Discussion
NSCLC, EGFR-mutant, toxicity, heterogeneous disease
DISEASE PROGRESSION, DISEASE, NSCLC
IIIA-N2 NSCLC with potentially resectable disease (IIIA3 with N2 confirmed by EBUS/Mediastinoscopy or PET/CT) represents a highly heterogeneous disease in treatment modalities and prognosis. The EMERGING-CTONG 1103 study is the first randomised phase II trial to evaluate the feasibility and safety of neoadjuvant and adjuvant targeted therapy with erlotinib compared with standard chemotherapy. The results of PFS have previously been published in the The CHEST study showed that preoperative Cisplatin and Gemcitabine followed by radical surgery had significantly prolonged PFS and OS compared with surgery alone in patients with clinical stage IIB/IIIA NSCLC.The CTONG 1104 study was the first to introduce targeted therapy into the post-operative setting and showed remarkable improvements in disease-free survival (DFS) compared with conventional chemotherapy.In addition, these updated results continued to demonstrate superior median PFS with erlotinib compared with chemotherapy, with approximately 10 months of PFS benefit. However, this PFS benefit did not translate into a significant difference in OS between the erlotinib and GC groups. This finding may result from the complex multifactorial therapeutic approaches and the introduction of other highly potent EGFR-TKIs during later lines of treatment. Related to this is the fact that more patients in the GC group received EGFR-TKIs than those in the erlotinib group (69.7% vs. 46.9%) when disease progression occurred; such therapeutic crossover during subsequent treatment may have confounded the OS results. Unsurprisingly, patients without subsequent treatment had the worst prognosis in both groups.We also explored whether patients who received upfront EGFR-TKIs may retain sensitivity to subsequent EGFR-TKIs and achieve a survival benefit. Among patients receiving subsequent EGFR-TKIs after disease progression, ORRs were 53.3% (erlotinib) and 47.8% (GC), and respective disease control rates were 93.3% (erlotinib) and 73.9% (GC). However, only 25% of patients in the erlotinib group responded to subsequent osimertinib treatment, while the ORR was 45.5% for patients who did not receive subsequent osimertinib. Due to the small number of patients receiving osimertinib (Recent advances in EGFR-TKI therapy development have resulted in highly potent EGFR-TKIs with increased intracranial penetration that might be additional therapeutic options for this patient population after disease progression. The ADAURA study,One of the main limitations of this study was that not all enroled patients had pathologically confirmed N2 disease, which may have led to an underestimation of the disease stage, thereby influencing the robustness of the survival analysis. Another limitation is that we did not obtain biopsy samples of all the recurrent lesions and could not further investigate if upfront targeted therapy may biologically impact subsequent treatment. Then, RCT studies with a larger sample size are needed to further explore the benefit of neoadjuvant EGFR-TKI on stage IIIA-N2 EGFR-mutant patients with NSCLC in the future.In conclusion, the updated analysis of CTONG1103 indicated that erlotinib continued to improve PFS and OS numerically compared with platinum-based chemotherapy. Moreover, there was no evidence of cumulative toxicity in erlotinib during the long-term follow-up. The present results support the use of erlotinib in both the neoadjuvant and adjuvant settings for resectable stage IIIA-N2 