Logo image
Back
Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses
Journal article   Open access   Peer reviewed

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses

Ronan J. Kelly, Blair V. Landon, Ali H. Zaidi, Dipika Singh, Jenna V. Canzoniero, Archana Balan, Russell K. Hales, K. Ranh Voong, Richard J. Battafarano, Blair A. Jobe, …
Nature medicine, v 30(4), pp 1023-1034
01 Apr 2024
DOI: https://doi.org/10.1038/s41591-024-02877-z
PMID: 38504015
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1038/s41591-024-02877-zView
Published, Version of Record (VoR) Open

Abstract

631/208/69 692/308/2779/109/1941 692/308/575 Article Biomedical and Life Sciences Biomedicine Cancer Research General Infectious Diseases Metabolic Diseases Molecular Medicine Neurosciences
Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n  = 16) or nivolumab–relatlimab (Arm B, n  = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 . In a phase Ib trial, neoadjuvant nivolumab or nivolumab/relatlimab prior to chemoradiotherapy were well tolerated and liquid biopsy analyses show that undetectable ctDNA was associated with longer survival.

Metrics

16 Record Views
106 citations in Web of Science
55 citations in Scopus

Details

UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

Source: SDGs in the Output

InCites Highlights

Data related to this publication, from InCites Benchmarking & Analytics tool:

Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Logo image