A Blood-based Assay for Assessment of Tumor Mutational Burden in First-line Metastatic NSCLC Treatment: Results from the MYSTIC Study.

Tumor mutational burden (TMB) has been shown to be predictive of survival benefit in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors. Measuring TMB in the blood (bTMB) using circulating cell-free tumor DNA (ctDNA) offers practical advantages compared with TMB measurement in tissue (tTMB); however, there is a need for validated assays and identification of optimal cutoffs. We describe the analytic validation of a new bTMB algorithm and its clinical utility using data from the phase III MYSTIC trial. The dataset used for the clinical validation was from MYSTIC, which evaluated first-line durvalumab (anti-PD-L1 antibody) ± tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody) or chemotherapy for metastatic NSCLC. bTMB and tTMB were evaluated using the GuardantOMNI and FoundationOne CDx assays, respectively. A Cox proportional hazards model and minimal P value cross-validation approach were used to identify the optimal bTMB cutoff. In MYSTIC, somatic mutations could be detected in ctDNA extracted from plasma samples in a majority of patients, allowing subsequent calculation of bTMB. The success rate for obtaining valid TMB scores was higher for bTMB (809/1,001; 81%) than for tTMB (460/735; 63%). Minimal P value cross-validation analysis confirmed the selection of bTMB ≥20 mutations per megabase (mut/Mb) as the optimal cutoff for clinical benefit with durvalumab + tremelimumab. Our study demonstrates the feasibility, accuracy, and reproducibility of the GuardantOMNI ctDNA platform for quantifying bTMB from plasma samples. Using the new bTMB algorithm and an optimal bTMB cutoff of ≥20 mut/Mb, high bTMB was predictive of clinical benefit with durvalumab + tremelimumab versus chemotherapy.

Si H ，Kuziora M ，Quinn KJ ，Helman E ，Ye J ，Liu F ，Scheuring U ，Peters S ，Rizvi NA ，Brohawn PZ ，Ranade K ，Higgs BW ，Banks KC ，Chand VK ，Raja R ... -  《-》

Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel.

Wang Z ，Duan J ，Cai S ，Han M ，Dong H ，Zhao J ，Zhu B ，Wang S ，Zhuo M ，Sun J ，Wang Q ，Bai H ，Han J ，Tian Y ，Lu J ，Xu T ，Zhao X ，Wang G ，Cao X ，Li F ，Wang D ，Chen Y ，Bai Y ，Zhao J ，Zhao Z ，Zhang Y ，Xiong L ，He J ，Gao S ，Wang J ... -  《-》

Tumor Mutational Burden as a Predictor of Survival with Durvalumab and/or Tremelimumab Treatment in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

Biomarkers that predict response to immune checkpoint inhibitors (ICI) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are needed. This retrospective study assessed tumor mutational burden (TMB) and outcomes in the phase II HAWK and CONDOR and phase III EAGLE studies of durvalumab with or without tremelimumab in platinum-resistant R/M HNSCC. Tumor samples from HAWK/CONDOR (N = 153) and blood samples from EAGLE (N = 247) were analyzed for TMB. Associations with survival were evaluated for tissue TMB (tTMB) at cutoffs from 10 to 20 mutations/megabase (mut/Mb) and for blood plasma TMB (bTMB) at cutoffs from 8 to 24 mut/Mb. In HAWK/CONDOR, overall survival (OS) with durvalumab with or without tremelimumab was longer for high versus low tTMB: statistically significant differences were observed with durvalumab plus tremelimumab at tTMB ≥ 10 mut/Mb [HR, 0.52 (95% confidence interval, CI, 0.28-0.98)] and tTMB ≥ 12 mut/Mb [HR, 0.46 (95% CI, 0.24-0.86)]. In EAGLE, a significant OS benefit versus chemotherapy was observed with durvalumab and durvalumab plus tremelimumab at bTMB≥16 mut/Mb [HR, 0.39 (95% CI, 0.20-0.76) and 0.38 (95% CI, 0.19-0.78), respectively] but not bTMB < 16 mut/Mb [HR, 0.92 (0.61-1.37) and 0.92 (95% CI, 0.62-1.36), respectively]. A significant progression-free survival benefit was also observed in the ICI arms versus chemotherapy at bTMB ≥ 16 mut/Mb. Findings support TMB as a biomarker for predicting survival in patients with platinum-resistant R/M HNSCC treated with ICIs. The analysis of EAGLE demonstrated that bTMB was predictive of survival with ICI treatment versus chemotherapy in a large, randomized controlled study population.

Wildsmith S ，Li W ，Wu S ，Stewart R ，Morsli N ，Raja R ，Zhang Q ，Ye J ，He P ，Shetty J ，Yovine A ，Holoweckyj N ，Real K ，Walker J ，Wrona M ，de Los Reyes M ，Barker C ，Whiteley J ，Haddad R ，Licitra L ，Ferris R ，Fayette J ，Zandberg DP ，Siu LL ，Mesía R ... -  《-》

Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial.

Rizvi NA ，Cho BC ，Reinmuth N ，Lee KH ，Luft A ，Ahn MJ ，van den Heuvel MM ，Cobo M ，Vicente D ，Smolin A ，Moiseyenko V ，Antonia SJ ，Le Moulec S ，Robinet G ，Natale R ，Schneider J ，Shepherd FA ，Geater SL ，Garon EB ，Kim ES ，Goldberg SB ，Nakagawa K ，Raja R ，Higgs BW ，Boothman AM ，Zhao L ，Scheuring U ，Stockman PK ，Chand VK ，Peters S ，MYSTIC Investigators ... -  《-》

Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial.

Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.

Kim ES ，Velcheti V ，Mekhail T ，Yun C ，Shagan SM ，Hu S ，Chae YK ，Leal TA ，Dowell JE ，Tsai ML ，Dakhil CSR ，Stella P ，Jin Y ，Shames DS ，Schleifman E ，Fabrizio DA ，Phan S ，Socinski MA ... -  《-》