New targeted treatments for non-small-cell lung cancer - role of nivolumab

Abstract

Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the survival has only improved significantly for lung cancer patients who have tumors harboring a driver mutation. Therefore, there is a clear unmet need for effective therapies for patients with no mutation. Immunotherapy has emerged as an effective treatment for different cancer types. Nivolumab, a monoclonal inhibitory antibody against PD-1 receptor, can prolong survival of NSCLC patients, with a manageable toxicity profile. In two Phase III trials, nivolumab was compared to docetaxel in patients with, respectively, squamous (CheckMate 017) and non-squamous NSCLC (CheckMate 057). In both trials, nivolumab significantly reduced the risk of death compared to docetaxel (41% and 27% lower risk of death for squamous and non-squamous NSCLC, respectively). Therefore, nivolumab has been approved in the US and in Europe as second-line treatment for advanced NSCLC. Unfortunately, accurate predictive factors for patient selection are lacking, making it difficult to decide who will benefit and who will not. Currently, there are many ongoing trials that evaluate the efficacy of nivolumab in different settings and in combination with other agents. This paper reviews the present literature about the role of nivolumab in the treatment of NSCLC. Particular attention has been given to efficacy studies, toxicity profile, and current and emerging predictive factors.

Keywords: advanced non-small-cell lung cancer; anti-PD-1; immunotherapy; nivolumab.

Figure 1

Multistep process for the diagnosis and characterization of lung cancer. Notes: (A) The two main lung cancer subtypes, SCLC and NSCLC, can be discriminated by a morphological analysis. NSCLC accounts for ~85%–90% of all lung cancers. (B) Immunohistochemistry allows different NSCLC subtypes to be distinguished. (C) Molecular testing allows possible driver mutations in the tumor to be identified (EGFR and ALK). Analysis of ROS1, BRAF, and MET should be considered for selected patients. Data from National Cancer Institute and Naidoo et al. Abbreviations: SCLC, small-cell lung cancer; NSCLC, non-small-cell lung cancer; NOS, non-squamous.

Figure 2

Immuno-modulatory role of PD-1 receptor and mechanism of action of nivolumab. Abbreviations: MHC, major histocompatibility complex; TCR, T-Cell Receptor; PD-1, programmed death 1; PD-L1, programmed death 1 – ligand 1; PD-L2, programmed death 1 – ligand 2.

Figure 3

Nivolumab development, from preclinical experience to clinical approval: focus on NSCLC. Notes: Timeline of nivolumab development from the preclinical studies to US FDA approval (dotted lines represent the starting date of the related trial). Abbreviations: PD-1, programmed death 1; PD-L1, programmed death 1 – ligand 1; NSCLC, non-small-cell lung cancer; CRC, colorectal cancer; RCC, renal cell carcinoma; Nivo, nivolumab; Ipi, ipilimumab; FDA, US Food and Drug Administration; SqNSCLC, squamous NSCLC.