ApplicationofEGFRTKIinAsia
http://www.100md.com
参见附件(100KB)。
Tony Mok MD
Department of Clinical Oncology, The Chinese University of Hong Kong
Metastatic NSCLC is a highly fatal illness with minimal chance of long term survival. Recent developments in 3 rd generation cytotoxic chemotherapy, molecular targeted therapy and phamacogenomic have significantly prolonged survival and positively improved the quality of life. We have shifted from doing minimal for metastatic NSCLC to the new paradigm of optimization of treatment outcome with multiple lines of therapy. The bench mark results of third generation doublet are best represented by the 5 completed randomized studies (ECOG 1594, SWOG 9509, TAX 326, Scagliotti et al, Van Meerbeck et al) involving over 3700 patients. These studies confirmed not only that platinum-based novel drug regimens were equal in efficacy but also provided a reference standard for first line therapy. Subsequent development in epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has further revolutionized management of advanced non-small cell lung cancer. Particularly in Asia , we observed high response rate and longer survival in selective groups of patients. Collective data of 31 published reports from Taiwan , Malaysia , Korea , China and Japan confirmed the tumor response rate of gelfitinib as second line therapy to be over 20% and disease control rate ranging from 30 to 70%. We observed a strong association of tumor response to non-smoker, female gender and adenocarcinoma. The findings also match the high incidence of EGFR mutation with patients holding these clinical characteristics. Despite the lack of survival benefit in ISEL subgroup analysis of the study has shown significant hazard ratio of 0.81, 0.67, 0.77 and 0.66 in adenocarcinoma, never smoker, female gender and oriental, respectively. EGFR-TKI is now one of the 2 nd or 3 rd line treatments for selective population in Asia . However, many questions remain unanswered. To develop this class of novel therapy as standard treatment for lung cancer patients we should address the following issues:
Patient Selection by Biomarker
We learnt from ISEL and BR-21 study of the survival prolongation in specific subgroup of patients and the significant benefit is mostly but not exclusive accounted by EGFR mutations. Mutations in exon 18-21 of the tyrosine kinase domain of EGFR are associated with higher response rate to EGFR TKI. Tumor response rate is approximately 80% in EGFR mutant comparing to about 10 to 20% in patients with wild-type EGFR. The two most common mutation are the deletion in exon 19 (44%) and point mutation in exon 21 (41%). About 5% have insertions in exon 20 but its nature in response to EGFR-TKI remains unclear. The point mutation of T790M at exon 20 is in fact associated with resistance to EGFR TKI.
Selection by EGFR mutation is a promising method to optimize the treatment outcome of EGFR-TKI. Paz-Ares et al (PASCO abst 7020, 2006) performed a phase II study of erlotinib in patients with proven EGFR mutation. After screening 297 patients they found 37 (12.5%) with either deletion (25) or point mutation L858R (11). Tumor response rate was 100% in tumors with exon 10 deletion and 75% in patients with L858R. In contrast, a CALGB randomized phase II study that selected patients with PS2 for either erlotinib or chemotherapy. Tumor response rate with erlotinib was only 2%. (PASCO abst 7022, 2006) However, the effect of EGFR mutations on survival is not well established. With the limited sample available in ISEL and BR-21 patients with EGFR mutation who were treated with EGFR-TKI failed to have a survival benefit.
EGFR gene amplification by FISH is another biomarker that can prove to be a useful for prediction of tumor response and survival. The advantage of FISH is that it can be performed in paraffin embedded material and relatively cheaper. In the ISEL study patient with FISH positive tumor (n=114) the hazard ratio (HR) for survival was 0.61 and the HR was even more pronounced at 0.55 if both FISH and IHC EGFR expression are positive. Similar benefit was also observed in BR-21. However, there was little information on the predictive value of EGFR gene amplification among Asian. Takano et al performed retrospective review of EGFR mutation in 364 patients who were treated by gefitinib. Only 66 patients had analysis of the EGFR gene copy number (by quantitative real-time PCR). He found increased gene copy in 29 patient and was associated with higher rate of EGFR mutation (76% versus 46%, P =0.014). In this limited study EGFR gene copy >3 is also a predictor of tumor response (Odd ratio of 7.6) but NOT a predictor of overall survival (Odd ratio of 0.95). Further investigation on the role of EGFR gene amplification by FISH in Asian population is indicated.
Patient Selection by Clinical Parameters
The two strongest clinical parameters are histology type of adenocarcinoma and smoking history. Wu et al (PASCO abst 7187, 2006) reviewed 407 cases from 5 centres in China. EGFR mutation rate in adenocarcinoma and non-adenocarcinoma was 42.5% and 9.5%; non-smoker and smoker was 39.2% and 18.5%, respectively. Tumor response rate to gelfitinib in patients with adenocarcinoma and EGFR mutation or wild type was 69.9% and 18.8%, respectively. None of the 10 patients with non-adenocarcinoma responded. Similar findings were reported by Sonobe et al (Br J Cancer 93:355, 2005) from Japan. Out of 108 adenocarcinoma, EGFR mutations were observed in 83% of never-, 50% of former and 15% of current smokers. In BR-21, ISEL and TRIBUTE trial never smokers enjoyed a significantly longer survival receiving EGFR-TKI as single agent 2 nd /3 rd line therapy or in combination with cytotoxic chemotherapy as first line therapy. Smoking status is also associated with EGFR gene copy number by FISH. Capuzzo et al (PASCO abst 7023, 2006) conducted a phase II study of gefitinib in patients with EGFR FISH positive tumor and/or never smoker. Tumor response rate was highest (71%) in never smoker with EGFR FISH positive and lowest (12%) in never smoker with EGFR FISH negative patients.......（后略) ......
Tony Mok MD
Department of Clinical Oncology, The Chinese University of Hong Kong
Metastatic NSCLC is a highly fatal illness with minimal chance of long term survival. Recent developments in 3 rd generation cytotoxic chemotherapy, molecular targeted therapy and phamacogenomic have significantly prolonged survival and positively improved the quality of life. We have shifted from doing minimal for metastatic NSCLC to the new paradigm of optimization of treatment outcome with multiple lines of therapy. The bench mark results of third generation doublet are best represented by the 5 completed randomized studies (ECOG 1594, SWOG 9509, TAX 326, Scagliotti et al, Van Meerbeck et al) involving over 3700 patients. These studies confirmed not only that platinum-based novel drug regimens were equal in efficacy but also provided a reference standard for first line therapy. Subsequent development in epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has further revolutionized management of advanced non-small cell lung cancer. Particularly in Asia , we observed high response rate and longer survival in selective groups of patients. Collective data of 31 published reports from Taiwan , Malaysia , Korea , China and Japan confirmed the tumor response rate of gelfitinib as second line therapy to be over 20% and disease control rate ranging from 30 to 70%. We observed a strong association of tumor response to non-smoker, female gender and adenocarcinoma. The findings also match the high incidence of EGFR mutation with patients holding these clinical characteristics. Despite the lack of survival benefit in ISEL subgroup analysis of the study has shown significant hazard ratio of 0.81, 0.67, 0.77 and 0.66 in adenocarcinoma, never smoker, female gender and oriental, respectively. EGFR-TKI is now one of the 2 nd or 3 rd line treatments for selective population in Asia . However, many questions remain unanswered. To develop this class of novel therapy as standard treatment for lung cancer patients we should address the following issues:
Patient Selection by Biomarker
We learnt from ISEL and BR-21 study of the survival prolongation in specific subgroup of patients and the significant benefit is mostly but not exclusive accounted by EGFR mutations. Mutations in exon 18-21 of the tyrosine kinase domain of EGFR are associated with higher response rate to EGFR TKI. Tumor response rate is approximately 80% in EGFR mutant comparing to about 10 to 20% in patients with wild-type EGFR. The two most common mutation are the deletion in exon 19 (44%) and point mutation in exon 21 (41%). About 5% have insertions in exon 20 but its nature in response to EGFR-TKI remains unclear. The point mutation of T790M at exon 20 is in fact associated with resistance to EGFR TKI.
Selection by EGFR mutation is a promising method to optimize the treatment outcome of EGFR-TKI. Paz-Ares et al (PASCO abst 7020, 2006) performed a phase II study of erlotinib in patients with proven EGFR mutation. After screening 297 patients they found 37 (12.5%) with either deletion (25) or point mutation L858R (11). Tumor response rate was 100% in tumors with exon 10 deletion and 75% in patients with L858R. In contrast, a CALGB randomized phase II study that selected patients with PS2 for either erlotinib or chemotherapy. Tumor response rate with erlotinib was only 2%. (PASCO abst 7022, 2006) However, the effect of EGFR mutations on survival is not well established. With the limited sample available in ISEL and BR-21 patients with EGFR mutation who were treated with EGFR-TKI failed to have a survival benefit.
EGFR gene amplification by FISH is another biomarker that can prove to be a useful for prediction of tumor response and survival. The advantage of FISH is that it can be performed in paraffin embedded material and relatively cheaper. In the ISEL study patient with FISH positive tumor (n=114) the hazard ratio (HR) for survival was 0.61 and the HR was even more pronounced at 0.55 if both FISH and IHC EGFR expression are positive. Similar benefit was also observed in BR-21. However, there was little information on the predictive value of EGFR gene amplification among Asian. Takano et al performed retrospective review of EGFR mutation in 364 patients who were treated by gefitinib. Only 66 patients had analysis of the EGFR gene copy number (by quantitative real-time PCR). He found increased gene copy in 29 patient and was associated with higher rate of EGFR mutation (76% versus 46%, P =0.014). In this limited study EGFR gene copy >3 is also a predictor of tumor response (Odd ratio of 7.6) but NOT a predictor of overall survival (Odd ratio of 0.95). Further investigation on the role of EGFR gene amplification by FISH in Asian population is indicated.
Patient Selection by Clinical Parameters
The two strongest clinical parameters are histology type of adenocarcinoma and smoking history. Wu et al (PASCO abst 7187, 2006) reviewed 407 cases from 5 centres in China. EGFR mutation rate in adenocarcinoma and non-adenocarcinoma was 42.5% and 9.5%; non-smoker and smoker was 39.2% and 18.5%, respectively. Tumor response rate to gelfitinib in patients with adenocarcinoma and EGFR mutation or wild type was 69.9% and 18.8%, respectively. None of the 10 patients with non-adenocarcinoma responded. Similar findings were reported by Sonobe et al (Br J Cancer 93:355, 2005) from Japan. Out of 108 adenocarcinoma, EGFR mutations were observed in 83% of never-, 50% of former and 15% of current smokers. In BR-21, ISEL and TRIBUTE trial never smokers enjoyed a significantly longer survival receiving EGFR-TKI as single agent 2 nd /3 rd line therapy or in combination with cytotoxic chemotherapy as first line therapy. Smoking status is also associated with EGFR gene copy number by FISH. Capuzzo et al (PASCO abst 7023, 2006) conducted a phase II study of gefitinib in patients with EGFR FISH positive tumor and/or never smoker. Tumor response rate was highest (71%) in never smoker with EGFR FISH positive and lowest (12%) in never smoker with EGFR FISH negative patients.......（后略) ......
附件资料：