Abstract LB512: RATIONALE-304: The association of tumor mutational burden (TMB) with clinical outcomes of tislelizumab (TIS) + chemotherapy (chemo) versus chemo alone as first-line treatment for advanced non-squamous non-small cell lung cancer (nsq-NSCLC)
Authors: Lu Shun , Sun Meili , Liu Yunpeng , Hu Yanping , Xie Yanyan , Wang Zhehai , Wang Dong , Yang Zhenzhou , Liang Liang , Huo Yi , Zhang Yun , Huang Ruiqi , Shi Yang , Shen Zhirong , Yu Yan 
Published: June 2022

Abstract
Background: In the primary analysis of RATIONALE-304 (NCT03663205), TIS + platinum-based chemo significantly improved clinical outcomes over chemo alone in treatment-naïve advanced nsq-NSCLC (median progression-free survival [PFS] by IRC [9.7 vs 7.6 months, HR=0.645, p=0.0044]). Here we report biomarker analysis of baseline tissue and blood TMB (tTMB and bTMB, respectively).
Methods: Patients with nsq-NSCLC were randomized 2:1 to TIS + platinum + pemetrexed or platinum + pemetrexed. TMB scores were evaluated on baseline tumor and blood samples by OncoScreen Plus®. The Spearman’s rank correlation of tTMB with bTMB was assessed. PFS by independent review committee (primary endpoint) was assessed within subgroups defined by TMB status, using a Cox proportional hazard model with disease stage and programmed death-ligand 1 (PD-L1) expression as stratification factors. Interaction p-values &lt; 0.05 were considered statistically significant without multiplicity adjustment.
Results: Of 325 patients treated in RATIONALE-304, without an EGFR sensitizing mutation, 177 (54.5%) had evaluable tTMB and 107 (32.9%) had evaluable bTMB. Median tTMB and bTMB were 7.2 and 3.1 mut/Mb, respectively. There was a modest correlation between tTMB and bTMB (r=0.71, p &lt; 0.001). Prolonged PFS benefit of adding TIS to chemo was oberved in patients with TMB-high status compared with TMB-low status (Table). Interaction analysis showed that neither tTMB nor bTMB significantly differentiated treatment-specific PFS benefit (interaction p-values &gt; 0.05; Table).
Conclusions: In this retrospective analysis, neither tTMB nor bTMB was significantly associated with PFS benefit, suggesting limited clinical utility of tTMB and bTMB in the setting of TIS + chemo as first-line therapy for advanced nsq-NSCLC.
Association of TMB with PFS benefit of TIS + chemo vs chemo tTMB bTMB Cutoffs mut/Mb N HR (95% CI) Interaction Cutoffs mut/Mb N HR (95% CI) Interaction p-value p-value BEP 177 0.76 (0.46, 1.25) NA BEP 107 0.48 (0.26, 0.87) NA ≥ 8 (TMB-high) 80 0.52 (0.25, 1.10) 0.208 ≥ 4 (TMB-high) 47 0.30 (0.12, 0.75) 0.212 &lt; 8 (TMB-low) 97 0.98 (0.51, 1.88) &lt; 4 (TMB-low) 60 0.64 (0.29, 1.39) BEP, biomarker evaluable population; bTMB, blood tumor mutational burden; CI, confidence interval; HR, hazard ratio; Mb, megabase; mut, mutation; NA, not applicable; PFS, progression-free survival; TIS, tislelizumab; TMB, tumor mutational burden; tTMB, tissue tumor mutational burden
Citation Format: Shun Lu, Meili Sun, Yunpeng Liu, Yanping Hu, Yanyan Xie, Zhehai Wang, Dong Wang, Zhenzhou Yang, Liang Liang, Yi Huo, Yun Zhang, Ruiqi Huang, Yang Shi, Zhirong Shen, Yan Yu. RATIONALE-304: The association of tumor mutational burden (TMB) with clinical outcomes of tislelizumab (TIS) + chemotherapy (chemo) versus chemo alone as first-line treatment for advanced non-squamous non-small cell lung cancer (nsq-NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB512.