Yonsei Med J.  2013 Jan;54(1):1-14. 10.3349/ymj.2013.54.1.1.

The Role of Pharmacoethnicity in the Development of Cytotoxic and Molecular Targeted Drugs in Oncology

• Saijo N

• KMID: 1776911
• DOI: http://doi.org/10.3349/ymj.2013.54.1.1

Abstract

The effective and toxic ranges of anticancer drugs are very narrow and, in some cases, inverted. Thus determination of the most appropriate dosage and schedule of administration is crucial for optimal chemotherapy. In common arm trials conducted in Japan and by Southwest Oncology Group (SWOG) that used the same doses and schedules for the administration of carboplatin plus paclitaxel, the frequency of hematological toxicity was significantly higher in the Japanese trials than in the SWOG trial, despite demonstrating similar response rates. The frequency of epidermal growth factor receptor (EGFR) mutations in tumors was significantly higher among East Asian populations, and these populations are also reported to demonstrate a higher response rates to epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs). The prevalence of interstitial lung disease induced by treatment with EGFR-TKIs has been shown to be quite high in the Japanese population. Clinical trials of cetuximab against non-small cell lung cancer and of bevacizumab against stomach cancer have shown that these agents are only active in Caucasians. In a trial examining the use of sorafenib after transarterial chemoembolization in Korean and Japanese patients with advanced hepatocellular carcinoma, the compliance and dose intensity of the drug were quite low compared with other trials. Although not only identified pharmacogenomics differences but also differences in social environment, and regional medical care, including pharmacoeconomics strongly influence ethnic differences in treatment response, further identification and understanding of the pharmacogenomics underlying ethnic differences will be essential to timely and reliable global development of new anticancer drugs.

Keyword

Ethnicity; cytotoxic drugs; molecular targeted drugs; common arm trial; EGFR-TKI; ILD; FLEX; AVAGAST; sorafenib

MeSH Terms

Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
Asian Continental Ancestry Group
Carcinoma, Non-Small-Cell Lung/drug therapy/ethnology
Chemoembolization, Therapeutic
Clinical Trials as Topic
Drug Design
Ethnic Groups
Humans
Japan
Lung Diseases, Interstitial/chemically induced
Lung Neoplasms/drug therapy/ethnology
Mutation
Pharmacogenetics/*methods
Receptor, Epidermal Growth Factor/genetics
Republic of Korea
Receptor, Epidermal Growth Factor

Figure

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  Fig. 1 Ethnic differences in survival outcome of NSCLC. A meta-analysis of randomized trials. Asian: 91 studies, Caucasian: 301 studies. Survival was better in Asian that Caucasian.12 EGFR-TKI, epidermal growth factor receptor tyrosine-kinase inhibitor; NSCLC, non-small cell lung cancer; CDDP, cisplatin.

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  Fig. 2 EGFR-TKI is effective in patients with distinct clinico-pathological and pharmacogenomical features. EGFR, epidermal growth factor receptor; TKI, tyrosine-kinase inhibitor; BAC, bronchial alveolar cell; FISH, fluorescence in situ hybrydization.

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  Fig. 3 ISEL study comparing gefitinib and placebo showed survival beneft only in Asian subset.34 MST, median survival time; ISEL, Iressa survival evaluation in lung cancer.

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  Fig. 4 Strange data of BR-21: erlotinib was effective only in non-Asian patients.29

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  Fig. 5 Significantly high EGFR mutation rate in Asian NSCLC patients. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

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  Fig. 6 Global Ist line clinical trials of Afatinib vs. CT for molecularly-selected NSCLC patients (LUX-LUNG3). EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

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  Fig. 7 Ethnic difference for molecular classification of adenocarcima. EGFR, epidermal growth factor receptor.

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  Fig. 8 Subgroup analysis of OS in AVAGAST Survival of pan-American is better in Avastin group.

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  Fig. 9 MET pathways.

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  Fig. 10 Phase I combination study with erlotinib in Japan. EM, extensive metabolizer; PM, poor metabolizer.

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