Adjuvant Epidermal Growth Factor Receptor Inhibitors in Non‐Small Cell Lung Cancer

Nonrandomized studies have suggested a potential benefit with use of an EGFR tyrosine kinase inhibitor in the adjuvant setting in patients with EGFR-mutated non-small cell lung cancer. These nonrandomized studies cannot substitute for well-conducted, adequately powered, prospectively randomized phase III trials. Such trials are under way, and their results are eagerly anticipated.The optimal initial treatment for patients with stage I–II non-small cell lung cancer (NSCLC) is surgical resection [1]. In the appropriate setting, patients with stage IIIA NSCLC may also be offered surgical resection following neoadjuvant chemotherapy with or without radiotherapy [2]. Adjuvant chemotherapy with a cisplatin-based regimen can be recommended for selected patients with stage IB disease with high-risk features as well as for patients with stages II–IIIA [3, 4]. Adjuvant chemotherapy improves the 5-year survival rate by approximately 4% [5]. Cisplatin may be combined with vinorelbine, vinblastine, etoposide, gemcitabine, pemetrexed, or docetaxel [6–8]. The LACE collaborative group’s analysis concluded that multiple different chemotherapy regimens with cisplatin are equally effective. Unfortunately, despite the advances in the management of stage I–III NSCLC, the 5-year survival of these patients still remains inferior compared with other early stage solid malignancies.In the past decade, targeted therapy has transformed treatment for a subset of patients with advanced NSCLC harboring mutations or translocations that mediate sensitivity to targeted treatments. The best described of these are EGFR mutations and ALK or ROS1 translocations. EGFR inhibitors such as erlotinib, gefitinib, and afatinib target the tyrosine kinase domain of the EGFR receptor. Sensitizing EGFR mutations that predict response to these tyrosine kinase inhibitors (TKIs) include in-frame deletions in exon 19 and L858R substitution in exon 21 [9–11]. EGFR inhibitors have been shown to improve progression-free survival and response rates in patients with advanced stage NSCLC with sensitizing EGFR mutations in the first-line setting compared with platinum-based chemotherapy (hazard ratio [HR] 0.48 at 12 months) [12].In general, we use our most active drugs in the adjuvant setting. Because EGFR and ALK inhibitors are more active than chemotherapy in patients with targetable mutations, it would be rational to test EGFR TKIs or ALK inhibitors in patients with resected tumors that harbor EGFR-activating mutations or ALK gene rearrangements, respectively. The possibility of targeted agents improving cure rates in the adjuvant setting is not without precedent. The use of trastuzumab in combination with chemotherapy in the adjuvant setting for early stage HER2 receptor-positive breast cancer with moderate to high risk of recurrence has improved both disease-free survival (DFS) and overall survival (OS; HR 0.63 for OS and 0.60 for DFS) [13]. Similarly, the use of imatinib in patients with completely resected gastrointestinal stromal tumors (GIST) significantly improved recurrence-free survival at 1 year compared with observation alone (HR 0.35) [14].