Circulating tumor DNA (ctDNA) dynamics and survival outcomes in patients (pts) with advanced non-small cell lung cancer (aNSCLC) and high (>50%) programmed cell death-ligand 1 (PD-L1) expression, randomized to cemiplimab (cemi) vs chemotherapy (chemo)

9022 Background: While ctDNA has emerged as a promising tool for monitoring response on therapy, there is a paucity of data from prospective, randomised Phase 3 studies to establish clear criteria for the clinical application of ctDNA. In the EMPOWER-Lung 1 study, first line (1L) cemi monotherapy improved overall survival (OS) vs platinum chemo in pts with aNSCLC, PD-L1 ≥50%, and no EGFR, ALK, or ROS1 aberrations and an acceptable risk/benefit profile. We performed personalized tumor-specific analysis of ctDNA from pts treated in the EMPOWER-Lung 1 study to determine the optimal time point and magnitude of ctDNA variation that are associated with OS and progression-free survival (PFS). Methods: Tumor tissue next-generation sequencing was performed to identify tumor-specific DNA variants. ctDNA levels were monitored using personalized pt specific probe sets (Natera, Foundation Medicine) in the plasma at baseline, end of week 3 (W3) and W9. Endpoints included overall response rate (ORR) complete or partial response (CR/PR), stable disease (SD) and progressive disease (PD) per RECIST 1.1, OS and PFS. Association between ctDNA decrease and clinical endpoints was tested in 3 groups of pts defined by sensitivity analysis: no-decrease, any decrease (molecular response, MR), and complete clearance (complete MR, cMR) of ctDNA. Results: ctDNA analysis was performed on samples from 175 pts (chemo n = 89; cemi n = 86). Baseline characteristics, ORR, OS, and PFS were comparable to those of the intention to treat population. At W9, cMR/MR was associated with clinical response to cemi (CR/PR: 97%, SD:58%, PD:17%), but not with clinical response to chemo, as it was detected in the majority of chemo pts across all RECIST categories (CR/PR: 100%, SD:90%, PD:80%). In the cemi arm, ctDNA cMR was associated with the longest survival, with median OS (mOS) not-reached compared to pts with MR (mOS of 29 months) and pts with no-decrease (mOS of 8 months), as well as statistically significant hazard ratios (cMR vs MR: W9 HR = 8, 95% CI 1.8-35, p = 0.0056; cMR vs no-decrease: W9 HR = 25, 5.7–110, p = 0.000021 and W3 HR = 5.9, 1.4-25, p = 0.017). Delayed MR/cMR (i.e., MR/cMR at W9 but not at W3) was observed in 8/66 pts (12%), and transient MR (i.e., MR at W3 but not W9) in 9/66 pts (14%), with available ctDNA data at both timepoints. Conclusions: This is the largest data set to date correlating ctDNA levels with efficacy outcomes from a randomized clinical trial comparing chemo with immunotherapy in 1L aNSCLC. The results indicate that lack of treatment-induced decrease in ctDNA may identify pts with inferior OS benefit from cemi monotherapy as early as 3 weeks following initiation of therapy and can inform future use of early ctDNA response assessment in prospective interventional studies. Clinical trial information: NCT03088540 .