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

3

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

6

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

?

8

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

10

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

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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

21

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

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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

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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%

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SAKK19/03: Erlotinib 1st line inunselected NSCLC patients (D’Addario; Ann Oncol 2008)

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Mutation in EGFR (Lynch, NEJM 2004)

8/9!

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L. Sequist, #7504 (iTARGET)

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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

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Results (Paz-Ares, ACO 2006)

mfu 7 months

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33

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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

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New Drugs:

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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

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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?

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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?