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Background High TMB is predictive of PFS benefit with anti-PD-(L)1 ± anti-CTLA-4 therapy in mNSCLC. Preliminary results from MYSTIC (NCT02453282), an open-label, Phase III trial of first-line durvalumab (D; anti-PD-L1), ± tremelimumab (T; anti-CTLA-4), vs platinum-based chemotherapy (CT) in mNSCLC, indicate that blood TMB (bTMB, ≥16 mut/Mb; GuardantOMNI [Guardant Health]) from circulating tumor DNA (ctDNA) correlates positively with tissue (t) TMB (≥10 mut/Mb) (Spearman’s correlation coefficient = 0.6) and is predictive of survival benefit with D±T vs CT. Efficacy outcomes were assessed using additional exploratory cut-offs for bTMB and ≥10 mut/Mb for tTMB. Methods Pts with EGFR and ALK wild-type, immunotherapy/CT-naïve mNSCLC were randomized (1:1:1) to D (20 mg/kg i.v. q4w); D (20 mg/kg i.v. q4w) + T (1 mg/kg i.v. q4w up to 4 doses); or CT. bTMB was evaluated with the GuardantOMNI platform. tTMB was evaluated with the FoundationOne tissue NGS platform. bTMB cut-off was defined as ≥20 mut/Mb (bTMB≥20). Data cut-off: Oct 4, 2018 (OS); Jun 1, 2017 (PFS). Results 1118 pts were randomized. Baseline sample datasets were: bTMB 809; tTMB 460 pts, with baseline characteristics balanced between treatment arms. bTMB≥20 was associated with improved OS (D+T vs CT: HR 0.49 [95% CI 0.32, 0.74]; D vs CT: HR 0.72 [95% CI 0.50, 1.05]) and PFS (D+T vs CT: HR 0.53 [95% CI 0.34, 0.81]; D vs CT: HR 0.77; [95% CI 0.52, 1.13]); 24-mo survival: D+T 48.1% (95% CI 35.5, 59.7), D 33.8% (95% CI 23.4, 44.5) and CT 19.4% (95% CI 11.0, 29.5). Data for tTMB are shown (table). Additional cut-offs will be presented. Conclusion MYSTIC provides the most comprehensive data set to date supporting TMB as a predictive biomarker of OS benefit with immunotherapy. In exploratory analyses, bTMB≥20 was associated with OS and PFS benefit with D±T vs CT, with the greatest magnitude of benefit observed for pts receiving D+T. bTMB ≥20 mut/MbbTMB Citation Format: Solange Peters, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Paul Baas, Manuel Cobo Dols, Alexey Smolin, David Vicente, Vladimir Moiseyenko, Scott J. Antonia, Kazuhiko Nakagawa, Sarah B. Goldberg, Edward Kim, Rajiv Raja, Philip Brohawn, Delyth Clemett, Piruntha Thiyagarajah, Urban Scheuring, Feng Liu, Naiyer Rizvi. Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT074.