Biomarkers for selection of therapies for the first-line management of NSCLC

The need for predictive biomarkers is crucial for the effective management of NSCLC. For example, nivolumab is highly active in a very select group of patients.¹ The use of archival tumor samples from pretreated patients in the pivotal phase 1 study may explain the differences in ORR according to PD-L1 expression. A phase 1 study demonstrated that anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.² Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response.

It is recognized that PD-L1 expression varies with the tumor microenvironment and thus PD-L1 expression at a single time point may not represent a dynamic immune response. Thus PD-L1 expression as a predictive biomarker may be difficult to implement. Further studies are needed to characterize immunologic correlates of response in the pretreatment and on-treatment setting. Research is ongoing to identify patients who are likely to respond to PD-1/PD-L1-inhibitors.

In the front-line setting, the pivotal KEYNOTE-024 trial revealed that pembrolizumab was better than chemotherapy in patients with advanced NSCLC and high PD-L1 expression, defined as a tumor proportion score (TPS) greater than 50%. In this patient subset, pembrolizumab significantly prolonged PFS and OS.³ The KEYNOTE-042 study found that pembrolizumab was superior to chemotherapy in patients with PD-L1 TPS >1%, although the OS benefits were greater in patients with higher PD-L1 expression (TPS >50%).⁴ In the KEYNOTE-189 trial, the combination of pembrolizumab plus chemotherapy in patients with advanced non-squamous NSCLC and no EGFR/ALK alterations significantly improved PFS and OS compared to chemotherapy alone. The largest benefit was observed in patients with PD-L1 TPS >50% (HR, 0.42), although patients with PD-L1 expression <1% also saw improvement (HR, 0.59).⁵ This data suggests that PD-L1 expression alone is not sufficient to predict which patient group will most benefit from immunotherapy.

Subsequently, tumor proportion score (TPS) levels for PD-L1 has emerged as the logical biomarker on which to guide molecular selection for NSCLC receiving PD-1/PD-L1 inhibitors. However, a number of issues related to the standardization of PD-L1 testing have been previously raised.⁶ This includes the standardization of the laboratory method of PD-L1 testing as well as determination of the appropriate specimen with which to measure PD-L1. In a recently reported study, the concordance between surgical specimens and corresponding biopsy specimens in terms of PD-L1 expression has been evaluated.⁷ In this study, PD-L1 expression was frequently discordant between surgical resection and matched biopsy specimens (the overall discordance rate =48%). Notably, the biopsy specimens underscored the PD-L1 status compared to the surgical specimens in almost all cases. These findings have an important relevance to the standardization of the procedure of PD-L1 measurement. Another concern with the use of PD-L1 testing is the dynamic status of this marker and changes in the PD-L1 level have been observed across the clinical course of NSCLC treatment.⁸ Whether a re-biopsy has to be made at each time of instituting PD-1/PD-L1 targeted treatment is not yet known. The appropriate cutoff value with which to consider a tumor specimen as PD-L1 positive has been variable among different clinical studies; with some studies using 1%, 5%, 10% or 25% as cutoff values.^9,10 A recent analysis indicates that a benefit exists even for PD-L >1% tumors compared to PD-L1 <1% tumors, suggesting that a cutoff value of 1% is a more suitable value to use in clinical studies.¹¹

Another potential biomarker for immune checkpoint inhibition is high tumor mutational burden (TMB). Tumor mutation burden is a quantitative biomarker that reflects the total number of mutations carried by tumor cells.¹² Tumor cells with high TMB have higher levels of neoantigens, which are thought to help the immune system recognize tumors and incite an increase in cancer-fighting T cells and an anti-tumor response.¹³ However, some patients with both high and low mutational burdens failed to respond to therapy, suggesting that other factors are involved in immunotherapy responses. These findings suggest that the degree of intratumor heterogeneity may be associated with a differential response to checkpoint blockade, and that multiple factors are involved in tumor immune responses.

An open-label, non-randomized, phase 2 (KEYNOTE-158) study, assessed the association of high tissue TMB (tTMB-high) with outcomes in patients treated with pembrolizumab with selected, previously treated, advanced solid tumors.¹⁴ Objective responses were observed in 30 (29%; 95% CI, 21%-39%) of 102 patients in the tTMB-high group and 43 (6%; 95% CI, 5%-8%) of 688 in the non-tTMB-high group (Figure 1). The data suggest that tTMB-high status identifies a subgroup of patients who could have a robust tumor response to pembrolizumab monotherapy (Figure 2). tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.