Targeted therapies nella pratica clinica: Neoplasie del polmone

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Targeted therapies nella pratica
clinicaNeoplasie del polmone

• Fortunato Ciardiello
• Seconda Università degli Studi di Napoli

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EGFR inhibitors in pretreated NSCLC patients
possible interpretration of clinical results
Non-Responders
SD
PR
10 - 15 20 - 30 55
- 70
No effect on tumor growth
Apoptosis
Growth arrest
Non-EGFR-dependent Growth
EGFR-dependent Growth
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Gefitinib in Pretreated NSCLC Patients IDEAL 1
and 2 Results
Fukuoka et al. JCO 2003 Kris et al. JAMA 2003.
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Phase II Studies of Erlotinib Antitumor Activity
1Finkler N et al. Proceedings of ASCO
2001. 2Senzer N et al. Proceedings of ASCO
2001. 3Perez-Soler R et al. JCO 2004.
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Erlotinib Phase II NSCLC StudySurvival by Grade
of Rash
1.00
Grade 2/3 (n17)
0.75
0.50
Survival distribution function
Grade 1 (n26)
None (n14)
0.25
0.00
Perez-Soler R, et al. Am Soc Clin Oncol Mol Ther
Symp. 2002
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Sub-populations and response to Gefitinib in
NSCLC
1Fukuoka et al, JCO 2003 2Kris et al, JAMA 2003
3Miller et al, JCO 2004
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Clinical Predictors of Gefitinib or Erlotinib
Efficacy in NSCLC

• Never smoker
• Female gender
• Adenocarcinoma
• Asian origin

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EGFR Gene Mutations in NSCLC

• Somatic EGFR gene mutations are present in a
  small (10) but defined subset of NSCLC patients
  (mostly adenocarcinoma).
• EGFR gene mutations are generally clustered in
  the tyrosine kinase domain (mostly within exons
  18, 19, 21).
• EGFR gene mutations are associated with increased
  sensitivity to small molecule EGFR-TK inhibitors,
  such as gefitinib and erlotinib.
• However, EGFR gene mutations are not functionally
  and clinically equal to each other. EGFR gene
  mutations which confer resistance to EGFR-TK
  inhibitors have been identified.
• EGFR gene mutations are generally more frequent
  in adenocarcinoma from never smokers, in Asian
  and in female patients.
• Is adenocarcinoma with no smoking history a
  distinct NSCLC subset with frequent EGFR gene
  mutations and high sensitivity to gefitinib or to
  erlotinib?

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Measuring the number of copies of the EGFR gene
by FISH (Fluorescent in situ hybridisation)
EGFR gene
EGFR CEP7
Courtesy of Capuzzo, Crinò, Bunn, Hirsch and
Varella-Garcia.
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Time to progression and survival by EGFR FISH
status
Courtesy of Capuzzo, Crinò, Bunn, Hirsch and
Varella-Garcia.
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BR.21 Study A Phase III Randomized Evaluation of
Erlotinib in Second and Third Line Treatment of
NSCLC
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BR.21 TrialPatient Characteristics
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BR.21 TrialPatient Characteristics
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BR.21 TrialResponse Data
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BR.21 Summary of Treatment Effect Response
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BR.21 Summary of Treatment Effect Response
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BR.21 TrialSurvival Results
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ISEL trial design

• 1692 patients in 210 centres across 28 countries
• Stratified for histology, gender, intolerant /
  refractory, PS and smoking history

• End points
• Primary
• Survival
• Secondary
• TTF
• ORR
• QoL, symptoms
• Safety
• Exploratory
• Tumour biomarker analysis (eg EGFR)

• Patients with
• Histologically / cytologically confirmed NSCLC
• Locally advanced or metastatic disease
• 1 or 2 prior CT regimens
• Intolerant to most recent CT regimen or
  progression lt90 days of last CT cycle

Gefitinib (250 mg/day) BSC
Randomisation(21 ratio)
Placebo BSC
CT, chemotherapy BSC, best supportive care
TTF, time to treatment failure ORR, objective
response rate QoL, quality of life
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Baseline characteristics
Median age, years Male, Asian ethnicity,
Never smokers, Adenocarcinoma histology,
WHO performance status (PS) 0-1, 1 prior CT
regimen, Refractory to most recent CT, Best
response to most recent CT, Objective
response Stable disease Progressive
disease / non-evaluable
Gefitinib (n1129) 62 67.4 20.8 22.1 47.9 65.4 48
.6 89.5 17.836.845.2
Placebo (n563) 61 67.1 19.0 22.2 48.1
68.9 48.7 90.9 18.936.844.2
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Survival in the overall population
Median follow-up 7 months (range 3-15), 58 deaths
Median, months 1-year survival, Log-rank HR
(95 CI), 0.89 (0.77, 1.02) p0.087Cox
analysis, p0.030
Gefitinib 5.6 27
Placebo 5.1 21
Proportionsurviving
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
HR, hazard ratio CI, confidence interval
Time (months)
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Survival in the adenocarcinoma population
Median, months 1-year survival, Log-rank HR
(95 CI), 0.84 (0.68, 1.03) p0.089Cox
analysis, p0.033
Gefitinib 6.3 30
Placebo 5.4 18
Proportionsurviving
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
At risk
812
669
446
262
145
66
18
1
Time (months)
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Survival effects in subsets (1)
Survival
Gefitinib ORR
Adenocarcinoma
0.4
0.6
0.8
1.0
1.5
HR and 95 CI
Favours gefitinib
Favours placebo
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Survival effects in subsets (2)
Survival
Gefitinib ORR
11.1
6.9
7.4
9.0
6.4
7.2
10.2
12.4
6.8
10.1
7.7
7.5
8.0
0.4
0.6
0.8
1.0
1.5
HR and 95 CI
Favours gefitinib
Favours placebo
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Survival by smoking history
Never smoked (n375)
Ever smoked (n1317)
Cox regression HR (95 CI), 0.92 (0.79, 1.06)
p0.242 Median 5.0 vs 4.9 months
Cox regression HR (95 CI), 0.67 (0.49, 0.92)
p0.012 Median 8.9 vs 6.1 months
1.0
0.8
0.6
Proportion surviving
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
14
16
Time (months)
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Survival by ethnic origin
Asian ethnicity (n342)
Non-Asian ethnicity (n1350)
Cox regression HR (95 CI), 0.92 (0.80, 1.07)
p0.294 Median 5.2 vs 5.1 months
Cox regression HR (95 CI), 0.66 (0.48, 0.91)
p0.010 Median 9.5 vs 5.5 months
1.0
0.8
0.6
Proportion surviving
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
14
16
Time (months)
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EGFR gene copy number status
FISH ve
FISH -ve
Percent surviving
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Summary of FISH data in ISEL

• EGFR gene copy number appears to be the strongest
  predictor of a gefitinib related effect on
  survival, even in patients with clinical factors
  associated with a poor effect
• Patients who are negative for EGFR increased copy
  number appear unlikely to benefit from gefitinib
  therapy

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How does ISEL compare with BR21?
Are the outcomes different?
Survival
ORR
Trial
EGFR-TKI
Patients, n
ISEL
Gefitinib
1692
8 vs 1
BR21
Erlotinib
731
9 vs 1
0.40
0.60
0.80
1.00
1.25
HR and 95 CI
Favours active agent
Favours placebo

• Are there any major differences in trial
  populations?
• ISEL patients were more refractory
• 90 were refractory to most recent CT
• only 18 responded (40 in BR21) to most recent
  CT
• 45 had progressed (21 in BR21) on most recent CT

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Response by FISH in ISEL and BR21
709 - Gefitinib
BR21 - Erlotinib
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Survival by FISH in ISEL and BR21
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TORCH A multicenter Italian-Canadian Trial

• Patient population
• NSCLC
• Age gt18 and lt70
• PS 0-1
• Stage IIIb-IV

Phase II analysis of activity after 103
patients have been assigned Erlotinib
900 patients planned as phase III (sample size
669 events required to demonstrate
non-inferiority in survival)
Erlotinib
Chemotherapy
R A N D O M
Erlotinib
Chemotherapy
First-line treatment
Second-line treatment (after PD)

• Stratification
• histology
• smoking status
• gender
• centre
• PS
• stage

• Erlotinib
• 150 mg/die p.o.
• until progression

• Chemotherapy
• Cisplatin, 80 mg/m2, day 1
• Gemcitabine, 1200 mg/m2, day 1 and 8
• every 3 weeks, for 6 cycles

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Open clinical issues for the therapeutic use of
EGFR-targeted drugs

• Appropriate selection of potentially responding
  patients to EGFR-targeted agents
• EGFR expression is necessary. Is EGFR expression
  sufficient?
• EGFR gene amplification and increased gene copy
  number.
• Gain of function somatic EGFR gene mutations.
• Acquired resistance somatic EGFR gene
  mutations.
• Expression of ligands and receptors of the erbB
  family.
• Downstream signaling molecules activation (i.e.,
  MAPK, AKT pathways).
• Timing and schedule for the combination of
  cytotoxic treatments and EGFR-targeted agents.
• Combination with other signal transduction
  inhibitors and molecular targeted therapies.
• Control of cancer cell resistance to
  EGFR-targeted agents.