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Immune Checkpoint Blockade in Oncogene-Driven Non-Small-Cell Lung Cancer.

ABSTRACT: Patients with oncogene-driven lung cancer have limited therapeutic options after progressing on their targeted tyrosine kinase inhibitor (TKI) therapy. Given the growing role of immune checkpoint inhibitor (ICI) therapy in the treatment of lung cancer, oncogene-driven cancer has warranted further evaluation regarding ICI therapy. However, initial ICI studies have suggested that ICI monotherapy is not only lacking in efficacy, but that it may be less tolerable in oncogene-driven non-small-cell lung cancer (NSCLC). We performed a detailed review of the literature using Pubmed, and present the current and impactful findings here. Studies evaluating the use of concurrent ICI therapy and TKI therapy have also suggested increased toxicity and lack of increased activity in these patients. Larger studies have suggested that the sequence of ICI therapy and TKI, such as utilizing ICI therapy after TKI as opposed to before TKI, may play a role in reducing toxicity (hepatotoxicity, pneumonitis); however, these studies are limited in number. Novel methods of patient selection, including low tumor mutational burden, inflamed phenotyping, and high CD8 + tumor infiltrating lymphocytes, may aid in determining ideal patients to give ICI therapy. Novel therapeutic combinations including the addition of anti-VEGF (vascular endothelial growth factor) therapy or radiotherapy show promising findings for these patients. Given the growing unmet need for therapeutic options in patients with oncogene-driven NSCLC who have failed TKI therapy, further research is warranted.

SUBMITTER: Somasundaram A

PROVIDER: S-EPMC8579493 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Despite the initial successes of immunotherapy, there is an urgent clinical need for molecular assays that identify patients more likely to respond. Here, we report that ultrasensitive measures of circulating tumor DNA (ctDNA) and T-cell expansion can be used to assess responses to immune checkpoint blockade in metastatic lung cancer patients (N = 24). Patients with clinical response to therapy had a complete reduction in ctDNA levels after initiation of therapy, whereas nonresponders had no significant changes or an increase in ctDNA levels. Patients with initial response followed by acquired resistance to therapy had an initial drop followed by recrudescence in ctDNA levels. Patients without a molecular response had shorter progression-free and overall survival compared with molecular responders [5.2 vs. 14.5 and 8.4 vs. 18.7 months; HR 5.36; 95% confidence interval (CI), 1.57-18.35; P = 0.007 and HR 6.91; 95% CI, 1.37-34.97; P = 0.02, respectively], which was detected on average 8.7 weeks earlier and was more predictive of clinical benefit than CT imaging. Expansion of T cells, measured through increases of T-cell receptor productive frequencies, mirrored ctDNA reduction in response to therapy. We validated this approach in an independent cohort of patients with early-stage non-small cell lung cancer (N = 14), where the therapeutic effect was measured by pathologic assessment of residual tumor after anti-PD1 therapy. Consistent with our initial findings, early ctDNA dynamics predicted pathologic response to immune checkpoint blockade. These analyses provide an approach for rapid determination of therapeutic outcomes for patients treated with immune checkpoint inhibitors and have important implications for the development of personalized immune targeted strategies.Significance: Rapid and sensitive detection of circulating tumor DNA dynamic changes and T-cell expansion can be used to guide immune targeted therapy for patients with lung cancer.See related commentary by Zou and Meyerson, p. 1038.

Project description:The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, analyses of tumor biopsies are the only parameter used to guide prognosis to ICI therapy. Tumor biopsies, however, are often difficult to obtain and tissue-based biomarkers are limited by intratumoral heterogeneity and temporal variability. In response, there has been a growing emphasis on the development of "liquid biopsy"‒ derived biomarkers, which offer a minimally invasive means to dynamically monitor the immune status of NSCLC patients either before and/or during the course of treatment. Here we review studies in which multiple blood-based biomarkers encompassing circulating soluble analytes, immune cell subsets, circulating tumor DNA, blood-based tumor mutational burden, and circulating tumor cells have shown promising associations with the clinical response of NSCLC patients to ICI therapy. These investigations have unveiled compelling correlations between the peripheral immune status of patients both before and during ICI therapy and patient outcomes, which include response rates, progression-free survival, and overall survival. There is need for rigorous validation and standardization of these blood-based assays for broader clinical application. Integration of multiple blood-based biomarkers into comprehensive panels or algorithms also has the potential to enhance predictive accuracy. Further research aimed at longitudinal monitoring of circulating biomarkers is also crucial to comprehend immune dynamics and resistance mechanisms and should be used alongside tissue-based methods that interrogate the tumor microenvironment to guide treatment decisions and may inform on the development of novel therapeutic strategies. The data reviewed here reinforce the opportunity to refine patient stratification, optimize treatments, and improve outcomes not only in NSCLC but also in the wider spectrum of solid tumors undergoing immunotherapy.

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Immune Checkpoint Blockade in Oncogene-Driven Non-Small-Cell Lung Cancer.

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