Harmonization and standardization of panel-based tumour mutational burden (TMB) measurement: Real-world results and recommendations of the QuIP study

Endris, Volker; Budczies, Jan; Merkelbach‐Bruse, Sabine; Dietmaier, Wolfgang; Siebolts, Udo; Maas, J.; Merino, Diana M.; Stewart, Mark; Allen, Jeff; Glimm, Hanno; Thiemann, Matthias; Aust, D.; Hummel, Michael; Moch, Holger; Jung, Andreas; Haller, Florian; Weichert, Wilko; Dietel, Manfred

doi:10.1093/annonc/mdz447

Cited by 6 publications

(5 citation statements)

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“…25) It should also be noted that CheckMate 275 is a singlearm trial, complicating the determination of any biomarker as being predictive versus prognostic. The evidence to date on the predictive value of TMB is inconsistent (6,(26)(27)(28)(29)(30)(31). In addition, there is a lack of standardization among TMB assays, making it difficult to implement into clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275

Galsky

Saci

Szabó

et al. 2020

Clinical Cancer Research

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Purpose: We report efficacy and safety with extended follow-up, and exploratory biomarker analyses from the phase II CheckMate 275 trial to identify biomarkers of response to nivolumab in platinum-resistant metastatic or unresectable urothelial carcinoma (mUC).Patients and Methods: Patients received nivolumab 3 mg/kg once every 2 weeks until disease progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was objective response rate (ORR) per blinded independent review committee (BIRC; using RECIST v1.1) in all treated patients and by tumor PD-L1 expression. Key secondary endpoints were progression-free survival (PFS) per BIRC using RECIST v1.1 and overall survival (OS) in all patients and by PD-L1 expression. Exploratory endpoints included safety and biomarker analyses of tumor mutational burden (TMB), PD-L1, and previously identified mutational signatures.Results: Of 270 treated patients, 139 had evaluable TMB. With 33.7 months' minimum follow-up, ORR per BIRC, median PFS, and median OS [95% confidence interval (CI)] in all treated patients were 20.7% (16.1-26.1), 1.9 months (1.9-2.3), and 8.6 months (6.1-11.3), respectively. No new safety signals were identified. Higher TMB was associated (P < 0.05) with improved ORR [OR (95% CI): 2.13 (1.26-3.60)], PFS [HR: 0.75 (0.61-0.92)], and OS [HR: 0.73 (0.58-0.91)]. TMB combined with PD-L1 better predicted ORR, PFS, and OS than PD-L1 alone. Higher mutational signature 2 score was associated with better OS but did not improve the predictive value of TMB.Conclusions: These results support the durable antitumor activity of nivolumab and suggest that TMB may enrich for better response in mUC. Future studies of TMB/PD-L1 as biomarkers for response to nivolumab in randomized trials are warranted.

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Section: Discussionmentioning

confidence: 99%

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275

Galsky

Saci

Szabó

et al. 2020

Clinical Cancer Research

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“…Thus, understanding the complexity of TMB applications is of great clinical relevance. Main challenges for accurate and robust TMB estimation remain in the harmonization across different assays, assessment of the impact of tumor purity and heterogeneity, and in establishing reliable thresholds for calling TMB-high [4,8,9]. One additional challenge is to understand how the use of different sample types as a source of DNA affects mutation calling and TMB estimation.…”

Section: Introductionmentioning

confidence: 99%

Robust assessment of tumor mutational burden in cytological specimens from lung cancer patients

et al. 2020

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Tumor mutational burden (TMB) has emerged as a promising predictive biomarker for immune checkpoint inhibitor therapy. While the feasibility of TMB analysis on formalin-fixed paraffin-embedded (FFPE) samples has been thoroughly evaluated, only limited analyses have been performed on cytological samples, and no dedicated study has investigated concordance of TMB between different sample types. Here, we assessed TMB on matched histological and cytological samples from lung cancer patients and evaluated the accuracy of TMB estimation in these sample types. Materials and Methods: We analyzed mutations and resulting TMB in FFPE samples and matched ethanol-fixed cytological smears (n = 12 matched pairs) by using a targeted next-generation sequencing assay (Oncomine™ Tumor Mutational Load). Two different variant allele frequency (VAF) thresholds were used to estimate TMB (VAF = 5% or 10%). Results: At 5% VAF threshold, 73% (107/147) of mutations were concordantly detected in matched histological and cytological samples. Discordant variants were mainly unique to FFPE samples (34/40 discordant variants) and mostly C:G > T:A transitions with low allelic frequency, likely indicating formalin fixation artifacts. Increasing the VAF threshold to 10% clearly increased the number of concordantly detected mutations in matched histological and cytological samples to 96% (100/106 mutations), and drastically reduced the number of FFPE-only mutations (from 34 to 4 mutations). In contrast, cytological samples showed consistent mutation count and TMB values at both VAF thresholds. Using FFPE samples, 2 out of 12 patients were classified as TMBhigh at VAF cutoff of 5% but TMB-low at 10%, whereas cytological specimens allowed consistent patient classification independently from VAF cutoff. Conclusion: Our results show that cytological smears provide more consistent TMB values due to high DNA quality and lack of formalin-fixation induced artifacts. Therefore, cytological samples should be the preferred sample type for robust TMB estimation.

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“…In this issue of the Journal of Thoracic Oncology, Stenzinger et al 14 report on the efforts toward Quality Assurance Initiative Pathology in collaboration with Friends of Cancer Research, 15 and have undertaken to directly compare TMB measurement across different targeted gene panels and testing centers. This is the first real-world study designed to identify the parameters that influence the accuracy of TMB assessment in a clinical setting.…”

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confidence: 99%

“…Using the Foundation One panel, the CheckMate 568 and 227 studies determined a psTMB threshold of 10 mut/Mb to differentiate low and high TMB in NSCLC. 6,8,17 Taking this value as a clinically relevant cutoff point, Stenzinger et al 14 calculated a wesTMB equivalent of 199 mutations. Using this value to bridge psTMB from the other panels in the study, they found that most panels yielded similar psTMB thresholds.…”

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confidence: 99%

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Balancing the Count: Harmonizing Panel-Based Tumor Mutational Burden Assessment

Sutherland

Vissers

2020

Journal of Thoracic Oncology

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Harmonization and standardization of panel-based tumour mutational burden (TMB) measurement: Real-world results and recommendations of the QuIP study

Cited by 6 publications

References 0 publications

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275

Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275

Robust assessment of tumor mutational burden in cytological specimens from lung cancer patients

Balancing the Count: Harmonizing Panel-Based Tumor Mutational Burden Assessment

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