Abstract: Immune checkpoint inhibitors (ICI) as monotherapy in selected patients as well as in combination with chemotherapy have become the standard of care in the first-line treatment strategy of advanced non-small cell lung cancer (NSCLC) patients. Combination treatment with ICI, such as nivolumab and ipilimumab or durvaluamb and ipilimumab, has also been proposed as potential strategies in this setting in selected advanced NSCLC patients. Characterizing predictive markers of long-term clinical benefit with ICI is a critical objective. Tumor mutational burden has been proposed as a potential predictive biomarker. In this review, we discuss the efficacy of nivolumab and ipilimumab in advanced NSCLC patients as well as the clinical utility of tumor mutational burden in the efficacy of this combination. Ongoing clinical trials with nivolumab and ipilimumab, and the efficacy of this combination in subgroups of NSCLC patients, such as elderly patients and patients with brain metastases, are also discussed.


Keywords: nivolumab, ipilimumab, tumor mutational burden, CheckMate trial, non-small cell lung cancer


INTRODUCTION

In the last decade, several immune checkpoint inhibitors (ICIs) have become the standard of care approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the treatment of advanced non-small cell lung cancer (NSCLC), either in the first-line setting (as monotherapy in selected patients1 or in combination with chemotherapy regardless the histologic subtype2–4) or beyond, mainly as monotherapy treatment.5–8 Other strategies, such as the combination of ICIs, have also been assessed in selected patients,9 but this strategy has not already been approved by health authorities as the standard of care. ICIs have shifted the prognosis of advanced NSCLC patients, therefore, characterizing predictive markers of long-term clinical benefit with ICI is a critical objective, mainly for avoiding potential toxicity and to limit economic expenses. There are plenty of data confirming the predictive, albeit imperfect, ability of programmed death-ligand 1 (PD-L1) expression to identify NSCLC patients with most favorable outcomes with ICI.10–12Despite its controversial results and constraints based on the responses observed in PD-L1 negative tumors,2,4,6,8 PD-L1 expression measured by immunohistochemistry is currently the main scaffold decision-making tool used in clinical practice for selecting those patients deriving the most benefit from ICIs at least in a first-line setting.1 Tumor mutational burden (TMB) has recently emerged as a biomarker, independent of PD-L1 expression, to identify patients who derive clinical benefit from anti-programmed death-1 (anti-PD-1) monotherapy, nivolumab, or the combination of anti-PD(L)1 and cytotoxic T-lymphocyte-associated antigen (CTLA-4) antibody.9,13–15 In this comprehensive review, we discuss the efficacy of nivolumab and ipilimumab in advanced NSCLC patients, as well as the clinical utility of TMB in the efficacy of this combination. Ongoing clinical trials with nivolumab and ipilimumab, and the efficacy of this combination in subgroups of NSCLC patients, such as elderly patients and patients with brain metastases, are also discussed.

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