Predictive and prognostic values of circulating tumor DNA (ctDNA) clearance in osimertinib treated advanced non-small cell lung cancer cohort.

person Yong Song Nanjing General Hospital of Nanjing Military Command (NGH)- Jinling Hospital, Nanjing, China info_outline Yong Song, Shenglin Ma, Meiqi Shi, Xingxiang Xu, Xueqin Chen, Yong Wang, Zhenhua Yang, Tengfei Zhang, Min Li, Haiyan Li, Lu Zhang, Xinru Mao

Authors person Yong Song Nanjing General Hospital of Nanjing Military Command (NGH)- Jinling Hospital, Nanjing, China info_outline Yong Song, Shenglin Ma, Meiqi Shi, Xingxiang Xu, Xueqin Chen, Yong Wang, Zhenhua Yang, Tengfei Zhang, Min Li, Haiyan Li, Lu Zhang, Xinru Mao Organizations Nanjing General Hospital of Nanjing Military Command (NGH)- Jinling Hospital, Nanjing, China, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China, Department of Oncology, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China, North Jiangsu General Hospital, Yangzhou, China, Department of Medical Oncology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China, Anhui Provincial Hospital, Anhui, China, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China, Burning Rock Biotech, Guangzhou, China Abstract Disclosures Research Funding Other Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. CtDNA, validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC pts. Methods: This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC pts who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 pts, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes. Results: Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 pts, p = 0.004) and P53 pathways (43 pts, p = 0.032) were associated with shorter OS ( p53 was excluded from analysis due to high mutation frequency). Interestingly, pts with undetectable ctDNA at first follow-up (within 50 d, n = 41) were correlated with longer PFS (p = 0.009) and OS (p = 0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 pts experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Pts with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p = 0.035) and p53 (p = 0.023) mutations at radiological PD. In addition, pts with CNA at radiological PD had shorter PFS (p = 0.002) and OS (p = 0.052). Conclusions: This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for pts undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.