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Regulatory Focus – Multi-stakeholder team addresses tumor mutational burden harmonization

Regulatory Focus – Multi-stakeholder team addresses tumor mutational burden harmonization

Harmonizing measurement and reporting of biomarkers in oncology represents a cross-disciplinary challenge that also cuts across industry, regulatory bodies, academic, and clinical practice. As cancer therapy becomes increasingly targeted, the need for validated biomarker measurement becomes more pressing.

In first addressing how biomarkers can be used in conjunction with tumor treatment, said Richard Pazdur, MD, the US Food and Drug Administration faced “a considerable regulatory challenge,” because “we weren’t just developing a drug, we were developing a drug along with a device.” Pazdur, director of the FDA’s Oncology Center of Excellence, spoke during a symposium hosted Tuesday by the Friends of Cancer Research (FCR) regarding the importance of harmonization of such biomarkers as tumor mutational burden. Addressing these issues, said Pazdur, becomes especially important in the new era of tissue-agnostic drug and biologic approvals.

Tissue-agnostic indications, said Pazdur, “really point to redefining diseases, in a sense… Will this be the future of oncology? I think it will be.” From a practical standpoint, “It makes it so much easier for us to approve a drug… it’s much easier to approve something that has a 60-, 70-, 80-percent response rate than something that has a 10-percent response rate, and then we’re arguing about the response rate with that drug.”

Tumor mutational burden (TMB) represents an increasingly important target in cancer treatment, since mutational burden – the number of somatic mutations per area of the genome of a tumor – can correlate with clinically meaningful response to cancer immunotherapies. However, how TMB is estimated and reported can vary across studies, limiting generalizability and clinical applicability of existing researching findings.

Friends of Cancer Research is collaborating with the US FDA and National Cancer Institute as well as academic, diagnostic, industry, and operational partners, building a consortium to achieve harmonization of TMB measurement and reporting.

In an April presentation at the virtual annual meeting of the American Association for Cancer Research (AACR), FCR presented an update on the TMB harmonization project, an effort to ensure alignment of TMB as measured on clinical samples. FCR’s Diana Merino Vega, PhD, explained that the multi-stakeholder TMB harmonization working group is working to “align on and publish universal best practices for defining TMB,” as well as find the best analytic validation approaches to use, with an eye to ensuring alignment with reference standards.

Phase 1 of the project involved in silico analysis of publicly available data from the Cancer Genome Atlas program at the National Cancer Institute.  Goals of this phase were to use whole-exome sequencing  as well as panels currently in clinical use to find sources of variability between TMB.

The harmonization project is currently wrapping up phase 2, where investigators conduct empirical analysis of cells derived from human tumors. In this phase, goals are to reach agreement on a universal reference standard using whole-exome sequencing, as well as to further identify sources of TMB variability after aligning scores to the agreed-upon standard.

In phase 3 of the investigators’ work, they plan to perform analyses using clinical samples with a goal of proposing standards to define how TMB can be applied in clinical settings.

The phase 2b work reported at AACR used 25 clinical tumor samples of a variety of types. Whole-exome sequencing paired with the TMB algorithm agreed upon by the research consortium was compared with clinical samples analyzed by a next-generation sequencing  (NGS) panel to which the laboratory TMB algorithm was applied. Researchers measured empirical variability in tumor mutational burden scores compared by these two methods.

Then, 3 different calibration strategies were applied to the clinical NGS panel. The smallest spread in panel TMB values for clinical samples was seen with a calibration approach that used the Cancer Genome Atlas data, indicating that this method “may be a viable approach to align across panel TMB scores,” said Merino. She and her coinvestigators are currently exploring how this calibration approach performed in TMB-high samples.

During the FCR-hosted discussion, Eric Rubin, MD, Vice President of Clinical Oncology for Merck, pointed out that the collaborative process teased out real-world issues that need to be addressed. “There are several tests that can measure tumor mutational burden; some of them are much more accessible in certain parts of the world than others,” so the FCR-convened meetings helped gather real-world information to allow “a nice discussion among the various stakeholders” to reach pragmatic decisions, such as a cutoff for what level of TMB would be considered high TMB in a clinical context, he said.

Further results from the TMB harmonization project will be shared in an upcoming 23 July FCR symposium at which National Cancer Institute director Ned Sharpless is slated to deliver a keynote address.…