Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB

BACKGROUND

Tumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.

METHODS

We evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.

RESULTS

Both panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N

CONCLUSIONS

Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.

Informations de copyright

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: LP-A has received honoraria for scientific advice and speaker fees from Lilly, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, PharmaMar, Merck, Astra-Zeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer and Blueprint, and participates as external member of the board of Genómica. He is founder and board member of Altum sequencing and has received institutional support for contracted research from Merck Sharp & Dohme, Bristol-Myers Squibb, Astra-Zeneca and Pfizer. EMG-M has received honoraria for scientific advice from Bristol-Myers Squibb and speaker fees from Illumina Inc and Pfizer and she is currently employee of PharmaMar. PG has received consultant and advisory fees from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Abbvie, Guardant Health, Novartis, Lilly, Astra-Zeneca, Janssen, Sysmex, Blueprint Medicines and Takeda. She has been the recipient of speaker fees from Takeda, Astra Zeneca, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer, Novartis, Boehringer Ingelheim, Gilead and Rovi, and institutional support for clinical trials from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Takeda, Lilly, Pfizer, Novartis, PharmaMar, Celgene, Sanofi, GlaxoSmithKline, Theradex Oncology and BluePrint Medicines. She has also received funding for contracted research from Guardant Health and Sysmex. FL-R. has received honoraria from Astra Zeneca, Abbvie, Bayer, Lilly, Merck Sharp & Dohme, Pfizer, Bristol-Myers Squibb, Roche, Thermo Fisher, and has received research funding from Bristol-Myers Squibb, Lilly, Roche and Thermo Fisher. SPA has received honoraria from Roche, Bristol-Myers Squibb, Merck Sharp and Dohme, Astra-Zeneca and Targovax, is a board member of Oncosur, and has received direct research funding as project lead from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb and Lilly. The remaining authors declare no competing financial interests. SHP has received honoraria from Roche and Bristol-Myers Squibb. ES has received grants from Thermo Fisher Scientific and Bristol-Myers Squibb.