Advanced non-small-cell lung cancer (NSCLC) patients may benefit from several chemotherapeutic or targeted agents. However, patients respond differently to the same treatment in terms of anticancer efficacy or side-effects. As the choices for patients increase over the time along with advances in clinical research, selecting the right agents that provide patients with best chance of anticancer activity and lowest possibility of toxicity is the main theme in future research and clinical practice. Gene expressions in tumor cells may be good biomarkers for selecting treatment. Somatic gene expression may indirectly affect tumor gene and also determine the toxicity to various treatment. Several biomarkers were found to be correlated well with efficacy of drug treatment. For example, mutations in the exon 21 (L858R) and deletion in exon 19 of epidermal growth factor receptor (EGFR) were found to be correlated well with responsiveness to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib. The discovery of EML4-ALK or a ROS1 translocation predicted good response to ALK inhibitor crizotinib. The above-mentioned predictive factors for drug responsiveness were also prognostic factors for survival time. For example, activating mutation of EGFR may be a good prognostic factor for advanced NSCLC patients in addition to its role as a good predictive factor for EGFR-TKI treatment response.
The results of Iressa Pan-Asian Survival Study (IPASS) have shown that patients whose tumor samples have tested positive for EGFR mutations may receive gefitinib as first-line treatment. The progression-free survival for those patients receiving gefitinib was longer than those receiving paclitaxel and carboplatin. The response rate of gefitinib for patients with EGFR mutation was 70% and that of wild-type patients was only 1%. In the updated final overall survival analysis, IPASS showed that overall survival was similar, with no significant difference, between gefitinib and carboplatin/paclitaxel in between treatment arms for OS in the subgroups defined by EGFR mutation status: EGFR mutation-positive patients (HR = 1.00, 95% CI 0.76–1.33, median OS 21.6 versus 21.9 months). The equalization of OS in overall population and in EGFR mutation positive or negative patients after significant difference in PFS in the first-line period is probably due to the extensive crossing over treatment patients received after they progressed on first-line treatment.
Several phase III studies selecting treatment-naïve patients with EGFR mutations and randomize to gefitinib versus docetaxel cisplatin (WJOG3405), gefitinib versus paclitaxel carboplatin (NEJ002), erlotinib versus gemcitabine carboplatin (OPTIMAL), erlotinib versus cisplatin regimen (EURTAC) all demonstrated same results of small molecule EGFR TKI superiority over combination chemotherapy on response rate, PFS and quality of life. It is advisable to send tumor for the EGFR mutation test in all adenocarcinoma lung patients and select EGFR-TKI if the test result turns out to be positive.
However, small fraction of EGFR mutation positive patients does not respond well to gefitinib or erlotinib. In addition, patients responded to gefitinib or erlotinib with limited period of time. Second-generation EGFR TKIs such as afatinib or dacomitinib are irreversible EGFR inhibitors. They have the potential to inhibit the proliferation of resistant exon 20 T790M mutation in the EGFR mutation-positive tumor cells. Afatinib was tested in 129 EGFR mutation-positive patients. The PFS of patients with del 19 and L858R were 13.7 months with independent review. The phase III study of afatinib versus pemetrexed cisplatin was recently presented in ASCO. The long of independent reviewed PFS of afatinib in these studies will be confirmed in a randomized study comparing afatinib to gefitinib.
Salvage treatment after EGFR-TKI failure has become an important issue recently when EGFR-TKI become a standard treatment of these patients. When EGFR-TKI was given as the first-line treatment, the salvage treatment of patients after EGFR-TKI is usually combination chemotherapy. However, there are limited publications on the efficacy of combination chemotherapy after failure of EGFR-TKI as first-line treatment. The response rates and progression-free survival time for EGFR-TKI-treated patients may not be the same as EGFR-TKI-naive patients. Therefore, more prospective study in this area should be carried out. Another unsolved question is whether patients with EGFR mutations are still addicted to EGFR pathways when they fail EGFR-TKI treatment and that whether continuing EGFR-TKI treatment even in combination with chemotherapy is necessary. Further randomized study should be considered in this aspect. For slow or minimal progression patients, it may be helpful for patients to stay on EGFR-TKI treatment beyond progression rather than switching to chemotherapy. Studies such as IMPRESS will address such questions. The emergence additional EGFR T790M mutation and/or cMET amplifcation was shown to be the predominant resistance mechanism in EGFR-TKI-acquired resistance patients. Novel agents that act on these resistance mechanisms such as irreversible EGFR-TKI or cMET inhibitors may play some role in the future as salvage treatment of EGFR mutation-positive patients who fail EGFR-TKI.