Erlotinib improves progression-free survival in early mutated non-small cell lung cancer

October 21, 2018

Munich, Germany, 21 October 2018 - 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), shows a randomised study comparing erlotinib with gemcitabine plus cisplatin as neoadjuvant treatment, presented at the ESMO 2018 Congress in Munich. (1)

"Our results suggest promise for the use of biomarker-guided neoadjuvant EGFR-tyrosine kinase inhibitor (TKI) treat-ment strategies in stage IIIA-N2 non-small cell lung cancer,' said Dr Yi-Long Wu, Tenured Professor of Guangdong Lung Cancer Institute, Guangzhou, China who is the principal investigator of the CTONG 1103 study.

"This is the first study to demonstrate progression-free survival (PFS) superiority for erlotinib over gemcitabine plus cisplatin chemotherapy in the neoadjuvant/adjuvant setting of stage IIIA-N2 EGFR mutated NSCLC," added Wu.

Results showed that a total of 386 patients from 17 centres in China were screened, and 72 were randomised 1:1 to therapy and included in the intention-to-treat population. The objective response rate (ORR) for neoadjuvant erlotinib versus gemcitabine plus cisplatin chemotherapy was 54.1% (95% CI: 37.2% to 70.9%) versus 34.3% (95% CI: 17.7% to 50.8%) with an odds ratio of 2.26 (95% CI: 0.87-5.84; p=0.092). After neoadjuvant therapy, 83.8% of patients in the erlotinib group and 68·6% in the gemcitabine plus cisplatin group underwent surgery.

Median progression-free survival (PFS) was significantly longer with erlotinib at 21·5 months (95% CI: 19.3-23.6) versus gemcitabine plus cisplatin chemotherapy at 11.9 months (95% CI: 9.1-14.7) with a hazard ratio of 0.42 (95% CI: 0.23-0.76; p=00003). Overall survival is too immature to report, said Dr Wu.

Current treatment strategies for resected stage IIIA-N2 EGFR mutated NSCLC is controversial, explained Dr Wu, but he added that EGFR-TKIs have been shown to improve the prognosis of patients with advanced EGFR-mutant NSCLC.

"Cisplatin-based doublet chemotherapy as neoadjuvant treatment for stage IIIA-N2 NSCLC only gives patients 5% five-year overall survival benefit," said Dr Wu, explaining the unmet medical need in this patient population. "Recently, the CTONG 1104 trial (2) showed for the first time that adjuvant EGFR-TKI gefitinib could improve disease free surviv-al (DFS) by 10 months compared to adjuvant chemotherapy (28.7 months vs 18.0 months) in N1N2 resected NSCLC. This raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting for this subgroup."

Grade 3 and 4 toxicities were fewer in the erlotinib arm (0%) compared to the gemcitabine plus cisplatin arm (29.4%).

Commenting on the study for ESMO, Tony Mok, Professor of Clinical Oncology, the Chinese University of Hong Kong, said that this was a long-awaited study on patients with EGFR mutation positive stage IIIA NSCLC. "It has always been tempting to offer neo-adjuvant EGFR TKI to downstage the patient for surgery, but the action stops short in absence of supporting evidence."

"This randomised study is the first to demonstrate improvement 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," he pointed out. He added that, "While the difference between EGFR TKI and chemotherapy is significant, the impact of neoadjuvant EGFR TKI is relatively disappointing. Response rate of 54% is lower than what is expected of TKI in stage IV disease (about 70%), and only 13% of patients had attained major pathologic response. The reason for this is unclear, but one may have to query if duration of neoadjuvant EGFR TKI for 42 days is sufficient. Overall, this im-portant study offers us the rationale to consider neo-adjuvant EGFR TKI. "
Notes to Editors

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1 Abstract LBA48_PR '"CTONG 1103: Erlotinib versus Gemcitabine plus Cisplatin as Neo-adjuvant Treatment for Stage IIIA -N2 EGFR-mutation Non-small-cell lung cancer (EMERGING): a Randomised Study" will be presented by Wen-Zhao Zhong during the Proffered Paper Session on Sunday, 21 October, 09:45 to 10:45 (CEST) in Hall A1 - Room 17. Annals of Oncology, Volume 29 Supplement 8 October 2018

2 Zhong WZ, Wang Q, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148.

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W.-Z. Zhong1, Y.-L. Wu2, K.-N. Chen3, C. Chen4, C.-D. Gu5, Q. Wang6, J. Wang7, W. Mao8, G.-B. Qiao9, Y. Cheng10, L. Xu11, C.-L. Wang12, M.-W. Chen13, X.-N. Yang1, H.-J. Chen1, H.-H. Yang1, J.-J. Yang2, Q. Zhou2

1Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou/China, 2Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou/China, 3Thoracic Department, Beijing Cancer Hospital, Beijing/China, 4Thoracic Department, Fujian Medical University Union Hospital, Fuzhou/China, 5Thoracic Department, The 1st hospital affiliated Dalian Medical University, Dalian/China, 6Thoracic Department, Fudan University Affiliated Zhongshan Hospital, Shanghai/China, 7Thoracic Department, The People's Hospital of Peking University, Beijing/China, 8Zhejiang Cancer Hospital, Department of Thoracic Surgery, hangzhou/China, 9Guangdong Lung Cancer Institute, Thoracic Surgery department, Guangzhou/China, 10Department Of Thoracic Oncology, Jilin Provincial Cancer Hospital, Changchun/China, 11Thoracic Surgery Department, Jiangsu Cancer Hospital, Nanjing/China, 12Thoracic Surgery Department, Tianjin Cancer Hospital, Tianjin/China, 13Thoracic Surgery Department, The 1st hospital affiliated Xi'An Jiaotong University, Xi'an/China

Background: Cisplatin-based doublet chemotherapy as neoadjuvant treatment for IIIA-N2 non-small cell lung cancer (NSCLC) give patients 5% survival benefit. EGFR-TKIs have been proved to prolong PFS of advanced EGFR-mutant NSCLC. CTONG1104 trial shown adjuvant gefitinib could improve 10 months (disease free survival) DFS than chemotherapy in N1/N2 resected NSCLC. It raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting. We conducted this randomized trial to compare the efficacy of erlotinib (E) and gemcitabine plus cisplatin (GC) as neoadjuvant/adjuvant treatment.

Methods: Eligible patients with N2 disease were randomly assigned in 1:1 ratio to E group for 42 days as neoadjuvant therapy and then for 12 months after surgery or GC group for 2 cycles neoadjuvant chemotherapy and 2 cycles after complete resection. The primary endpoint is objective response rate (ORR). secondary endpoints included downstaging rates of pathological lymph nodes, pathological complete response (pCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability.

Results: A total of 386 patients from 17 centers were screened, 72 were randomized and included in the intention-to-treat population. The ORR for neoadjuvant E versus GC was 54.1% (95% CI, 37.2% to 70.9%) vs 34.3% (95% CI, 17.7% to 50.8%) (OR 2.26; 95% CI, 0·87-5.84; p=0·092). After neoadjuvant therapy, 31 patients (83·8%) in the E group and 24 (68·6%) in the GC group underwent surgery. Overall, lymph node downstaging occurred in 13% in the E and 4·2% in the GC group. The major pathological response (MPR) occurred in 3 of 28 patients (10.7%) in the E and no MPR (0/22) in the GC group. Median PFS was significantly longer with E (21·5 months; 95% CI, 19·3-23·6) versus GC (11·9 months; 95% CI, 9·1-14·7; HR 0·42; 95% CI, 0·23-0·76; p=0·003), whereas OS data was immature. The incidence of grade 3/4 toxicities was lower in the E group (0%) than that in the GC group (29·4%). No unexpected AEs were found.

Conclusions: Neoadjuvant/adjuvant erlotinib improved ORR, and significantly prolonged PFS compared with GC chemotherapy in patients with stage IIIA-N2 EGFR mutation NSCLC.

Clinical trial identification: NCT01407822

Legal entity responsible for the study: Chinese Thoracic Oncology Group

Funding: Foundation or academic group WITH funding from a pharma, biotech, or other commercial company - Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (No.2012A061400006); National Health and Family Planning Commission of People's Republic of China (No.201402031); Guangzhou Science and Technology Bureau (2014Y200050); Roche China

Disclosure: W. Zhong: Speaker fees from AstraZeneca and Roche.

Y. Wu: Received Speaker fees from AstraZeneca, Roche, Pfizer, Eli Lilly, Boehringer-Ingelheim and Sanofi;

All other authors have declared no conflicts of interest.

European Society for Medical Oncology

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