非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂（英文）

Epidermal growth factor receptor- tyrosine kinase inhibitor in non- small-cell lung cancer Yuh-Min Chen, MD, PhD. Chest Dept., Taipei VGH Date 1YMC Survival (anti-apoptosis) PI3-K Activation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK): a pivotal driver of carcinogenesis EGFR-TK EGFR Ligand RAS RAF SOS GRB2 PTEN AKT STAT3 MEK Gene transcription Cell-cycle progression DNA Myc Myc Cyclin D1 JunFos P P MAPK Proliferation/ maturation Chemotherapy/ radiotherapy resistance Angiogenesis Metastasis Balaban et al 1996; Akimoto et al 1999; Wells 1999; Woodburn 1999; Hanahan 2000; Raymond et al 2000 Cyclin D1 pY pY pY Date 2YMC R p p R Extracellula r Intracellular Membrane p K p K p p p TGFa Substrate Substrate Signalling Molecules Proliferation Inhibit Apoptosis Angiogenesis Metastasis Nucleus Monoclonal Antibodies EGFR Tyrosine Kinase Inhibitors Date 3YMC IDEAL 1 and 2 trial design Gefitinib 250 mg/day Gefitinib 500 mg/day Continue gefitinib until disease progression or unacceptable toxicity IDEAL, IressaTM Dose Evaluation in Advanced Lung cancer Randomisation l IDEAL 1 (n=209) 1 or 2 prior regimens l IDEAL 2 (n=216) 2 prior regimens Primary endpoints l Objective tumour response l Symptom improvement (IDEAL 2) l Safety (IDEAL 1) Date 4YMC Median time to improvement - symptoms and QOL *Time of 1st assessment Median time to improvement, days Symptom/QOL measure LCS FACT-L 8* 29* Date 5YMC IDEAL 1 and 2: overall survival by symptom improvement (250 mg/day) Probability1.0 0.8 0.6 0.4 0.2 0.0 IDEAL 1 Months from randomisation Improvement No improvement 27 40 18 30 13.3 3.5 Patients (n) Deaths (n) Median (months) 0 2 4 6 8 101214161820 44 58 26 56 13.6 3.7 Patients (n) Deaths (n) Median (months) 1.0 0.8 0.6 0.4 0.2 0.0 Probability IDEAL 2 Months from randomisation 0 2 4 6 8 101214161820 Douillard et al 2002; Lynch et al 2003 Date 6YMC ISEL (IRESSA Survival Evaluation in Lung Cancer): Clinical Trial Design Randomisation Gefitinib (250 mg) + *BSC Placebo + *BSC SURVIVAL Secondary: TTF, OR QoL, safety Primary endpoint: E N D B E N E F I T 2:1 ratio A double blind Phase III survival study comparing IRESSA (250mg) plus BSC vs. placebo plus BSC in patients with advanced NSCLC who have received 12 prior chemotherapy regimens and are refractory or intolerant to their most recent regimen 1692 patients in 210 centres across 28 countries 342 patients of oriental origin No Japanese/US sites *BSC= Best Supportive Care Lancet 2005;366:1527-37 Date 7YMC ISEL - Overall Survival Percent surviving Time (months) At risk: Gefitinib 1129 1023 901 761 588 455 325 245 175 113 76 45 19 9 IRESSA - Placebo Placebo 563 517 446 382 289 220 160 115 77 44 28 20 12 4 2 Gefitinib placebo Median (months) 5.6 5.1 1 yr survival 27% 21% HR=0.89 (0.77, 1.02), p=0.0871 Stratified log rank test N=1692, deaths=976 Cox analysis, p=0.0299 Date 8YMC ISEL Survival: Orientals Percent surviving Time (months) At risk: Gefitinib 235 221 199 179 145 119 95 78 64 51 40 25 12 8 IRESSA - Placebo Placebo 107 97 84 74 56 43 35 29 22 13 8 7 3 1 1 5.5 M 9.5 M Date 9YMC J Chemother 2005;17:679 Date 10YMC RESULTS 3 CR, 9 PR, with a R.R. of 33.3% SD 14, control rate of 72.2% All treatment-related toxicities were few and mild in severity, except one patient suffered from reversible grade 3 interstitial pneumonitis J Chemother 2005;17:679 Date 11YMC % Survival Median survival: 9.5 months One-year survival rate: 45.1% J Chemother 2005;17:679 Date 12YMC % Survival Fig. 1 0 10 20 30 40 50 60 70 80 90 100 0 3 6 9 12 15 18 21 Months Complete or partial response (n=12) median 20.1M Stable or progressive disease (n=24) median 4.7M Survival according to response or not 15.4月 J Chemother 2005;17:679 Date 13YMC Study Design of BR.21 Stratified by: Centre PS (0/1 vs 2/3) Response to prior treatment (CR/PR:SD:PD) Prior regimens (1 vs 2) Prior platinum (yes vs no) Tarceva 150mg daily Placebo R A N D O M I S E PS = performance status 2 1 N Engl J Med 2005;353:12332Date 14YMC BR.21: Significant clinical predictors of response to Tarceva Tarceva treated pts (n) R.R. (%) p value* Gender Female (146) 14.4 0.006 Male (281) 6.1 Histology Adenocarcinoma (209) 13.9 65 years 82 13.7 Wu JY et al. AJRCCM 2008 Date 47YMC No survival difference in 152 chemonaive or chemo-treated EGFR mutated patients in NTUH Chmo nave gefitinib (n=91) Chemotherapy treated gefitinib (n=61) log rank Chmo nave gefitinib (n=91) Chemotherapy treated gefitinib (n=61) log rank=0.24 Wu JY et al. AJRCCM 2008 Date 48YMC 2003.9.15 s/p 4 line C/T since 20010629, PS 3 FiO2 50% 2003.9.29 Iressa 2 weeks PS 1 room air Another 1.5 year Date 49YMC Ms. Ree Hx No 31676887 75 Y/O 20021202 SOB for months, PS 2-3, NC 3L/min pre C/T 20050804 post NGC; taxotere; under Iressa-N, PS 0 Date 50YMC s/p renal transplantation with adenocarcinoma, LUL, 2:1-11 Kwak et al. Pro Nat Acad Sci USA 2005; 102: 7665- 70 8 of 16 TKI treated had 2nd mutation: 7 of 8 was T790M Clin Cancer Res 2006;12:6494-501 T790M accounts for 50% acquired resistance to EGFR-TKIs C-MET amplification accounts for 25% And Date 52YMC EGFR and MET each independently activate ErbB3 in the resistant cells AKT P13K P110 P85 PPP Adapted from review by C1 Arteaga Nature Medicile.2007 EGFR ErbB3 Met Edu Session ASCO 2008 Date 53YMC The IGF-IR pathway is activated by a loss of IGF Binding Proteins (IGFBPs) Cell SurvivalCell Death EGFR ErbB3 IGF IGF-IR IGF-BPs EGFR gefitinib gefitinib ErbB3 IGF-IR P13k p110 p85pIRS-1 AKT p Parental (Sensitive) Resistant Edu Session ASCO 2008 Date 54YMC Acquired Resistance to EGFR Inhibitors Mechanism Treatment T790M Irreversible EGFR inhibitors MET amplifications MET + EGFR inhibitors IGF-1R activation IGF-1R (or PI3K) + EGFR inhibitors Heterogenicity of resistance may necessitate combinations ( eg. Irreversible EGFR & MET inhibitors) Should these combinations be moved to initial therapy to produce greater TTP similar to strategy for HIV and TB? Edu Session ASCO 2008 Date 55YMC Conclusions: Clinical Predictors of EGFR-TKIs Responsiveness Response rate, %* Setting 1st lin