Abs. 6165)
BR.21 Phase III
Erlotinib – Erlotinib – Second or Third LineSecond or Third Line
Erlotinib – Erlotinib – Second or Third LineSecond or Third LineBR.21 Phase III
Stratification
• Center
• PS: 0-1 vs. 2-3
• Previous response: PR vs. SD vs. PD
• Previous CT: 1 vs. 2
• Previous cisplatin: Yes or No
RANDOMISE
Erlotinib: 150 mg/day
Placebo: “150 mg”/day
2
1
Erlotinib – Erlotinib – Second or Third LineSecond or Third LineBR.21 Phase III
TarcevaTarceva
(n=488)(n=488)
PlaPlacceboebo
(n=243)(n=243)
RR (%)RR (%) 8.98.9 <1<1
MedMedianian ssurvivalurvival 6.7 6.7 mtsmts** 4.7 4.7 mtsmts
PFSPFS 2.2 2.2 mtsmts** 1.8 1.8 mtsmts
Shepherd FA et al. NEJM 2005
En sık yan etki: kızarıklık, diyare
BR.21 Study-Survival
HR=0.73, P<0.001*
MedianSurvival (mts)
1-yearSurvival (%)
6.7 31.2
4.7 21.5
Months
% S
urv
iva
l
Erlotinib
Placebo
100
0 5 10 15 20 25 30
80
40
20
0
60
BR.21: BR.21: ToxicityToxicityPatientsPatients % %
ErlotinibErlotinib(n=485)(n=485)
PlaPlacceboebo(n=242)(n=242)
TotalTotal Grade 3Grade 3 Grade 4Grade 4 TotalTotal Grade 3Grade 3 Grade 4Grade 4
RashRash 7575 88 <1<1 1717 00 00
DiDiarrheaarrhea 5454 66 <1<1 1818 <1<1 00
AnoreksiAnoreksiaa 5252 88 11 3838 55 <1<1
FatigueFatigue 5252 1414 44 4545 1616 44
DDyspneyspne 4141 1717 1111 3535 1515 1111
CoughCough 3333 44 00 2929 22 00
EmesisEmesis 3333 33 00 2424 22 00
InfectionInfection 2424 44 00 1515 22 00
VomittingVomitting 2323 22 <1<1 1919 22 00
Tarceva (erlotinib) PI.
BR.21 BR.21 SummarySummary
Erlotinib Erlotinib has confered a survival advantage in previously treated and relapsed NSCLC has confered a survival advantage in previously treated and relapsed NSCLC
patientspatients
Erlotinib is effective in both subgroupsErlotinib is effective in both subgroups
Therapy is well toleratedTherapy is well tolerated
– Most frequent toxicity is rash and diarrheaMost frequent toxicity is rash and diarrhea
– Pulmonary toxicity is rare, but 30% fetalPulmonary toxicity is rare, but 30% fetal
BR.21BR.21 ISELISEL
No. of patientsNo. of patients 731731 16921692
Response rateResponse rate
Overall survivalOverall survival
1 1 year survivalyear survival
HRHR
P P valuevalue
%8.9%8.9
Tarceva = 6.7 Tarceva = 6.7 mtsmts
Plasebo = 4.7 Plasebo = 4.7 mtsmts
%31 vs. %21%31 vs. %21
0.730.73
<0.001<0.001
%8%8
Iressa = 5.6 Iressa = 5.6 mtsmts
Plasebo = 5.1 Plasebo = 5.1 mtsmts
%27 vs. %22%27 vs. %22
0.890.89
0.11 0.11
Response to TKI- Important factorsResponse to TKI- Important factors
GrGroupoup Response rateResponse rate (%)(%) pp
Male vs. FemaleMale vs. Female 19 v19 vs.s. 3 3 0.0010.001
AAsian vs. Non-sian vs. Non-AsianAsian 27.5 v27.5 vs.s. 10.4 10.4 0.00230.0023
AdAdeno. vs. otherseno. vs. others 13 v13 vs.s. 4 4 0.0460.046
BAC vBAC vs.s. adeno adeno 38 v38 vss 14 14 <0.001<0.001
Nonsmoker vs. Nonsmoker vs. smokersmoker 36 v36 vs.s. 8 8 <0.001<0.001
Fukuoka JCO 2003;21:2237-46. Kris JAMA 2003;290:2149-58. Miller JCO 2004;22:1103-09.
Erlotinib - Faz II Erlotinib - Faz II Survival & Grade of RashSurvival & Grade of Rash
Su
rviv
al
0.00
0.25
0.50
0.75
1.00
Months
0 5 10 15 20 25 30
Grade 2/3 (n=17)
Grade 1 (n=26)
Yok (n=14)
Grade Median survival (95% CI)
No rash 1.5 (1 2.2)
Grade 1 8.5 (4.8 14.8) p<0.0001*
Grade 2/3 19.6 (10.8 +) p<0.0001* *vs no rash
Perez-Soler R, et al. Am Soc Clin Oncol Mol Ther Symp. 2002
NSCLC & EGFR Mutations
Gefitinib-EGFR mutaGefitinib-EGFR mutation andtion and amplifiamplificationcation
EGFREGFR EGFREGFR amplifi amplificationcation muta mutationtion
+ - + - + - + -
%%3333 %67 %67 %%17 %8317 %83
Obj. Obj. responseresponse(%)(%) 3636 3 (<.001)3 (<.001) 53 53 5 5 (<.001)(<.001)
Med. SMed. Survivalurvival (ay) (ay) 18.7 7.0 (.03) 18.7 7.0 (.03) 20.820.8 8.4 (.09)8.4 (.09)
1 y1 year survivalear survival (%)(%) 57 33 (.03) 57 33 (.03) 5757 38 38 (.22)(.22)
Cappuzzo JNCI 97:643,2005
Targeted TherapiesTargeted Therapies
EGFR EGFR IInhibitornhibitorss– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)
Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodybody– Cetuximab (Erbitux)Cetuximab (Erbitux)
Anti-Anti-VEGF MonoVEGF Monocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)
Single agent Cetuximab
Phase II studyPhase II study
(n=60, ≥1 (n=60, ≥1 chemochemo):):
Response rateResponse rate: % 3.3: % 3.3
MedMediian TTPan TTP: 2.3 : 2.3 ayay
MedMediian an survivalsurvival: 8.1 mo.: 8.1 mo.
Well toleratedWell tolerated ((Most frequent adverse effectMost frequent adverse effect: : rashrash))
Lilenbaum ASCO 2005
Cetuximab-with chemotherapyCetuximab-with chemotherapy
Docetaxel 75 mg/m2
Every 3 weeksCetuximab400 mg/m2 every week then,250 mg/m2 every week
Kim ES. 2005 ASCO
Patients (no.=47)Stage IIIB/IV 1 previous CT Median KPS 80Faz II study
RR: % 28,SD %17TTP: ~3 mtsWell tolerated(rash, neutropenia)
Cetuximab- With chemotherapyCetuximab- With chemotherapy
RANDOMISATION
Cisplatin 80 mg/m2 Day 1Vinorelbin 25 mg/m2
Day 1,8. Every 3 weeksCetuximab 400 mg/m2
week 1, then 200 mg/m2
week 2 and 3
Cisplatin 80 mg/m2 Day 1Vinorelbin 25 mg/m2
Day 1,8 Every 3 weeks
Rosell 2004 ASCO
Patients (No.=86)Stage IV (%92)Chemo-naiveMedian KPS 90Faz II study
Cetuximab- With chemotherapyCetuximab- With chemotherapy
RR (%)RR (%)
((GAGA))
MedMediian an survivalsurvival
((mts)mts)
MedMediian an TTP (TTP (mtsmts))
Cisplatin/Vinor.Cisplatin/Vinor.2020
(7.6-32.4)(7.6-32.4)7.07.0 4.24.2
Cisplatin/Vinor.Cisplatin/Vinor.
++CetuximabCetuximab
3232
(17.5-46.0)(17.5-46.0)8.38.3 4.74.7
Rosell 2004 ASCO
Targeted TherapiesTargeted Therapies
EGFR EGFR IInhibitornhibitorss– Gefitinib (Iressa)Gefitinib (Iressa)– Erlotinib (Tarceva)Erlotinib (Tarceva)
Anti-Anti-EGFR MonoEGFR Monocclonal antilonal antibodybody– Cetuximab (Erbitux)Cetuximab (Erbitux)
Anti-Anti-VEGF MonoVEGF Monocclonal antilonal antibodybody– Bevacizumab (Avastin-Altuzan)Bevacizumab (Avastin-Altuzan)
What is VEGF?What is VEGF?
Key Key driverdriver of angiogenesis of angiogenesisStimulates angiogenic remodelling and Stimulates angiogenic remodelling and sproutingsproutingStimulates growth of endothelial cellsStimulates growth of endothelial cells, , promotes endothelial cell survival (i.e promotes endothelial cell survival (i.e prevents endothelial cell apoptosis and prevents endothelial cell apoptosis and vessel regression)vessel regression)Also known as VEGF-AAlso known as VEGF-ARelated molecules are VEGF-B, C and D, Related molecules are VEGF-B, C and D, placental growth factor (PlGF)placental growth factor (PlGF)When angiogenesis is stimulated , a When angiogenesis is stimulated , a region of the mature vessel becomes region of the mature vessel becomes destabilized and undergoes angiogenic destabilized and undergoes angiogenic sprouting if VEGF is presentsprouting if VEGF is presentBinds VEGF receptor-2 Binds VEGF receptor-2
VEGF ReceptorsVEGF Receptors
The biological effects of VEGF appear to be The biological effects of VEGF appear to be exerted through binding to VEGF receptor-2, exerted through binding to VEGF receptor-2, which is expressed predominantly on vascular which is expressed predominantly on vascular endothelial cellsendothelial cells
VEGF-2 receptor consists of 7 extracellular Ig VEGF-2 receptor consists of 7 extracellular Ig like domains, a transmembrane region and an like domains, a transmembrane region and an intracellular domain having tyrosine kinase intracellular domain having tyrosine kinase activityactivity
VEGFVEGF
This binding to trans-membrane receptors This binding to trans-membrane receptors activatesactivates;;
Proliferation of vascular endothelial cellsProliferation of vascular endothelial cells
Migration of vascular endothelial cellsMigration of vascular endothelial cells
Survival of immature endothelial cellsSurvival of immature endothelial cells
Increased vascular permeabilityIncreased vascular permeability
AngiogenesisAngiogenesis
The primary factor controlling vessel formation is The primary factor controlling vessel formation is lack of oxygenlack of oxygen
This triggers the secretion of pro-angiogenic This triggers the secretion of pro-angiogenic factors, principally vacular endothelial growth factors, principally vacular endothelial growth factor (VEGF) factor (VEGF)
TGF alfa/beta, fibroblast growth factor(FGF) are TGF alfa/beta, fibroblast growth factor(FGF) are other two pro-angiogenic growth factorsother two pro-angiogenic growth factors
AngiogenesisAngiogenesis
Tumor angiogenesis can be considered to Tumor angiogenesis can be considered to involve two phases ;involve two phases ;
Avascular phaseAvascular phase: lesions remain dormant and are not : lesions remain dormant and are not more than 1-2 mm diameter, proliferation and apoptosis more than 1-2 mm diameter, proliferation and apoptosis are balancedare balanced
Vascularization phaseVascularization phase: new vessels continue to form as : new vessels continue to form as long the tumor growslong the tumor grows
Why inhibit angiogenesis in NSCLC?Why inhibit angiogenesis in NSCLC?
Angiogenesis plays a role at several stages in the growth Angiogenesis plays a role at several stages in the growth and progression of all types of solid tumourand progression of all types of solid tumour
– tumours are incapable of growth beyond 1–2mm in the absence tumours are incapable of growth beyond 1–2mm in the absence of vasculatureof vasculature11
Expression of high levels of VEGF, the key mediator of Expression of high levels of VEGF, the key mediator of angiogenesis, is associated with poor prognosis in angiogenesis, is associated with poor prognosis in NSCLCNSCLC2–42–4
Novel combinations of existing chemotherapy agents are Novel combinations of existing chemotherapy agents are not predicted to provide increased survival benefit in not predicted to provide increased survival benefit in advanced NSCLC, suggesting that new therapeutic advanced NSCLC, suggesting that new therapeutic strategies are requiredstrategies are required55
1Folkman J. J Natl Cancer Inst 1990;82:4–6; 2Volm M, et al. Int J Cancer 1997;74:64–8 3O’Byrne KJ, et al. Br J Cancer 2000;82:1427–32; 4Fontanini G, et al. Br J Cancer 2002;86:558–63
5Socinski MA. Respir Care Clin N Am 2003;9:207–36
Why inhibit angiogenesis in NSCLC?Why inhibit angiogenesis in NSCLC?
Inhibition of angiogenesis, using antiangiogenic Inhibition of angiogenesis, using antiangiogenic agents has shown to be effective in preventing agents has shown to be effective in preventing tumor growthtumor growth
In some cases tumor regression has also been In some cases tumor regression has also been shownshown
Many antiangiogenic agents are currently in Many antiangiogenic agents are currently in devolopment, targeting various factors and devolopment, targeting various factors and stages in the regulation of angiogenesisstages in the regulation of angiogenesis
Anti-angiogenic agents in clinical Anti-angiogenic agents in clinical development for NSCLCdevelopment for NSCLC
DrugDrugMechanism Mechanism of actionof action Molecular target(s)Molecular target(s)
Stage of Stage of developmentdevelopment
BevacizumabBevacizumab Anti-VEGF Anti-VEGF antibodyantibody
VEGFVEGF Phase IIIPhase III
Sorafenib Sorafenib (BAY43-9006)(BAY43-9006)
TKITKI Raf-1, VEGFR-2, -3, PDGFR-Raf-1, VEGFR-2, -3, PDGFR-, Flt-3, c-, Flt-3, c-KitKit
Phase IIIPhase III
Sunitinib Sunitinib (SU11248)(SU11248)
TKITKI VEGFR-1, -2, -3, Flt-3, PDGFR-VEGFR-1, -2, -3, Flt-3, PDGFR-, -, -, c-, c-KitKit
Phase IIPhase II
Vatalanib Vatalanib (PTK787)(PTK787)
TKITKI VEGFR-1, -2, -3, PDGFR-VEGFR-1, -2, -3, PDGFR-, c-Kit, c-, c-Kit, c-FmsFms
Phase IIPhase II
CP-547,632CP-547,632 TKITKI VEGFR-2VEGFR-2 Phase IIPhase II
ZD6474ZD6474 TKITKI VEGFR-2, -3, EGFRVEGFR-2, -3, EGFR Phase IIPhase II
AG-013736AG-013736 TKITKI VEGFR-1, -2, -3VEGFR-1, -2, -3 Phase IIPhase II
Monoclonal antibodies against VEGFMonoclonal antibodies against VEGF Inhibitors of VEGF receptor tyrosine Inhibitors of VEGF receptor tyrosine kinaseskinases
Directly block interaction between Directly block interaction between VEGF and its receptorsVEGF and its receptors
Block signalling by activated VEGF Block signalling by activated VEGF receptorsreceptors
Prevent activation of downstream Prevent activation of downstream signalssignals
Down-regulate signalling pathways Down-regulate signalling pathways which are already activatedwhich are already activated
Bind specifically to VEGFBind specifically to VEGF Interact with other receptor tyrosine Interact with other receptor tyrosine kinases; effects are not all specific to kinases; effects are not all specific to angiogenesis inhibitionangiogenesis inhibition
Specific action on VEGF; minimal Specific action on VEGF; minimal effects on normal physiologyeffects on normal physiology
Non-specific action could produce Non-specific action could produce unexpected side effectsunexpected side effects
Inhibit all functions of VEGFInhibit all functions of VEGF May not inhibit all functions of VEGFMay not inhibit all functions of VEGF
Different mechanisms of anti-angiogenesis: VEGF Different mechanisms of anti-angiogenesis: VEGF versus VEGF receptorversus VEGF receptor
Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25
Angiogenesis is involved throughout tumour Angiogenesis is involved throughout tumour formation, growth and metastasisformation, growth and metastasis
Stages at which angiogenesis plays a role in tumour progression
Premalignantstage
Malignanttumour
Tumourgrowth
Vascularinvasion
Dormantmicrometastasis
Overtmetastasis
(Avasculartumour)
(Angiogenicswitch)
(Vascularisedtumour)
(Tumour cellintravasation)
(Seeding indistant organs)
(Secondaryangiogenesis)
Effects of VEGF inhibition:Effects of VEGF inhibition:regression of microvasculatureregression of microvasculature
Inai T, et al. Am J Pathol 2004;165:35–52
Reduction in tumour blood flow after 1 day of Reduction in tumour blood flow after 1 day of anti-VEGF therapyanti-VEGF therapy
Effects of VEGF inhibition:Effects of VEGF inhibition:normalisation of existing vasculaturenormalisation of existing vasculature
Abnormal vasculature is ‘normalised’ following VEGF inhibitionAbnormal vasculature is ‘normalised’ following VEGF inhibition
Inai T, et al. Am J Pathol 2004;165:35–52
Summary: mechanism Summary: mechanism of action of anti-VEGF therapyof action of anti-VEGF therapy
Inhibition of VEGF may act against tumours in three waysInhibition of VEGF may act against tumours in three ways– regression of existing microvasculatureregression of existing microvasculature– normalisation of mature vasculature normalisation of mature vasculature – inhibition of production of new vasculatureinhibition of production of new vasculature
EARLY BENEFIT CONTINUED BENEFIT
Regressionof existing microvasculature
Normalisationof surviving microvasculature
Inhibitionof vessel regrowth and neovascularisation
BevacizumabBevacizumab
VEGFR-2VEGFR-1P
PPPP
PPP
Endothel
VEGF
Anti-VEGF antibody
(Bevacizumab)
Presta et al. Cancer Res. 1997;57:4593.
Phase II trial of bevacizumab in Phase II trial of bevacizumab in NSCLC: summaryNSCLC: summary
Addition of bevacizumab to carboplatin and paclitaxel Addition of bevacizumab to carboplatin and paclitaxel improved response rate, time to progression and overall improved response rate, time to progression and overall survival in patients with advanced NSCLCsurvival in patients with advanced NSCLC
Patients with non-squamous cell histology appear to be a Patients with non-squamous cell histology appear to be a subpopulation with improved outcome and acceptable subpopulation with improved outcome and acceptable safety riskssafety risks
Recommended dose of bevacizumab for further Recommended dose of bevacizumab for further evaluation is 15mg/kg every 3 weeksevaluation is 15mg/kg every 3 weeks
The promising benefit of bevacizumab with chemotherapy The promising benefit of bevacizumab with chemotherapy in this trial warrants further investigationin this trial warrants further investigation
Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): study design(ECOG 4599): study design
Primary objective: to assess overall survival in patients with Primary objective: to assess overall survival in patients with advanced non-squamous NSCLC treated with CPadvanced non-squamous NSCLC treated with CP (carboplatin/paclitaxel)(carboplatin/paclitaxel) versus CP + bevacizumab versus CP + bevacizumab
Secondary objective: to assess response rates, time to Secondary objective: to assess response rates, time to progression and toxicityprogression and toxicity
Previously untreated stage
IIIB/IV non-squamous
NSCLC(n=878)
CP 6 (n=444)
Bevacizumab (15mg/kg)
every 3 weeks + CP 6 (n=434)
PD*
PD
*No cross over will be permitted
Bevacizumab every
3 weeks until progression
Sandler A, et al. J Clin Oncol 2005;23(Suppl 16 Pt I):2s (Abs. 4)
Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): k(ECOG 4599): key eligibility criteriaey eligibility criteria
Chemotherapy-naChemotherapy-naïïve stage IIIB (pleural or pericardial ve stage IIIB (pleural or pericardial effusion only) or stage IV effusion only) or stage IV non-squamousnon-squamous NSCLC NSCLCMeasurable or non-measurable diseaseMeasurable or non-measurable diseaseECOG PS 0–1ECOG PS 0–1INR <1.5 and a PTT no greater than upper limits of INR <1.5 and a PTT no greater than upper limits of normal within 1 week prior to randomisation normal within 1 week prior to randomisation No history of thrombotic or haemorrhagic disordersNo history of thrombotic or haemorrhagic disordersNo gross haemoptysis (defined as bright red blood of a No gross haemoptysis (defined as bright red blood of a 1/2 teaspoon or more) 1/2 teaspoon or more) Brain metastases were not allowedBrain metastases were not allowed
Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. LBA4)
Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): patient population(ECOG 4599): patient population
90909191CaucasianCaucasian
50505858MaleMale
40403838ECOG PS 0ECOG PS 0
43434444Age Age 65 years65 years
28282828Prior weight loss Prior weight loss 5%5%
91919191Measurable diseaseMeasurable disease
13131414Stage IIIB Stage IIIB
CP + bevacizumab CP + bevacizumab n=424 (%)n=424 (%)
CPCPn=431 (%)n=431 (%)
Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. LBA4)
Phase III trial of bevacizumab Phase III trial of bevacizumab in NSCLC (E4599): efficacyin NSCLC (E4599): efficacy
CPCPCP + CP +
bevacizumabbevacizumab
p valuep value
(HR)(HR)
Complete response, n (%)Complete response, n (%) 0 (0)0 (0) 5 (1.4)5 (1.4)
Partial response, n (%)Partial response, n (%) 35 (10)35 (10) 92 (25.8)92 (25.8)
Overall response rate, n (%)Overall response rate, n (%) 35 (10)35 (10) 97 (27.2)97 (27.2) <0.0001<0.0001
Median OS (months)Median OS (months) 10.210.2 12.5 12.5 0.0070.007
(0.77)(0.77)
Median PFS (months)Median PFS (months) 4.54.5 6.46.4<0.0001<0.0001
(0.62)(0.62)
Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. 4)
ECOG 4599 ECOG 4599 - - SSurvivalurvival
Sandler et al. ASCO 2005; 23:LBA4.
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
363630302424181812126600
% 16.9% 16.9% 43.7% 43.7
% 22.1% 22.1% 51.9 % 51.9
24 ay24 ay12 ay12 ay
AyAy
Pro
babi
lity
Medyan: 10.2, 12.5Medyan: 10.2, 12.5
PCBPCB
PCPC
HR: 0.77 (0.65, 0.93)HR: 0.77 (0.65, 0.93)
P = 0.007P = 0.007
ECOG 4599 ECOG 4599 - - PPFSFS
363630302424181812126600
0.00.0
0.20.2
0.40.4
0.60.6
0.80.8
1.01.0
MtsMts
Pro
babi
lity
% 6.4% 6.4% 32.6% 32.6
% 14.6% 14.6% 55.0% 55.0
12 12 mtsmts6 6 mtsmts
MedMediian: 4.5, 6.4an: 4.5, 6.4
PCBPCB
PCPC
HR: 0.62 (0.53, 0.72)HR: 0.62 (0.53, 0.72)
Sandler et al. ASCO 2005; 23:LBA4.
P < 0.0001P < 0.0001
Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): h(ECOG 4599): haematological toxicityaematological toxicity
*Includes one death on each arm due to neutropenic fever
CPCP(n=427)(n=427)Grade 4Grade 4
CP + CP + bevacizumabbevacizumab
(n=420)(n=420)Grade 4Grade 4 p valuep value
Neutropenia Neutropenia (%)(%) 16.416.4 2424 0.0060.006
Thrombocytopenia (%)Thrombocytopenia (%) 00 1.41.4 0.010.01
Anaemia (%)Anaemia (%) 0.70.7 00 NSNS
Febrile Febrile neutropenia (%)neutropenia (%) 1.9*1.9* 3.3*3.3* NSNS
Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. LBA4)
Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): n(ECOG 4599): non-haematological toxicityon-haematological toxicity
CP n (%)
>Grade 3
CP + bevacizumab n (%)
>Grade 3 p value
Haemorrhage Haemoptysis CNS GI Other
3 (0.7)1 (0.2)02 (0.5)1 (0.2)
19 (4.5)8 (1.9)4 (1.0)5 (1.2)4 (1.0)
<0.00 10.040.03
NS NS
Hypertension 3 (0.7) 25 (6.0) <0.001
Venous thrombosis 13 (3.0) 16 (3.8) NS
Arterial thrombosis 4 (1.0) 8 (1.9) NS
Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. LBA4)
Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): (ECOG 4599): treatment-related deathstreatment-related deaths
CP (n=427)
CP + bevacizumab (n=420)
Haemorrhage
Haemoptysis
GI bleed
0
1
5
2
Neutropenic fever 1 1
Total 2 8
Sandler A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):2s (Abs. LBA4)
Phase III trial of bevacizumab in NSCLCPhase III trial of bevacizumab in NSCLC(ECOG 4599): c(ECOG 4599): conclusionsonclusions
The addition of bevacizumab (15mg/kg every 3 The addition of bevacizumab (15mg/kg every 3 weeks) to CP improves OS, RR and PFS in weeks) to CP improves OS, RR and PFS in patients with NSCLCpatients with NSCLC
In certain patients, bevacizumab plus CP is In certain patients, bevacizumab plus CP is associated with life-threatening and fatal associated with life-threatening and fatal haemorrhagehaemorrhage
– event is associated with squamous cell histologyevent is associated with squamous cell histology
– patients with squamous cell NSCLC excluded patients with squamous cell NSCLC excluded from ongoing trialsfrom ongoing trials
Bevacizumab in first-line advanced Bevacizumab in first-line advanced NSCLCNSCLC
Bevacizumab is the first novel agent combined Bevacizumab is the first novel agent combined with standard chemotherapy to significantly with standard chemotherapy to significantly improve overall survival in unselected patients improve overall survival in unselected patients with advanced NSCLC in the first-line settingwith advanced NSCLC in the first-line setting
Bevacizumab plus CP is now the ECOG Bevacizumab plus CP is now the ECOG reference standard for the first-line treatment of reference standard for the first-line treatment of advanced non-squamous NSCLCadvanced non-squamous NSCLC
Bevacizumab + ErlotinibPhase II study
Erlotinib 150 mg/dayBevacizumab 15mg/kgevery 3 weeks
Herbst RS. JCO 2005; 23:2544-55.
Patients (No.=40)Stage IIIB/IV Nonsquamous typePreviously treated with chemoMedian KPS 80
RR: % 20Med. survival 12.6 mtsTTP: 6.2 mtsWell tolerated
ReRecurrent NSCLCcurrent NSCLC Erlotinib Erlotinib Bevacizumab Bevacizumab
ResultsResults
Gefitinib does not prolong survivalGefitinib does not prolong survival
Erlotinib prolongs survivalErlotinib prolongs survival– There is no advantage when added to standard There is no advantage when added to standard
chemochemo– Efficacy is better in nonsmokers, asians, Efficacy is better in nonsmokers, asians,
adenocarcinomas, femalesadenocarcinomas, females– Response rates are higher in patients who have EResponse rates are higher in patients who have Exon xon
19 19 - - 21 21 mutationsmutations andand gen genee amplifi amplificationcation – If there isIf there is K-rasK-ras mutation response rates are lowermutation response rates are lower
ResultsResults
There is no advantage to add cetuximab to There is no advantage to add cetuximab to standard chemostandard chemo
Bevacizumab + chemotherapy Bevacizumab + chemotherapy combination is an effective optioncombination is an effective option
Bevacizumab + Erlotinib Bevacizumab + Erlotinib combination may combination may have sinergic effecthave sinergic effect
FutureFuture
Molecular biology of lung cancer has many unknown aspectsMolecular biology of lung cancer has many unknown aspects
New agents acting on different signal transduction pathwaysNew agents acting on different signal transduction pathways
Important and significant predictive factors must be definedImportant and significant predictive factors must be defined
Chemotherapy + Targeted therapiesChemotherapy + Targeted therapies
To understand which patients will benefit the most from targeted To understand which patients will benefit the most from targeted
therapiestherapies
Targeted therapies in the early stages of the diseseTargeted therapies in the early stages of the disese
Future plans for bevacizumab and Future plans for bevacizumab and ErlotinibErlotinib in NSCLC in NSCLC
Planned and ongoing trials of bevacizumab in Planned and ongoing trials of bevacizumab in NSCLC include:NSCLC include:– combination with chemotherapy and radiotherapycombination with chemotherapy and radiotherapy– combination with other novel agents combination with other novel agents – neo-adjuvant and adjuvant settings neo-adjuvant and adjuvant settings – SAiL (Safety of bevacizumab in Lung) in 2006SAiL (Safety of bevacizumab in Lung) in 2006
Planned and ongoing trials of Planned and ongoing trials of erlotiniberlotinib in NSCLC in NSCLC include:include:– sequencing with chemotherapysequencing with chemotherapy– monotherapy trialsmonotherapy trials