Elsevier

The Lancet Oncology

Volume 19, Issue 1, January 2018, Pages 139-148
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(17)30729-5Get rights and content

Summary

Background

Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II–IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB–IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II–IIIA (N1–N2) NSCLC.

Methods

We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18–75 years with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079.

Findings

Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8–44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months [95% CI 24·9–32·5]) than with vinorelbine plus cisplatin (18·0 months [13·6–22·3]; hazard ratio [HR] 0·60, 95% CI 0·42–0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related.

Interpretation

Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II–IIIA (N1–N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature.

Funding

Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.

Introduction

Roughly 20–25% of patients diagnosed with non-small-cell lung cancer (NSCLC) are suitable for surgical resection with curative intent.1 Findings of meta-analyses have shown that adjuvant chemotherapy after surgery improves the survival of patients with early-stage NSCLC.2 The recommended standard-of-care adjuvant treatment for stage IIA–IIIB resected NSCLC—irrespective of EGFR mutation status—is cisplatin-based chemotherapy (vinorelbine plus cisplatin),3, 4, 5, 6, 7, 8 which has shown significantly increased overall survival and disease-free survival compared with that for observation in patients with completely resected, early-stage (IB–IIIA) NSCLC.8 However, 5-year survival for patients with stage II–IIIA NSCLC is poor (14–30%) and a clear, unmet need remains.9

Research in context

Evidence before this study

We searched PubMed and ClinicalTrials.gov with the terms “resected NSCLC” and “EGFR”, to identify trials of adjuvant treatments for patients with early-stage non-small-cell lung cancer (NSCLC) and EGFR mutations. We restricted our search to reports published in English between Jan 1, 2002, and Dec 31, 2016. We retrieved reports for two randomised trials—one of gefitinib (BR19) and one of erlotinib (RADIANT)—in which an EGFR tyrosine kinase inhibitor was compared with placebo as adjuvant treatment for resected NSCLC. Results from these trials reported no benefit of EGFR tyrosine kinase inhibitors in the adjuvant setting, although most patients enrolled in both studies had EGFR wild-type tumours. However, results from retrospective analyses and the prospective phase 2 SELECT study suggest that patients with EGFR-mutant stage IB–IIIA resected NSCLC might benefit from adjuvant EGFR tyrosine kinase inhibitor treatment.

Added value of this study

To our knowledge, our study is the first head-to-head, prospective, phase 3 trial to show that adjuvant gefitinib leads to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with resected stage II–IIIA (N1–N2) NSCLC whose tumours harbour EGFR mutations. Safety, tolerability, and health-related quality of life also favoured gefitinib, and no cases of interstitial lung disease were reported.

Implications of all the available evidence

Adjuvant gefitinib could be considered as a treatment option for patients with stage II–IIIA (N1–N2) EGFR-mutant NSCLC. However, mature overall survival data are needed, and the optimum duration of treatment with tyrosine kinase inhibitors beyond 24 months is uncertain.

EGFR tyrosine kinase inhibitors are standard first-line treatment for EGFR-mutant advanced NSCLC, having shown superior progression-free survival compared with that for doublet chemotherapy in this setting.10, 11, 12, 13, 14 However, evidence is scant for EGFR tyrosine kinase inhibitors as adjuvant treatment for patients with EGFR-mutant early-stage NSCLC. Researchers on the Southwestern Oncology Group (SWOG) S0023 trial15 and BR19 study16 assessed adjuvant gefitinib in unselected patients with inoperable stage III NSCLC or completely resected stage IB–IIIA NSCLC, respectively. Most patients had received extensive systemic treatment in the neoadjuvant or adjuvant setting before administration of adjuvant gefitinib. In both studies, no improvement was reported in disease-free survival or overall survival, in patients who received gefitinib 250 mg once daily compared with placebo.15, 16 Data supporting the use of adjuvant EGFR tyrosine kinase inhibitors were reported in two retrospective analyses17, 18 and two prospective trials (RADIANT19 and SELECT20) which showed encouraging improvements in survival for patients with EGFR-mutant stage I–III NSCLC who received adjuvant EGFR tyrosine kinase inhibitors compared with those who did not. Collectively, these results suggest that patients with EGFR-mutant, stage IB–IIIA resected NSCLC might benefit from adjuvant EGFR tyrosine kinase inhibitor treatment.

Because of the limited benefit of adjuvant chemotherapy, the associated toxicity, and because EGFR mutation frequencies are known to be higher in Asian populations compared with white European populations,21, 22 we initiated a randomised phase 3 trial (ADJUVANT/CTONG1104) to study the efficacy of gefitinib compared with cisplatin-based chemotherapy in Chinese patients who have undergone complete resection for EGFR-mutant stage II–IIIA (N1–N2) NSCLC.

Section snippets

Study design and participants

We did a randomised, open-label, phase 3 trial at 27 centres in China (appendix pp 1, 2). We enrolled patients with completely resected (R0), pathological stage II–IIIA (N1–N2) NSCLC and EGFR-activating mutations (exon 19 deletion or exon 21 Leu858Arg). Patients had to have undergone either pulmonary lobectomy or pneumonectomy and systemic intrathoracic lymph node dissection with at least six stations of lymph nodes, including three stations of N2 (including subcarinal) lymph nodes and three

Results

Between Sept 19, 2011, and April 24, 2014, 483 patients were screened for study inclusion and 222 patients with EGFR-mutant NSCLC were randomly assigned, 111 to gefitinib and 111 to vinorelbine plus cisplatin (intention-to-treat population; figure 1). Of those assigned gefitinib, 66 (59%) underwent disease staging with CT, 27 (24%) with PET–CT, and 18 (16%) with MRI or another type of scan. Of patients assigned vinorelbine plus cisplatin, 64 (58%) were staged with CT, 24 (22%) with PET–CT, and

Discussion

The findings of the phase 3 ADJUVANT study show that treatment with gefitinib was associated with significantly longer disease-free survival than was vinorelbine plus cisplatin in patients with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant NSCLC. To our knowledge, ADJUVANT is the first head-to-head phase 3 study to show a significant improvement in disease-free survival with an EGFR tyrosine kinase inhibitor compared with standard-of-care adjuvant doublet chemotherapy in this

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