The Landscape of Immunotherapy Resistance in NSCLC

Abstract

Lung cancer is the leading cause of cancer mortality worldwide. Immunotherapy has demonstrated clinically significant benefit for non-small-cell lung cancer, but innate (primary) or acquired resistance remains a challenge. Criteria for a uniform clinical definition of acquired resistance have been recently proposed in order to harmonize the design of future clinical trials. Several mechanisms of resistance are now well-described, including the lack of tumor antigens, defective antigen presentation, modulation of critical cellular pathways, epigenetic changes, and changes in the tumor microenvironment. Host-related factors, such as the microbiome and the state of immunity, have also been examined. New compounds and treatment strategies are being developed to target these mechanisms with the goal of maximizing the benefit derived from immunotherapy. Here we review the definitions of resistance to immunotherapy, examine its underlying mechanisms and potential corresponding treatment strategies. We focus on recently published clinical trials and trials that are expected to deliver results soon. Finally, we gather insights from recent preclinical discoveries that may translate to clinical application in the future.

Response to Abemaciclib and Immunotherapy Rechallenge with Nivolumab and Ipilimumab in a Heavily Pretreated TMB-H Metastatic Squamous Cell Lung Cancer with CDKN2A Mutation, PIK3CA Amplification and TPS 80%: A Case Report

“…If progression occurs several months or years after the last dose, rechallenge may still be an option, even in lung cancer [ 17 ]. The lack of tumor antigens, defective antigen presentation, modulation of critical cellular pathways, epigenetic changes, and changes in the tumor microenvironment are all examples of resistance mechanisms that have been well-documented [ 36 ].…”

Moving Immune Checkpoint Inhibitors to Early Non-Small Cell Lung Cancer: A Narrative Review

“…However, results from clinical trials and daily practice suggest that the majority of unselected patients with metastatic lung cancer are refractory to ICIs, or develop acquired resistance, for reasons that are not fully understood [ 87 ].…”

Antibody Diversity in Cancer: Translational Implications and Beyond

“…While there is a possibility of immunotherapy resistance, it should be understood that this is only for a subset of cancer patients. Notably, there are promising clinical trials underway that are investigating overcoming immunotherapy resistance, one being NCT05304546, a Phase 2 trial using pembrolizumab, encorafenib, or binimetinib to overcome primary resistance to immunotherapy (singular inhibitor or immune checkpoint blockade) in Stage IV or inoperable stage III metastatic melanoma patients with a BRAF V600 E/K mutation [ 113 , 114 ].…”