Clinical development of EGFR-tyrosine kinase inhibitors in Japan

Abstract

Although the initial impact of the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib may have been less than spectacular in the field of non-small cell lung cancer (NSCLC), this EGFR-TKI does offer a therapy that, at least in the short term, markedly reduces tumors without bone marrow suppression including neutropenia and without causing severe nausea and vomiting even in NSCLC patients with the worst prognosis. This raises the possibility of putting the disease under control if only temporarily. Now we must be aware that overcoming gene mutation in lung cancer is the next significant milestone for new therapeutics. This report discusses clinical trials of EGFR-TKIs focusing on Japanese contributions to current knowledge, EGFR mutation, and future directions. A Japanese phase I clinical trial saw the first super-responders to gefitinib. Two randomized phase II trials identified Japanese, females, and those with adenocarcinoma of the lung as specific populations sensitive to gefitinib. Unexpectedly, in the context of first-line chemotherapy four phase III trials gave completely negative results for additional clinical benefit by EGFR-TKIs combined with standard chemotherapy. However, subset analysis suggested efficacy of this treatment strategy in nonsmokers and patients harboring activated-type EGFR mutations. In the settings of second-line and later therapy, two independent randomized placebo-controlled trials, BR.21 with erlotinib and ISEL with gefitinib, revealed better duration of overall survival, time to progression, and response rate in the EGFR-TKI versus control groups, although the result was nonsignificant in the latter study. Data suggesting that adenocarcinoma, Asian race, female, and nonsmoker are associated with better response to EGFR-TKI may be closely related with phenotype of EGFR mutations, making this parameter a “response predictive marker.” On the other hand, some reports have stated that gene amplification of EGFR by FISH analysis shows better correlation with clinical benefit of EGFR-TKIs than that assessed by other means in large-scale phase III trials (BR21 and ISEL). Further validation of response predictive markers is needed. Recent studies of EGFR-TKIs in NSCLC provide novel biological insights and have given birth to the concept of patient selection for this disease. Further investigation of the biological significance of EGFR mutation and its validation as response predictive marker will lead to better treatments to come for NSCLC.