Neoadjuvant erlotinib delays disease progression in stage IIIA-N2 EGFR-mutated non-small cell lung cancer

Results of the CTONG 1103 study demonstrate that neoadjuvant erlotinib benefits selected epidermal growth factor receptor (EGFR)-mutated patients who undergo complete resection of stage IIIA-N2 stage non-small cell lung cancer (NSCLC). In this study, neoadjuvant erlotinib prolonged the progression-free survival (PFS) with almost 10 months compared to neoadjuvant chemotherapy with gemcitabine and cisplatin (GC). In addition to this significant delay in the disease progression, neoadjuvant erlotinib was also associated with a higher response rate compared to chemotherapy (54.1% vs. 34.3%). On a critical note, the erlotinib response rate of 54% is lower than what could be expected from the experience in stage IV disease, where EGFR tyrosine kinase inhibitors (TKIs) were found to induce a response in about 70% of patients.

The current treatment of patients with stage IIIA-N2 NSCLC is multimodal and may include definitive chemoradiotherapy, surgery followed by adjuvant chemotherapy, or neoadjuvant therapy followed by surgical resection. The CTONG1104 trial previously demonstrated that adjuvant gefitinib was associated with an improved disease-free survival (DFS) compared to chemotherapy in N1/N2 resected NSCLC. This formed the basis to evaluate whether EGFR-TKIs may also be beneficial in the neoadjuvant setting.

CTONG 1103 is an open-label, randomized trial in which NSCLC patients with N2 disease were randomly assigned in a 1:1 ratio to 42 days of neoadjuvant erlotinib followed by surgery and an additional 12 months of adjuvant erlotinib, or 2 cycles of neoadjuvant GC chemotherapy followed by 2 GC cycles after complete resection. The primary endpoint of the trial was objective response rate (ORR), with PFS, downstaging rates of pathological lymph nodes, pathological complete response (pCR), overall survival (OS) and safety as secondary objectives.

A total of 386 patients from 17 centres in China were screened, and 72 were randomised to therapy and included in the intention-to-treat population. The ORR with neoadjuvant erlotinib and with GC chemotherapy was 54.1% and 34.3%, respectively (OR[95%CI]: 226[0.87-5.84]; p=0.092). After neoadjuvant therapy, 83.8% of patients in the erlotinib group and 68.6% in the GC group underwent surgery. Lymph node downstaging was reported in 10.8% of patients in the erlotinib group and in 2.9% of patients treated with neoadjuvant GC. The 21.5 months median PFS with erlotinib was significantly longer than the 11.9 months median PFS seen in the GC arm, with a hazard ratio of 0.42 (95%CI: 0.23-0.76; p=0.0003). The OS data were not yet mature at the time of the analysis. The adverse event profiles of the two treatment regimens in this study were as could be expected from earlier reports. Importantly, grade 3 and 4 toxicities were less frequent in the erlotinib arm (0%) compared to the gemcitabine plus cisplatin arm (29.4%).

In summary, this randomised study is the first to demonstrate improvements in multiple parameters including tumour response rate, resection rate, major pathologic response and PFS with the use of neoadjuvant EGFR TKI followed by adjuvant TKI. While the difference between EGFR TKI and chemotherapy is significant, the impact of neoadjuvant EGFR TKI is however relatively disappointing. In fact, the response rate of 54% is lower than what could be expected from the TKI experience in stage IV disease and only 13% of patients obtained a major pathologic response. The reason for this is unclear, but one possibility could be that the duration of neoadjuvant erlotinib of 42 days is not sufficient. However, it is safe to conclude that this study provides a rationale to further evaluate neoadjuvant EGFR TKI therapy in this setting.

Reference

Zhong W-Z, Wu Y-L, Chen K-N, et al. CTONG 1103: erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment for stage IIIA-N2 EGFR-mutation non-small cell lung cancer (emerging): a randomised study. Presented at ESMO 2018; Abstract LBA48_PR.