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Targeted therapies nella pratica clinica: Neoplasie del polmone

Targeted therapies nella pratica clinica: Neoplasie del polmone. Fortunato Ciardiello Seconda Università degli Studi di Napoli. EGFR inhibitors in pretreated NSCLC patients: possible interpretration of clinical results. Non-Responders. SD. PR. 10 - 15% 20 - 30% 55 - 70%.

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Targeted therapies nella pratica clinica: Neoplasie del polmone

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  1. Targeted therapies nella pratica clinica:Neoplasie del polmone Fortunato Ciardiello Seconda Università degli Studi di Napoli

  2. 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

  3. Gefitinib in Pretreated NSCLC Patients: IDEAL 1 and 2 Results Fukuoka et al. JCO 2003; Kris et al. JAMA 2003.

  4. 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.

  5. 0 5 10 15 20 25 30 Months Erlotinib Phase II NSCLC StudySurvival by Grade of Rash 1.00 Grade 2/3 (n=17) 0.75 0.50 Survival distribution function Grade 1 (n=26) None (n=14) 0.25 0.00 Perez-Soler R, et al. Am Soc Clin Oncol Mol Ther Symp. 2002

  6. Sub-populations and response to Gefitinib in NSCLC 1Fukuoka et al, JCO 2003; 2Kris et al, JAMA 2003; 3Miller et al, JCO 2004

  7. Clinical Predictors of Gefitinib or Erlotinib Efficacy in NSCLC • Never smoker • Female gender • Adenocarcinoma • Asian origin

  8. 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?

  9. Balanced trisomy Balanced disomy Balanced polysomy Gene amplification 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.

  10. 1.0 1.0 Cumulative distributionfunction Cumulativesurvivalfunction p=0.0005 p=0.028 0.8 0.8 0.6 0.6 EGFR gene positive 0.4 0.4 EGFR gene positive 0.2 0.2 EGFR gene negative EGFR gene negative 0.0 0.0 0 10 20 30 0 10 20 30 40 Time to progression (months) Survival (months) Time to progression and survival by EGFR FISH status Courtesy of Capuzzo, Crinò, Bunn, Hirsch and Varella-Garcia.

  11. R A N D O M I Z E Erlotinib: 150 mg/day • Stratification Factors: • Center • PS: 0-1 vs. 2-3 • Prior Resp: PR vs. SD vs. PD • Prior Rx: 1 vs. 2 • Prior CDDP: yes vs. no 2 1 Placebo: “150 mg”/day BR.21 Study: A Phase III Randomized Evaluation of Erlotinib in Second and Third Line Treatment of NSCLC

  12. BR.21 TrialPatient Characteristics

  13. BR.21 TrialPatient Characteristics

  14. BR.21 TrialResponse Data

  15. BR.21 Summary of Treatment Effect: Response

  16. BR.21 Summary of Treatment Effect: Response

  17. BR.21 TrialSurvival Results

  18. ISEL trial design • 1692 patients in 210 centres across 28 countries • Stratified for histology, gender, intolerant / refractory, PS and smoking history 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 <90 days of last CT cycle • End points • Primary: • Survival • Secondary: • TTF • ORR • QoL, symptoms • Safety • Exploratory: • Tumour biomarker analysis (eg EGFR) Gefitinib (250 mg/day) + BSC Randomisation(2:1 ratio) Placebo + BSC CT, chemotherapy; BSC, best supportive care; TTF, time to treatment failure; ORR, objective response rate; QoL, quality of life

  19. 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 (n=1129) 62 67.4 20.8 22.1 47.9 65.4 48.6 89.5 17.836.845.2 Placebo (n=563) 61 67.1 19.0 22.2 48.1 68.9 48.7 90.9 18.936.844.2

  20. Gefitinib Placebo At risk: 1692 1347 877 485 252 104 31 2 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); p=0.087Cox analysis, p=0.030 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)

  21. Gefitinib Placebo Survival in the adenocarcinoma population Median, months 1-year survival, % Log-rank HR (95% CI), 0.84 (0.68, 1.03); p=0.089Cox analysis, p=0.033 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)

  22. 11.9% Non-adenocarcinoma 4.8% Never smoked 18.1% Ever smoked 5.3% Refractory 7.9% Intolerant 9.4% 1 prior line 7.6% 2 prior lines 8.4% PS 0, 1 8.8% PS 2, 3 6.6% Female 14.7% Male 5.1% All patients 8.0% 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

  23. Prior docetaxel No prior docetaxel <65 years >65 years Time since Dx: <6 months Time since Dx: 6-12 months Time since Dx: >12 months Asian ethnicity Non-Asian ethnicity Prior CT response: CR/PR Prior CT response: SD Prior CT response: PD/NE All patients 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

  24. Gefitinib Placebo Survival by smoking history Never smoked (n=375) Ever smoked (n=1317) Cox regression HR (95% CI), 0.67 (0.49, 0.92); p=0.012 Median: 8.9 vs 6.1 months Cox regression HR (95% CI), 0.92 (0.79, 1.06); p=0.242 Median: 5.0 vs 4.9 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)

  25. Gefitinib Placebo Survival by ethnic origin Asian ethnicity (n=342) Non-Asian ethnicity (n=1350) Cox regression HR (95% CI), 0.66 (0.48, 0.91); p=0.010 Median: 9.5 vs 5.5 months Cox regression HR (95% CI), 0.92 (0.80, 1.07); p=0.294 Median 5.2 vs 5.1 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)

  26. 1.0 1.0 N = 256, E = 157 Cox HR = 1.16 (0.81 – 1.64), p = 0.42 N = 114, E = 68 Cox HR = 0.61 (0.36 – 1.04), p = 0.067 0.8 0.8 0.6 0.6 Gefitinib Gefitinib Percent surviving 0.4 0.4 Placebo Placebo 0.2 0.2 0.0 0.0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 16 14 Time (months) Time (months) EGFR gene copy number status FISH +ve FISH -ve Percent surviving

  27. 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

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

  29. Response by FISH in ISEL and BR21 709 - Gefitinib BR21 - Erlotinib

  30. ISEL EGFR gene No. of pts HR CI P* P** Low copy 256 1.16 0.81-1.64 0.42 0.045 High copy 114 0.61 0.36-1.04 0.067 BR21 EGFR gene No. of pts HR CI P* P** Low copy 69 0.86 0.48-1.51 0.59 0.10 High copy 56 0.44 0.23-0.82 0.008 *P value for subgroup compared to placebo **P value for interaction Survival by FISH in ISEL and BR21

  31. TORCH: A multicenter Italian-Canadian Trial • Patient population: • NSCLC • Age >18 and <70 • 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 Chemotherapy Erlotinib 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

  32. 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 erbBfamily. • 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.

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