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.

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. 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. 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. 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. 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.

Zhong WZ ，Wang Q ，Mao WM ，Xu ST ，Wu L ，Shen Y ，Liu YY ，Chen C ，Cheng Y ，Xu L ，Wang J ，Fei K ，Li XF ，Li J ，Huang C ，Liu ZD ，Xu S ，Chen KN ，Xu SD ，Liu LX ，Yu P ，Wang BH ，Ma HT ，Yan HH ，Yang XN ，Zhou Q ，Wu YL ，ADJUVANT investigators ... -  《-》

Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial.

Zhong WZ ，Wang Q ，Mao WM ，Xu ST ，Wu L ，Wei YC ，Liu YY ，Chen C ，Cheng Y ，Yin R ，Yang F ，Ren SX ，Li XF ，Li J ，Huang C ，Liu ZD ，Xu S ，Chen KN ，Xu SD ，Liu LX ，Yu P ，Wang BH ，Ma HT ，Yang JJ ，Yan HH ，Yang XN ，Liu SY ，Zhou Q ，Wu YL ... -  《-》

Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial.

Adjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC. In this randomised, open-label, phase 2 trial, eligible patients aged 18-75 years who had undergone complete (R0) resection of histologically or pathologically confirmed stage IIIA EGFR mutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m2 intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m2 intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov, number NCT01683175. Between Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33·0 months (IQR 17·8-43·1). 2-year disease-free survival was 81·4% (95% CI 69·6-93·1) in the erlotinib group and 44·6% (26·9-62·4) in the chemotherapy group (relative risk 1·823 [95% CI 1·194-2·784; p=0·0054). The difference in 2-year disease-free survival between the groups was 36·7% (95% CI 15·5-58·0; p=0·0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two [4%] of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported. Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy in EGFR mutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC. National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd.

Yue D ，Xu S ，Wang Q ，Li X ，Shen Y ，Zhao H ，Chen C ，Mao W ，Liu W ，Liu J ，Zhang L ，Ma H ，Li Q ，Yang Y ，Liu Y ，Chen H ，Wang C ... -  《-》

Randomized Phase III Study of Gefitinib Versus Cisplatin Plus Vinorelbine for Patients With Resected Stage II-IIIA Non-Small-Cell Lung Cancer With EGFR Mutation (IMPACT).

Tada H ，Mitsudomi T ，Misumi T ，Sugio K ，Tsuboi M ，Okamoto I ，Iwamoto Y ，Sakakura N ，Sugawara S ，Atagi S ，Takahashi T ，Hayashi H ，Okada M ，Inokawa H ，Yoshioka H ，Takahashi K ，Higashiyama M ，Yoshino I ，Nakagawa K ，West Japan Oncology Group ... -  《-》

Quality of life with adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant non-small-cell lung cancer: Results from the ADJUVANT (CTONG1104) study.

Health-related quality of life (HRQoL) data complement conventional clinical endpoints when comparing adjuvant gefitinib with chemotherapy in patients with early-stage non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) mutations. This study aimed to assess changes in HRQoL with adjuvant gefitinib vs chemotherapy in this patient group. In the phase III ADJUVANT trial, patients with completely resected, stage II-IIIA (N1-N2), EGFR-mutant NSCLC were randomized (1:1) to receive either gefitinib for 24 months or vinorelbine plus cisplatin (VP) every 3 weeks for four cycles. HRQoL was assessed as a secondary endpoint using the Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L), Lung Cancer Symptom Scale (LCSS) questionnaires, and Trial Outcome Index (TOI) composite score. HRQoL dynamics, improvements, and time to deterioration were compared between groups. At baseline, 104 of 106, and 80 of 87 patients receiving gefitinib and VP, respectively, completed two questionnaires (FACT-L and LCSS). Baseline scores were balanced between groups. Although HRQoL fluctuated and gradually improved in both groups, longitudinally higher scores were reported with gefitinib than VP (FACT-L, odds ratio 418.16, 95 % confidence interval [CI] 2.75-63509.05, p =  0.019; LCSS, 1.13, 1.04-1.22, p =  0.003; TOI, 88.39, 4.40-1775.05, p =  0.003). Time to deterioration in HRQoL was delayed with gefitinib compared with VP (FACT-L, median 69 vs 6 weeks, hazard ratio 0.62, 95 % CI 0.42-0.90, p =  0.013; LCSS, median 45 vs 6 weeks, 0.63, 0.43-0.93, p =  0.020; TOI, median 164 vs 9 weeks, 0.51, 0.33-0.77, p =  0.001). Adjuvant gefitinib is associated with improved HRQoL over VP, supporting its use in patients with stage II-IIIA (N1-N2), EGFR-mutant NSCLC.

Zeng J ，Mao WM ，Chen QX ，Luo TB ，Wu YL ，Zhou Q ，Yang XN ，Yan HH ，Zhong WZ ，Wang Q ，Xu ST ，Wu L ，Shen Y ，Liu YY ，Chen C ，Cheng Y ，Xu L ，Wang J ，Fei K ，Li XF ，Li J ，Huang C ，Liu ZD ，Xu S ，Chen KN ，Xu SD ，Liu LX ，Yu P ，Wang BH ，Ma HT ... -  《-》