| Title: |
A Blood-based Assay for Assessment of Tumor Mutational Burden in First-line Metastatic NSCLC Treatment: Results from the MYSTIC Study. |
| Authors: |
Si, H.; Kuziora, M.; Quinn, K.J.; Helman, E.; Ye, J.; Liu, F.; Scheuring, U.; Peters, S.; Rizvi, N.A.; Brohawn, P.Z.; Ranade, K.; Higgs, B.W.; Banks, K.C.; Chand, V.K.; Raja, R. |
| Publication Year: |
2021 |
| Collection: |
Université de Lausanne (UNIL): Serval - Serveur académique lausannois |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1557-3265 |
| Relation: |
Clinical Cancer Research; https://iris.unil.ch/handle/iris/49991; serval:BIB_1004EC355F9F; 000630142100006 |
| DOI: |
10.1158/1078-0432.CCR-20-3771 |
| Availability: |
https://iris.unil.ch/handle/iris/49991; https://doi.org/10.1158/1078-0432.CCR-20-3771 |
| Accession Number: |
edsbas.83925C3E |
| Database: |
BASE |