Second-Line Treatment of Non-Small-Cell Lung Cancer with Wild-Type EGFR Status. What Is the Best Approach?

The EditorCurrent Oncology31 August 2015We read with great interest the article of Ma and colleagues titled “An exploratory comparative analysis of tyrosine kinase inhibitors or docetaxel in second-line treatment of EGFR wild-type non-small-cell lung cancer: a retrospective real-world practice review at a single tertiary care centre”1. The authors presented a retrospective cohort study including patients with EGFR wild-type non-small-cell lung cancer (nsclc) who received tyrosine kinase inhibitor (tki) as second- or third-line therapy, and they compared clinical outcomes for tki and single-agent docetaxel in second-line treatment.In the article, the authors concluded that second-line therapy with tki for EGFR wild-type nsclc (compared with docetaxel) was associated with statistically better progression-free survival (pfs) and event-free survival, and noninferior overall survival. That finding is quite surprising and might be related to the many limitations of the study. Indeed, in addition to the limitations reported by the authors (the relatively small size of the cohort, the selection bias, the variability in the timing of imaging, and the retrospective nature of the analysis), we can make several comments.First, considering the results of two large randomized phase iii trials (delta and tailor)2,3 and a meta-analysis4, it is now well established that chemotherapy is better than erlotinib in terms of pfs in the second-line treatment of nsclc with wild-type EGFR status. It is difficult to consider the results of a retrospective study such as that in the article from Ma and colleagues rather than those from the more methodologically strong studies.Second, Ma et al. did not specify in the article how they defined EGFR wild-type patients. That information is important, because if the authors excluded only patients with classical EGFR mutation (exon 19 deletion and L834R substitution mutations), it is possible that some patients classified as EGFR wild-type in the study might have some rare activating EGFR mutations (non-classical mutations in exons 18–21).When receiving tkis, those patients might consequently achieve a longer pfs than do those with true EGFR wild-type mutations, thus leading to a better pfs than is seen in patients receiving docetaxel. Furthermore, the detection method used for the EGFR mutation analysis (not reported in the study) might also have affected the study results, because the currently available methods have different sensitivities and specificities5.Third, the treatment-free interval after the prior line of chemotherapy is another important parameter to take into consideration. Indeed, Odabaset al.6 recently reported that the time elapsed after first-line treatment (≥3 months vs. u003c3 months) was an independent prognostic factor. In their article, Ma et al. did not provide information about treatment-free interval before start of second-line treatment, which might not lead to an accurate assessment of survival.For all the above reasons, we suggest that docetaxel is more effective than erlotinib for the second-line treatment of nsclc with wild-type EGFR status, and that the study finding is probably the result of the many limitations of the study. Also, we believe that neither docetaxel nor erlotinib are miracle solutions for the second-line treatment of previously treated patients with nsclc who have wild-type EGFR tumours. To improve outcomes for such patients, some recently approved approaches include chemotherapy and targeted-therapy combinations (docetaxel plus ramucirumab, docetaxel plus nintedanib) and immunotherapy (nivolumab).