Genomic Signature for Personalized Adjuvant Therapy in Resected <i>EGFR</i>-Mutant Stage II-III Non-Small Cell Lung Cancer: Results from Phase 3 ADJVANT/CTONG1104 Study

Abstract

Background: The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival (DFS) of resected EGFR-mutated stage II-IIIA non-small cell lung cancer (NSCLC). However, inconsistent clinical benefits have necessitated precise genetic categorization to reevaluate the benefit and risk assessment. Methods: Total 171 baseline surgical specimens from the ADJUVANT trial (n=95, gefitinib arm; n=76, VP arm) underwent targeted sequencing of 422 cancer-related genes. Predictive biomarkers of DFS were identified by Cox proportional hazard regression with gene-by-treatment interactions. A multi-gene composite score, MINERVA (Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies), that incorporates the predictive value of selected biomarkers, was developed for survival stratification based on the ratio of 2-year DFS rate and the difference in median DFS. The model was internally validated using ten-fold and leave-one-out cross-validation methods. Findings: TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC were identified as significant predictors for DFS and integrated into MINERVA score. Although updated overall OS presented no difference between adjuvant TKI and chemotherapy, MINERVA categorized patients into three subgroups. In Highly TKI-Preferable group (n=60, 35%), gefitinib achieved significantly longer median DFS than chemotherapy (34.5 vs 9.1 months; hazard ratio (HR) 0.21; p<0.001), higher 2-year DFS rate (70.3% vs 11.0%, 6.4 times) and 5-year OS rate (67.3% vs 38.3%; HR 0.43; p=0.018). Conversely, in the Chemo-Preferable group (n=24, 14%), gefitinib led to shorter median DFS (19.3 vs 34.2 months; HR 3.06; p=0.041), lower 2-year DFS rate (41.6% vs 69.2%, -1.7 times) and 5-year OS rate (28.3% vs. 61.5%; HR 2.47; p=0.12). Finally, in the TKI-Preferable group (n=87, 51%), relative survival benefit was similar to that of the pre-categorized cohort. Interpretation: MINERVA score of integrated genomic signature has potential for personalized adjuvant therapy of resected stage II-IIIA EGFR-mutant NSCLCs. Funding Statement: The study was sponsored by the Chinese Thoracic Oncology Group (CTONG) and the following grants: Key Lab System Project of Guangdong Science and Technology Department -Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Prof. Yi-Long Wu), National Natural Science Foundation of China (Grant No.81872510, to Prof. Wen-Zhao Zhong), and Guangdong Provincial People's Hospital Intermural Program (Grant No. DFJH201917, to Dr. Si-Yang Liu). Declaration of Interests: LW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. W-ZZ declares speaker fees from AstraZeneca and Roche. Y-LW reports consulting and advisory services and declare speaker fees for Roche, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Sanofi, MSD and BMS. HB, YeC, XT, XW, and YS are employees of Geneseeq Technology Inc., Nanjing, China. All other authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the research ethics boards of the participating hospitals, and was conducted in accordance with the ethical principles of the Declaration of Helsinki. All the patients provided written informed consent for participating in this predefined biomarker study.