LAUSR

Background: The role of circulating tumor DNA (ctDNA) in monitoring response to immunotherapy in NSCLC is unconfirmed. This is a retrospective analysis of association between longitudinal ctDNA levels and clinical outcomes in 1L TIS (anti-PD-1) + chemo-treated patients (pts) with nonsquamous or squamous NSCLC from RATIONALE-304 (NCT03663205) and 307 (NCT03594747), respectively. Methods: Blood samples were collected at baseline (BL), first response (FR, complete or partial response assessed by investigators), and progressive disease (PD). ctDNA level was tested by OncoScreen Plus520 (Burning Rock) and the variant allele fraction categorized as undetectable (UD)/detectable (D). Paired ctDNA analysis of BL and post-BL (FR or PD) values was by Wilcoxon sign-rank test. Median PFS and OS was calculated by Kaplan-Meier methodology. PD-L1 expression stratified Cox model was used to evaluate the effect of ctDNA on PFS and OS for BL and FR (adjusted with BL ctDNA) in each study. Impact of other BL characteristics was also assessed. Results: Of 217 pts treated with TIS + chemo in RATIONALE-304, 76 (35%) at BL, 40 (18%) at FR, and 30 (14%) at PD had ctDNA results. Of 238 pts treated with TIS + chemo in RATIONALE-307, 80 (34%) at BL, 65 (27%) at FR, and 33 (14%) at PD had ctDNA results. Paired ctDNA analysis showed significantly decreased ctDNA levels from BL to FR (P<0.0001 in 304 and 307); no obvious change was detected from BL to PD in both studies. Pts with UD ctDNA status at FR had notably longer median PFS and OS compared with pts with D ctDNA; no such association was observed using BL ctDNA status in either study (Table). Conclusions: FR ctDNA level is decreased from BL, and seems to correlate with clinical outcomes of 1L TIS in combination with chemotherapy in NSCLC; ctDNA has potential to be a surrogate biomarker for efficacy. This requires further prospective validation. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Simon Lancaster, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Table. Analysis summary of ctDNA and PFS/OS by visit Baseline (BL) First response (FR) Study RATIONALE-304 RATIONALE-307 RATIONALE-304 RATIONALE-307 ctDNA UD D UD D UD D UD D n 19 57 8 72 32 8 43 22 mPFS, mo (95% CI)a 9.23(5.75, 9.89) 9.69(7.33, 14.52) NR(4.93, NR) 9.76(7.52, 14.55) 17.31(9.89, NR) 9.20(3.71, 11.99) 20.01(9.82, NR) 9.56(7.39, 13.9) PFS HR (95% CI), UD/D 1.14 (0.61, 2.21) 0.40 (0.09, 1.73) 0.16 (0.05, 0.5) 0.54 (0.24, 1.21) PFS P-valueb 0.6421 0.2205 0.0019 0.1322 mOS, mo (95% CI) NR(9.72, NR) NR(14,23, NR) NR(NR, NR) NR(16.89, NR) NR(NR, NR) 18.78(9.92, NR) NR(NR, NR) NR(12.85, NR) OS HR (95% CI), UD/D 1.04 (0.48, 2.25) NE 0.16 (0.04, 0.69) 0.48 (0.15, 1.51) OS P-valueb 0.9254 NE 0.0147 0.2079 aPrimary endpoint assessed by IRC; bP-values are reported for descriptive purposes only in this exploratory study. Abbreviations: CI, confidence interval; D, detectable ctDNA status; HR, hazard ratio; IRC, independent review committee; mo, months; mOS, median overall survival; mPFS, median progression-free survival; NE, not evaluable; NR, not reached; OS, overall survival; PFS, progression-free survival; UD, undetectable ctDNA status Citation Format: Shun Lu, Jie Wang, Meili Sun, Jun Zhao, Chunhong Hu, Mengzhao Wang, Jianying Zhou, Yong Song, Qinghua Zhou, Jiayuan Zhang, Yang Shi, Ruiqi Huang, Xikun Wu, Wanyu He, Xiaofei Qu, Yun Zhang, Zhirong Shen, Yan Yu. Longitudinal ctDNA levels and clinical outcomes of first-line (1L) tislelizumab (TIS) + chemotherapy (chemo) treatment for advanced non-small cell lung cancer (NSCLC) in the RATIONALE-304 and 307 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB289.