IMPORTANCECheckpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.OBJECTIVE To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTSThis open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.INTERVENTIONS Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. MAIN OUTCOMES AND MEASURESThe primary end points, assessed in patients with Ն25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.

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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 <20 mut/MbtTMB ≥10 mut/MbtTMB <10 mut/MbD+TDCTD+TDCTD+TDCTD+TDCTn6477702042091856060671048584OSMedian, mos21.912.610.08.511.011.616.618.611.98.410.113.895% CI11.4, 32.87.8, 18.68.1, 11.76.7, 9.88.9, 14.99.6, 13.19.7, 27.39.3, 22.09.1, 16.05.3, 10.36.4, 14.610.1, 16.3HR*0.490.72-1.160.93-0.720.70-1.391.26-95% CI0.32, 0.740.50, 1.05-0.93, 1.450.74, 1.16-0.48, 1.090.47, 1.06-1.00, 1.920.90, 1.77-PFSMedian, mos4.22.74.42.02.85.03.13.15.12.42.55.695% CI2.8, NR1.8, 4.44.1, 5.41.7, 2.82.2, 3.14.2, 5.51.5, 6.82.3, 12.74.2, 5.61.6, 3.01.8, 3.44.2, 7.0HR*0.530.77-1.551.19-0.970.86-1.981.49-95% CI0.34, 0.810.52, 1.13-1.23, 1.940.94, 1.50-0.63, 1.490.55, 1.33-1.42, 2.781.05, 2.13-*HRs refer to comparison of experimental regimen to CT; NR, not reached 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.

1783OPatient reported outcomes from a randomized phase II trial comparing standard-dose with high-dose twice daily (BID) thoracic radiotherapy (TRT) in limited stage small cell lung cancer (LS SCLC