TMB in NSCLC: A Broken Dream?

Sara Bravaccini,Paola Ulivi,Giuseppe Bronte

doi:10.3390/ijms22126536

Abstract

Although immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the total number of somatic/acquired mutations per coding area of a tumor genome (Mut/Mb), has emerged as a potential predictive biomarker of response to immune checkpoint inhibitors. We found that the limited use of TMB in clinical practice is due to the difficulty in its detection and compounded by several different biological, methodological and economic issues. The incorporation of both TMB and PD-L1 expression or other biomarkers into multivariable predictive models could result in greater predictive power.

Highlights

Tumor mutation burden (TMB) detection in liquid biopsy compared to its evaluation in tissue warrants further investigation
Food and Drug Administration (FDA) approval of the use of pembrolizumab in solid tumors with high TMB score opened the need to improve the definition of predictive biomarkers for treatment with immune checkpoint inhibitors (ICIs)
Immunotherapy should be used at a specific point in treatment sequence of Non-small-cell lung carcinoma (NSCLC) because chemotherapy can be mutagenic and may induce a higher TMB score

Summary

Etiopathogenesis of Lung Cancer

Lung cancer is the most common cause of death from cancer worldwide, with only 30–40% of tumors diagnosed at an early and resectable stage of disease [1]. Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for a variety of cancers, including NSCLC, not all patients respond to immunotherapy in the same way. The only biomarker approved for patient selection in clinical practice is PD-L1 expression, evaluated by immunohistochemistry (IHC) [6,7,8]. This methodology is inexpensive and can be performed using standard histopathology equipment. The recommendation of the Food and Drug Administration (FDA) includes the use of a specific anti-PD-L1 clone, whereas European Medicines Agency (EMA) guidelines advise the use of validated IHC test. Another common problem is the number of cells present in small biopsies, often insufficient for the correct evaluation of TMB

TMB Detection

TMB Pitfalls How Many Genes Need to Be Analyzed for “a Perfect” TMB?

TMB in Clinical Practice

Findings

Conclusions