Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors As Adjuvant Therapy in Completely Resected Non–Small-Cell Lung Cancer

More than 10 years ago, the role of adjuvant chemotherapy in early stage non–small-cell lung cancer (NSCLC) was definitively established for stage II and III disease, whereas subset analyses suggested a benefit in patients with large IB tumors. Currently, any attempt to improve results of cisplatin-based chemotherapy by means of pharmacogenomics approaches has failed, and results of additional studies are eagerly awaited. In the article that accompanies this editorial, Kelly et al report the mature data of the RADIANT trial. It is noteworthy that only 51% of subjects in the erlotinib arm and 57% in the placebo arm received adjuvant chemotherapy. This situation was quite likely related to the relevant proportion of enrolled patients with stage IB disease for which the value of adjuvant chemotherapy is still debatable in the absence of prospective data for large IB tumors. No statistically significant difference was shown in disease-free survival (DFS), which was the primary endpoint of the study, whereas a trend suggestive of improved outcomes with erlotinib was demonstrated in the subgroup of patients (16.5%) with an epidermal growth factor receptor (EGFR) –sensitizing mutation. EGFR mutation status was not among the stratification factors. In addition, an imbalance was observed in some patients’ characteristics, such as performance status, in the comparison of the control arm in the EGFR mutant subgroup with the intention-to-treat population. Therefore, no definitive conclusion can be drawn. The choice of DFS as the primary endpoint deserves comment. Although the correlation between progression-free survival (PFS) and overall survival (OS) has been demonstrated for advanced NSCLC, in the recognition of PFS as an acceptable surrogate endpoint for OS, the same information is not available for the early-disease setting. For adjuvant studies, OS remains the preferred primary endpoint, and DFS may be considered only if a futility-based interim analysis is planned to drive continuation of the trial or not. The selection of patients was based on fluorescence in situ hybridization and EGFR immunohistochemistry, which are less sensitive tests for biomarkers than mutation testing. In the IPASS (Iressa Pan-Asia Study) trial, it was shown that the PFS benefit in patients with EGFR high copy number was entirely driven by the mutationpositive subgroup. In the era of personalized therapy, it is challenging to appropriately design a clinical trial that will preserve overtime the validity of the study hypothesis, especially in the adjuvant setting, where prolonged follow-up is needed. On another note, the recent revision of the lung cancer staging system with significant changes in stage allocation, and with further changes anticipated, represents an additional layer of complexity in the data interpretation. Given the existing evidence, one reasonable clinical question could be, “Should all patients with resected adenocarcinoma be tested for EGFR mutation?” The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology expert consensus opinion, endorsed by the American Society of Clinical Oncology, encourages EGFR and anaplastic lymphoma kinase testing at diagnosis for all patients with early-stage adenocarcinoma. The benefit of this approach is that it enables rapid initiation of treatment in patients who experience a recurrence because molecular information is immediately available. This also favors their enrollment onto clinical trials, and a definitive trial to evaluate erlotinib and crizotinib in molecularly selected patients is planned in the United States (ALCHEMIST trial; NCT02201992, NCT02193282). Other randomized trials are ongoing in China (ADJUVANT; CTONG 1104) and Japan (IMPACT; WJOG6401L) in patients with completely resected IIIA-II/N2-N1 NSCLC with EGFR mutation who are randomly assigned to receive gefitinib versus a combination of vinorelbine plus platinum as adjuvant treatment. The disadvantage is the extra cost incurred by molecular testing of patients with early-stage disease who do not experience a relapse, as well as the possibility that the molecular profile could change at the time of relapse. At the present time, the role of targeted agents as adjuvant therapies remains largely unknown. Patients with sensitizing mutations might derive more benefit from adjuvant chemotherapy, and chemotherapy may reduce the frequency of EGFR sensitizing mutations, suggesting a preferred response of EGFR mutated subclones to chemotherapy. In a Japanese phase III study, investigators administered adjuvant gefitinib or placebofor2yearstopatientswithcompletelyresectedNSCLCinstageIB to IIIA for 4 to 6 weeks after surgery until recurrence or withdrawal. Recruitment was stopped after 38 patients were randomly assigned; this was because of interstitial lung disease. In another phase III study, researchers compared gefitinib with placebo after cisplatin-based chemotherapy.Thisstudywasprematurelyclosedasconsequenceofthenegative JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 34 DECEMBER 1 2015