MS04.01 EGFR TKIs for Resected EGFRmut NSCLC

Abstract

Adjuvant chemotherapy became the standard treatment for resected stage 2-3 non-small cell lung cancer (NSCLC). It increased overall survival (OS) by 5% at 5 years, and resected NSCLC was considered "curable disease." Stage II to IIIA resected NSCLC is heterogeneous. The 5-year survival was only 40% -50%. There is a huge medical need to improve the long-term survival for these patients whose cancers are destined to recur after surgery. BR.19, the first trial to evaluate an EGFR TKI (gefinitib) in the adjuvant setting, and the subsequent RADIANT trial, which compared erlotinib to placebo, were not designed specifically for patients with EGFR mutations. Thus, these two adjuvant TKIs failed to show meaningful benefits.1,2 The ADJUVANT trial, first randomized phase 3 trial compared gefitinib with doublet chemotherapy for stage 2 and 3 (N1N2) resected EGFR mutant NSCLC. The results showed that adjuvant gefitinib significant improved disease-free survival (DFS). HR for recurrence was 0.60 with 28.7 months in gefitinib vs 18.0 months in chemotherapy3. Subsequently the EVAN -- another Chinese phase 2 trial confirmed that adjuvant erlotinib was superior to chemotherapy in DFS4. SELLECT trial from American once again confirmed that adjuvant EGFR TKI improved DFS5. The both Chinese adjuvant trials targeted the patients with the highest risk of recurrence and are more likely to respond to EGFR TKIs in patients harboring an EGFR mutation. Unlike BR.31 and RADIAN EGFR TKIs were used following adjuvant chemotherapy. the ADJUVANT trial was a direct comparison of adjuvant TKIs with Vinorelbine plus cisplatin instead of comparing TKIs with placebo after chemotherapy, as evaluated in the BR.19 and RADIANT trials. Compliance with adjuvant TKIs (95.5%) was better than that with chemotherapy (78.4%) in ADJUVANT trial. This means that patients receiving adjuvant TKIs were more likely to complete treatment than patients receiving standard chemotherapy. The design of ADJUVANT is different from RADIANT, and the hypothesis of the two trials designs is different. The ADJUVANT study was created to test whether an EGFR TKI might be a viable treatment alternative to chemotherapy in the adjuvant setting, specifically in EGFR mutant (+) NSCLC. In this situation, using DFS as the primary endpoint was rational. The U.S. Food and Drug Administration has stated that a prolonged delay in the development of metastatic disease is an objective and a clinically relevant outcome and that agents can be approved based on metastasis-free survival (MFS) if substantial effects on this endpoint are demonstrated and the safety profile is acceptable.6 In addition, after adjuvant gefitinib or erlotinib, patients with disease recurrence still have the opportunity to be re-challenged with TKIs. And the median duration of treatment approximates the DFS in a de novo advanced EGFR-mutant population.7 Recently Zhong et al reported a phase 2 trial on neo-adjuvant setting for EGFR mutant stage 3A resectable NSCLC. Of 386 patients screened, 72 were randomized to treatment. The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54·1% versus 34·3% (p=0·092). pCR was 10·7% vs 0. Median DFS was significantly longer with erlotinib (21·5 months) versus GC chemotherapy (11·9 months; HR 0·42; 95% CI, 0·23–0·76; p=0·003)8. The results of neo-adjuvant EGFR TKI treatment in CTONG 1103 was similar to adjuvant EGFR TKI in CTONG 1104. The difference of DFS comparing with chemotherapy in both trials are 10 months. Definitely EGFR TKIs could be safely and effectively used in early resected NSCLC. The treatment paradigm for early resectable NSCLC is evolving. Similar to advanced NSCLC early stage NSCLC should be divided to driver mutation or wild type NSCLC. For wild NSCLC check point blockade should be tested in peri-operation. For driver mutation NSCLC TKIs including EGFRi or ALKi even other rare mutation should be tested. Some issues should be evaluated. One issue is how to select populations more precisely for adjuvant or neo-adjuvant treatment. Whether circulating tumor DNA (ctDNA) could serve as biomarker of minimal residual disease (MRD) and how to monitor it9? Second issue is what is the primary endpoint for neo-adjuvant or adjuvant treatment in NSCLC? Apparent OS is rational but the trial will last a long time even beyond 10 years. The third issue is how to choose neo-adjuvant or adjuvant treatment for recectable NSCLC either clinical trial or clinical practice. For personalized adjuvant treatment in the future, we need to identify patients precisely and match the appropriate treatment with appropriate patient. 1. Goss GD, O'Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326. 2. Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2015;33(34):4007-4014. 3. Zhong W-Z, Wang Q, Mao W-M, 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;19(1):139-148 4. Yue D, Xu SD, Wang Q, et al. Erlotinib verse vinorebine plus cisplatin as adjuvant therapy in Chinese patitents with stage 3A EGFR mutantion-positive non-small-cell lung cancer (EVAN): a randomised, open-lable. phase 2 trial. Lancet Res Med 2018; 6(11):863-873 5. Pennell NA, Neal JW, Chaft JE, et al. SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. J Clin Oncol. 2019;37(2):97-104. 6. Mauguen A, Pignon JP, Burdett S, et al. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data. Lancet Oncol. 2013;14(7):619-626. 7. Oxnard GR, Janjigian YY, Arcila ME, et al. Maintained sensitivity to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer recurring after adjuvant erlotinib or gefitinib. Clin Cancer Res. 2011;17(19):6322-6328 8. Zhong WZ, Chen KN, Chen C, et al. Erlotinib verse gemcitabine plus cisplatin as neoadjuvant treatment for stage IIIA-N2 EGFR-mutant NSCLC (EMERGING-CTONG 1103): a randomized phase II study, J Clin Oncol 2019 in press. 9. Ng TL, Camidge DR. Lung cancer's real adjuvant EGFR targeted therapy questions. Lancet Oncol. 2018;19(1):15-17.