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Lung cancer perspectives. Targeted therapy :
one for all or a few for one ?
Miklos Pless, Winterthur26.3.2009
2
Standard first line
Schiller, NEJM 2002
Any of these
Cis- or Carboplatin
+
“new” agent
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Second-line Chemotherapy
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Shepherd et al 2000
0 3 6 9 12 15 180.0
0.2
0.4
0.6
0.8
1.0
Months
Docetaxel vs BSC
4
Option 2: Pemetrexed(Hanna, JCO 2004)
5
Two types of NSCLC:
Adeno carcinoma
In stage IV better prognosis
Cancer of non-smokers
More likely in women
More likely to harbor EGFR mutation
Squamous cell
Worse prognosis in stage IV
"Only" in smokers
Mostly men
Only rarely with EGFR mutation
DIFFERENT PROGNOSIS
DIFFERENT SENSITIVITIES AND SIDE EFFECTS TO DRUGS
DIFFERENT PROGNOSIS
DIFFERENT SENSITIVITIES AND SIDE EFFECTS TO DRUGS
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Study Design: 1º endpoint OSPre-specified subset analyses: randomization factors plus age,
ethnicity, smoking & histology
Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8
Randomization Factors
• Stage
• Performance status
• Gender
• Histologic vs cytologic diagnosis
• History of brain metastases
R
Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1
Vitamin B12, folate, and dexamethasone given in both arms
Non-inferiority study, OS-difference HR >1.17 excluded
Each cycle repeated q3 weeks up to 6 cycles
Scagliotti GV et al, Presented at 12th World Conference on Lung Cancer: Sept 5, 2007; Seoul, Korea.
7Scagliotti JCO
2008
?
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Prognostic Variables*
*From separate Cox models, controlling for treatment, disease stage, ECOG PS, gender, and basis of diagnosis
Subgroups HR (95% CI) Superiority P-value
Females vs males 0.76 (0.67, 0.86) < 0.001
Ever- vs never-smoker 1.74 (1.44, 2.09) < 0.001
Age (continuous) 1.00 (0.99, 1.00) 0.656
Caucasian vs others 1.36 (1.18, 1.57) < 0.001
E/SE Asian vs others 0.65 (0.54, 0.78) < 0.001
ECOG PS 0 vs 1 0.65 (0.58, 0.73) < 0.001
Stage IIIB vs IV 0.82 (0.71, 0.93) 0.003
Histo vs Cyto Dx 1.02 (0.91, 1.15) 0.693
Adeno vs others 0.75 (0.67, 0.84) < 0.001
Squamous cell vs others 1.12 (0.98, 1.27) 0.088
Large cell vs others 1.29 (1.07, 1.54) 0.007
Scagliotti JCO 2008
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Current options
EGFR Inhibitors Gefitinib/Erlotinib TKI
Cetuximab mAB
Angiogenesis Inhibitors BevacizumabmAB
EGFR Inhibitors Gefitinib/Erlotinib TKI
Cetuximab mAB
Angiogenesis Inhibitors BevacizumabmAB
Vessel disrupting agents ASA404SM
Angiogenesis Inhibitors Sunitinib/AxitinibTKI
IGF1-R Inhibitors many mAB
Vessel disrupting agents ASA404SM
Angiogenesis Inhibitors Sunitinib/AxitinibTKI
IGF1-R Inhibitors many mAB
In clincial trials
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Sandler, NEJM 2006
Bevacizumab
median 10.2 vs 12.5 mo
1-and 2-y OS
PC 44% and 17%
PCB 52% and 22%
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PFS in AVAiL trialReck, JCO 2009
12
13
1.0
0.8
0.6
0.4
0.2
0
Pro
bab
ility
of
OS
Time (months) 0 6 12 18 24 30 36
ITT (intent-to-treat) population
Placebo+ CG
Bev 7.5mg/kg
+ CG
Bev15mg/kg
+ CG
HR 0.93 1.03p value 0.42 0.76
Median OS (months) 13.1 13.6 13.4
AVAiL: OS
Manegold ESMO 2008
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Bevacizumab
2 randomized trials positive (only one for survival)
Toxicity manageable
Platinum/Bevacizumab containing triplet =
new Standard for first line treatment of stage IV Adeno-NSCLC?
Effect in patients >70 disputed (Ramalingam, JCO 2008)
Brain metastases and SCC tumors safe? Under investigation
Anticoagulation and central tumors seem safe
PROBLEMS: only non-squamous, only with Gemcitabine, many contra-indications
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16
17
18
19
Cetuximab
1 randomized trial positive
Toxicity manageable
Platinum/Cetuximab containing triplet =
the new Standard for first line treatment of stage IV NSCLC?
Problems: PFS!
Vinorelbine combination
effect marginal
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Second line targeted TrialsEGFR Inhibitor vs BSC
Gefitinib: ISEL Erlotinib: BR.21
Thatcher, Lancet 2005 Shepherd, N Engl J Med 2005
mOS 4.7 vs 6.7 momOS 5.1 vs 5.6 mo
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Gefitinib! Defies EBM!Gefitinib versus docetaxel in previously treated non-small-cell
lung cancer (INTEREST): a randomised phase III trialEdward S Kim et al, Lancet 2008
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Gefitinib and Erlotinib?
From P Jaenne, Clin Cancer Res, 2006
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Response alone no pedictor for benefit with erlotinib
Patients without objective response to Erlotinib
Tarceva(n=367)
Placebo(n=204)
Median OS(months)
Median OS(months)
HR p value
SD/PD 8.25 6.8 0.82 0.037
OSI Pharmaceuticals and F. Hoffmann-La Roche; data on file
24
BR.21: overall survival according to gender
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n 1.00
0.75
0.50
0.25
00 5 10 15 20 25
Placebo (n=83)
Tarceva (n=173)
MaleRR=6.0%
Placebo (n=160)
Tarceva (n=315)
0 5 10 15 20 25 30
Shepherd FA, et al. N Engl J Med 2005;353:123–32
1.00
0.75
0.50
0.25
0
Time (months) Time (months)
FemaleRR=14.4%
25
Shepherd FA, et al. N Engl J Med 2005;353:123–32; Tarceva Summary of Product Characteristics, F. Hoffmann-La Roche, 2007
BR.21: overall survival according to tumour histology
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
Tarceva (n=246)
AdenocarcinomaRR=13.9%
Placebo (n=119) Placebo (n=78)
Tarceva (n=144)
Squamous-cell carcinomaRR=3.8%
Adenocarcinoma: HR=0.7; p=0.008*
Squamous-cell carcinoma: HR=0.67; p=0.0007*
HR*Log-rank test 0.5 1
Time (months) Time (months)
1.00
0.75
0.50
0.25
00 5 10 15 20 25 30 0 5 10 15 20 25
1.00
0.75
0.50
0.25
0
26
BR.21: OS in male current/former smokers with squamous-cell
carcinoma
Su
rviv
al d
istr
ibu
tio
n f
un
ctio
n
1.00
0.75
0.50
0.25
0 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
HR=0.66(95% CI: 0.47– 0.92)
Time (months)
Clark GM, et al. Clin Lung Cancer 2006;7:389–94
Median OS (months)
Tarceva (n=100) 5.5
Placebo (n=57) 3.4
RR=6.8%
27
SAKK19/03: Erlotinib 1st line inunselected NSCLC patients (D’Addario; Ann Oncol 2008)
28
Mutation in EGFR (Lynch, NEJM 2004)
8/9!
29
L. Sequist, #7504 (iTARGET)
30
Spanish prospective phase II trial
(Paz-Ares, ACO 2006)
1047 NSCLC screened
127 (15%) Mutations of EGFR
Mutations in 67 (19%) of all Chemonaive patients
40 Patients treated with Erlotinib and evaluated
65% Female
85% PS 0/1
75% Adenocarcinoma
70% Never-smokers
31
Results (Paz-Ares, ACO 2006)
mfu 7 months
32
33
34
Erlotinib
150 mg/dNon-squamous NSCLC stage
IIIB/IV
Chemonaive
EGFR-mutated
4-6 cycles
Cis or Carbo- combinations with
Gemcitabine or Taxotere
Primary endpoint: increase of PFS of 3 months in Erlotinib arm (7 vs 4 months)Secondary endpoints: OS, ORR, QoL
n = 147
(screen n= 1500)
EURTAC - European Tarceva vs. Chemotherpay, Phase III
PD
PD Erlotinib
150 mg/d
R
4-6 cycles
Cis or Carbo- combinations with
Gemcitabine or Taxotere
35
New Drugs:
36
37
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39
40
41
42
43
IF YOU REALLY REALLY CAN NOT PUT THE PATIENT ON A TRIAL:
1st line
•DDDP/Pemetrexed for Adeno
•DDDP/Gem/Docetacel (SCC)
•Consider adding Bevacizumab (Adeno)
•Consider adding Cetuximab (SCC)
•Consider EGFR TKI for mutated tumors
1st line
•DDDP/Pemetrexed for Adeno
•DDDP/Gem/Docetacel (SCC)
•Consider adding Bevacizumab (Adeno)
•Consider adding Cetuximab (SCC)
•Consider EGFR TKI for mutated tumors
2nd line
•EGFR TKI or Chemotherapy
•Start early?!
Soon:
•Better Angiogenesis Inhibitors
•IGFR-1 Inhibitors
•VDA
2nd line
•EGFR TKI or Chemotherapy
•Start early?!
Soon:
•Better Angiogenesis Inhibitors
•IGFR-1 Inhibitors
•VDA
44
Targeted therapy???
Learned a lot about prognostic factors
• Adeno-, female-, never-smokers, asians
Don't know enough about predictive factors
• Histology? EGFR Mutation? K-ras Mutation?
Do we really have targeted treatments???
Do we have the right tools to detect efficacy?
45
Model: randomized trial 2nd line NSCLCNew vs. Docetaxel
New targets 25% and “cures” them
710 339 228 139 89 46 24 7 0 0503
0 4 8 12 16 20 24 28 32 36 40
0.0
0.2
0.4
0.6
0.8
1.0
Months
Probabilityof survival
At risk :
Docetaxel
p 0.05??
46
…all clear?