Tumor mutational burden (TMB) is a predicted total number of somatic changes discovered in the tumor genome, which has become a significant biomarker across advanced cancer types, especially when it comes to monitoring the treatment response to checkpoint immunotherapy. However, researchers have found that TMB often displays conflicting results in prospective and retrospective trials, which limits a more extensive application of tumor mutational burden as a biomarker in ordinary clinical settings. Retrospective studies have shown that TMB's clinical benefits vary according to cancer types and clinical endpoints.
Considering little research has been done to look into the relationship between tumor mutational burden and clinical outcomes in a large group of patients with different advanced malignancies, scientists from the Division of Hematology/Oncology at Northwestern University have recently conducted a study to better understand the validity of a standard TMB biomarker across diverse advanced cancers in a large cohort and proposed that different research results may be a result of differences in the used biomarker testing panel types and the threshold for TMB from study to study.
The study included 674 patients whose tumors were sequenced using next-generation sequencing (NGS) technology. The retrospective and observational data were collected from patients with 8 distinct advanced cancers and more than 20 histologies from 199 community sites and 101 academic sites. By performing a TMB analysis of 674 patients with advanced solid tumors who were treated with FDA–approved immune checkpoint inhibitors, researchers concluded that cancer patients with high tumor mutational burden (with 10 or more genomic mutations) demonstrated improved outcomes on immune checkpoint inhibitors (ICIs) than patients who had low-TMB cancers.
The study of TMB's clinical benefit is established on the principle that highly mutated tumor cells can produce high-quality neoantigens, and subsequently, those new antigens would increase the reactivity of T cells. In return, the efficacy of immune checkpoint blockade treatment is improved among the studied population, in which the most common cancer is non–small cell lung cancer, accounting for 49% of the patients, followed by 22.0% of bladder cancer patients, and 14% of head and neck squamous cell carcinoma.
The research result indicated that no matter what the ICI type is, patients with high-TMB cancers always witnessed an overall survival benefit. These findings were robust to the ICI administered and remained significant after adjustment for programmed cell death-ligand 1 and microsatellite instability status. However, the investigation was restricted by its retrospective nature and the scarcity of data for follow-up on patients who had received ICIs prior to testing. Furthermore, the effectiveness endpoints might be surrogates for more known and potential FDA-grade efficacy endpoints.
Despite these limitations, the research group comprised a variety of advanced cancer types and the TMB biomarker category was a consistent indicator of ICI benefit. Generally speaking, this study highlights the use of clinical genomic data sets to evaluate emerging molecular biomarkers and clinical outcomes under different conditions that are more reflective of actual practice patterns than clinical trials.