CTONG1104: Adjuvant gefitinib versus chemotherapy for resected N1-N2 NSCLC with EGFR mutation—Final overall survival analysis of the randomized phase III trial 1 analysis of the randomized phase III trial.

Abstract

9005 Background: ADJUVANT-CTONG1104, a randomized phase 3 trial showed adjuvant gefitinib treatment significantly improved disease-free survival (DFS) vs standard doublet chemotherapy in patients (pts) with epidermal growth factor receptor ( EGFR) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). 5-year survival rate of N1N2 were 38%-50% in IASLC staging system. Here, we present the final overall survival (OS) results from the study. Methods: From Sep 2011 to April 2014, 222 patients, aged 18-75 years, with EGFR activating mutation through completely resection and diagnosed as stage II-IIIA (N1-N2) NSCLC pathologically from 27 sites were enrolled. The enrolled patients were 1:1 randomized to receive adjuvant gefitinib (250 mg once per day) for 24 months (G, n=111) or vinorelbine (25 mg/m2, d1 and d8) plus cisplatin (75 mg/m2, d1) every 3 weeks for 4 cycles (C, n=111). The primary endpoint was DFS in the ITT population. Secondary endpoints included OS, 3 and 5-year DFS rate, 5-year OS rate. The subsequent therapy data were collected, including crossover from C to G, re-challenge TKI and other treatment. Data cut-off date was Jan. 13, 2020. Results: A median follow-up was 76.9 months. The median OS (mOS) was 75.5 months based on 95 (42.8%) events in ITT whole population. The mOS was 75.5m in G arm and 79.2m in C arm (HR 0.96, 95%CI 0.64-1.43, p=0.823). The 3, 5-year OS rate were 68.6%, 53.8% in G and 67.5%, 52.4% in C respectively. DFS in 3, 5-y were 40.3%, 23.4% in G and 33.2%, 23.7% in C, respectively (P3-y=0.395, P5-y=891). All predefined subgroups including age, gender, lymph node, EGFR mutation type had no significant difference in statistics but in favor of G arm in trend. Subsequent treatment especially targeted therapy contributed most to OS (HR = 0.46, 95% CI 0.26 – 0.83). Median OS of patients receiving subsequent target therapy was75.5m (n=35), 36.4m in other treatment (n=33; (P<0.001). For G mOS were 75.5 (n=15; target therapy) and 35.0 (n=18; other, p<0.001), for C 62.8m (n=20) and 46.8m (n=15; p=0.251). The RR was 26.7%, DCR 66.7%, mPFS 14.1m and mOS 19.6m for patients with rechallenged EGFR TKI in G arm (n=15). No novel unexpected SAE was observed during follow up. Conclusion The DFS survival advantage did not translate to OS difference in ADJUVANT trial. The OS with 75.5m was the best one of survival in completely resected N1N2 NSCLC comparing with historical data and sequent TKI treatment contribute to overall survival. Clinical trial information: NCT01405079.

Targeted Therapies in Early Stage NSCLC: Hype or Hope?

“…The CTONG1104/ADJUVANT trial is a phase 3 study that compared the standard cisplatin-vinorelbine chemotherapy to gefitinib, a first-generation EGFR TKI in fully resected stage II to IIIA EGFR mutant NSCLC [ 12 ]. Chemotherapy was administered for four cycles, while gefitinib was given until progression for up to two years.…”

“…While the HR of DFS is certainly impressive, there is much controversy about whether these immature data should lead to a change in practice, as the real question is whether patients will live longer if treated earlier. Furthermore, at the ASCO 2020, the final analysis of the CTONG1104/ADJUVANT trial was presented, showing that treating EGFR positive patients with EGFR TKI delayed the relapse but did not translate into OS benefit [ 12 ]. Moreover, the ADAURA trial doesn’t address the question about the importance and need for adjuvant chemotherapy in these patients, as the majority of them received it before being randomized in the trial.…”

“…The question of whether targeted therapy could fill this unmet medical need is far from new. Over the last several years, different targeted therapies have been evaluated in early stage NSCLC with no survival benefit in unselected patients [ 9 , 10 , 11 , 12 ]. However, the identification of reliable predictive biomarkers to these agents in the metastatic setting, the design of molecularly-oriented studies, and the availability of novel potent and less toxic agents paved the way for a novel era in early stage NSCLC treatment ( Figure 1 ).…”

Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC)

“…Updated OS analysis with a median follow-up of 76.9 months showed no difference between groups: 75.5 months for gefitinib and 79.2 months for chemotherapy, HR 0.96, p = 0.823. The 3 and 5 year OS rates were 68.6% and 53.8% for gefitinib and 67.5% and 52.4% for vinerolbine plus cisplatin, respectively [ 47 ]. The EVAN phase II study compared adjuvant erlotinib with cisplatin and vinerolbine in 102 patients with resected stage IIIA EGFR-positive NSCLC.…”

ADAURA: Mature Enough for Publication, Not for Prime Time

“…Currently, the only mature OS data we have with tyrosine kinase inhibitors (TKI) for the EGFR-mutated NSCLC come from the above-mentioned CTONG1104 phase III trial which showed a nonsignificant HR for death of 0.92 (95% CI 0.62-1.36; p=0.674) for gefitinib versus cisplatin-vinorelbine, corresponding to a 2.1% non-significant survival improvement in favour of chemotherapy 4 .…”