On Thursday, July 23, 2020, Friends of Cancer Research (Friends) hosted the second in a two-part virtual meeting series, TMB Results: The Future Use of Complex Biomarkers, that focused on the harmonization of tumor mutational burden (TMB). The event covered the results from the TMB Harmonization Project and how the project’s efforts will impact the future use of complex biomarkers, such as TMB. In the opening keynote, Director of the National Cancer Institute (NCI), Ned Sharpless, praised the efforts of the TMB Harmonization Project. He discussed why this is such an important development as it provides a new way to identify treatment for patients and addresses the need for a better molecular standardization system.
“We need to make sure assays are analytically validated, harmonized, and work across different patient populations and different labs and that’s really the work of the TMB Harmonization Project.” – Ned Sharpless, NCI
Mickey Williams of Frederick National Lab presented the latest project results. In his summary of the findings, he described the variability in the association between TMB measured by many different gene panels and TMB measured by whole exome sequencing (WES), which the TMB Harmonization Consortium considered the gold standard. The variability observed in the three different tissue sources examined (in silico TCGA samples, human derived cell lines, and clinical samples) was comparable. Additionally, three different factors that impact panel TMB estimation were identified and further examined: panel size, gene content, and germline filtering. Williams also highlighted that a collaborative approach is integral to improve consistency and reliability of TMB estimates to be used in clinics.
Lisa McShane of the NCI presented the application and operationalization of a calibration tool. The development of a calibration tool addresses the problem of variation in the estimated association between panel and WES TMB across laboratories, allowing for alignment across panels. This tool will enable laboratories to perform calibration for their gene panel and adapt it for their own needs. Potential applications for the calibration tool include adjusting TMB values to be more comparable to those generated by the reference standard method and reliably inform subsequent clinical decision-making.
Victor Weigman from Q² Solutions then moderated a panel discussion with Nicholas Botwood, Bristol-Myers Squibb; Dave Fabrizio, Foundation Medicine; Reena Philip, U.S. FDA; and Naiyer Rizvi, Cancer Immunotherapy at Columbia University Irving Medical Center.
The panel addressed how the project’s findings will reduce future variability across platforms and ensure consistent clinical application of TMB for therapeutic decision making. The panel agreed that TMB standardization allows laboratories to compare appropriately and understand the relevant cut offs and how they look across trials, not only in the U.S., but with health authorities and patients across the world. More importantly, as the field moves toward the use of TMB in prospective studies it is important to understand how best to determine appropriate TMB cut offs and how they apply to different tumor types. From an FDA perspective, the opportunity of a universal reference method could promote the alignment and analytical values for panel TMB values. Finally, the panel closed with an announcement the calibration tool will be available once the Phase II paper is published.
These findings will be available in the upcoming manuscript to be submitted later in the year. Friends would like to acknowledge the work that took place for this project, the accomplishments of the consortium, and thank the TMB Harmonization working group members and our partners for their critical contributions. The efforts of the project will ultimately improve patient care by creating methods that promote consistent TMB reporting in clinical settings.