The Landscape of Immunotherapy in Advanced NSCLC: Driving Beyond PD-1/PD-L1 Inhibitors (CTLA-4, LAG3, IDO, OX40, TIGIT, Vaccines)

Abstract

Purpose of review: In this review, we analyzed the current landscape of non-PD-(L)1 targeting immunotherapy.

Recent findings: The advent of immunotherapy has completely changed the standard approach toward advanced NSCLC. Inhibitors of the PD-1/PD-L1 axis have quickly taken place as first-line treatment for NSCLC patients without targetable "driver" mutations. However, a non-negligible portion of patients derive modest benefit from immune-checkpoint inhibitors, and valid second-line alternatives are lacking, pushing researchers to analyze other molecules and pathways as potentially viable targets in the struggle against NSCLC. Starting from the better characterized CTLA-4 inhibitors, we then critically collected the actual knowledge on NSCLC vaccines as well as on other emerging molecules, many of them in their early phase of testing, to provide to the reader a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 inhibitors.

Keywords: CTLA4; IDO; Immunotherapy; LAG3; Non-small cell lung cancer; OX40; TIGIT; Vaccines.

Fig. 1

Interaction between T cell and APC/Cancer cell within the tumor microenvironment. APC: antigen-presenting cell; MHC: major histocompatibility complex; CTLA-4: cytotoxic T-lymphocyte antigen 4; LAG3: lymphocyte activation gene-3; IDO: indoleamine 2,3-dioxygenase 1; PD(L)1: programmed death (ligand) 1. Created with BioRender.com

Fig. 2

Tumor vaccines and anti-cancer immunity. MHC: major histocompatibility complex; TCR: T-cell receptor; CTLA-4: cytotoxic T-lymphocyte antigen 4. Created with BioRender.com

Fig. 3

Summary of phase III studies reporting PFS and/or OS data. PFS: progression-free survival; OS: overall survival; TRAEs: treatment-related adverse events; NIVO: nivolumab; IPI: ipilimumab; PEMBRO: pembrolizumab; CHEMO: chemotherapy; DURVA: durvalumab; TREME: tremelimumab