%0 Journal Article
%T Tumor mutational burden assessment as a predictive biomarker for immunotherapy in lung cancer patients: getting ready for prime-time or not?
%A Paul Hofman
%A Simon Heeke
%J SCIE-indexed Journal
%D 2018
%X The introduction of cancer immunotherapy for the treatment of non-small cell lung cancer (NSCLC) has revolutionized treatment algorithms for advanced and metastatic patients and has massively improved survival rates for certain groups of patients. Pembrolizumab, a PD-1 blocking monoclonal antibody (mAB), has been approved by the Food and Drug Administration (FDA) for first-line treatment of NSCLC patients with a PD-L1 tumor proportion score >50% and in second-line treatment for patients with PD-L1 expression >1% (1). Additionally, it was recently shown to be beneficial in first-line treatment, irrespective of PD-L1 expression, when administered in combination with pemetrexed or carboplatin (2,3) and was consequently approved by the FDA as a first-line treatment (4). Additionally, nivolumab, another PD-1 blocking mAB, has been approved for the second line treatment of metastatic NSCLC after failed chemotherapy for patients with PD-L1 expression >1% (5). Furthermore, atezolizumab (an anti-PD-L1 mAB) has been approved for second-line treatment of metastatic NSCLC (6), and durvalumab (an anti-PD-L1 mAB) was also approved for the maintenance therapy of unresected stage III NSCLC after successful chemoradiotherapy (7). However, while the biological concept of immune checkpoint inhibition has been extensively studied, not all aspects of immunotherapy are fully understood at present (8). While many patients respond to the treatment and show stable disease over long periods (9-11), cancer immunotherapy is not effective in other patients or is even associated with tumor hyperprogression (12). The only biomarker that is currently used as surrogate marker for the selection of patients eligible for cancer immunotherapy, and FDA approved as a companion diagnostic test (CDx), is the expression of PD-L1 in tumor cells as detected by immunohistochemistry (IHC) (13). However, while all currently approved immunotherapy treatments in NSCLC target the PD1-PD-L1 interaction, the use of PD-L1 as a biomarker has its limitations (13). PD-L1 expression (>1% or >5%) has been reported in only 24¨C60% of NSCLC (14). Furthermore, high expression of PD-L1 (>50%) is limited to only 25¨C30% of all NSCLC (15-17) and the objective response rate (ORR) was for example only 44.8% in the PD-L1 >50% group in the KEYNOTE-024 trial which compared first line treatment of pembrolizumab in patients with PD-L1 >50% versus chemotherapy (17). Consequently, there are currently many challenges concerning the effective use of PD-L1 IHC as a biomarker to select patients for immunotherapy, and it is
%U http://tlcr.amegroups.com/article/view/23261/18840