Journal article
Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses
Nature medicine, v 30(4), pp 1023-1034
01 Apr 2024
PMID: 38504015
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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
Details
- Title
- Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses
- Creators
- Ronan J. Kelly - Baylor University Medical CenterBlair V. Landon - Sidney Kimmel Comprehensive Cancer CenterAli H. Zaidi - Allegheny Health NetworkDipika Singh - Sidney Kimmel Comprehensive Cancer CenterJenna V. Canzoniero - Sidney Kimmel Comprehensive Cancer CenterArchana Balan - Sidney Kimmel Comprehensive Cancer CenterRussell K. Hales - Sidney Kimmel Comprehensive Cancer CenterK. Ranh Voong - Sidney Kimmel Comprehensive Cancer CenterRichard J. Battafarano - Johns Hopkins MedicineBlair A. Jobe - Allegheny Health NetworkStephen C. Yang - Johns Hopkins MedicineStephen Broderick - Johns Hopkins MedicineJinny Ha - Johns Hopkins MedicineKristen A. Marrone - Sidney Kimmel Comprehensive Cancer CenterGavin Pereira - Sidney Kimmel Comprehensive Cancer CenterNisha Rao - Sidney Kimmel Comprehensive Cancer CenterAryan Borole - Sidney Kimmel Comprehensive Cancer CenterKaterina Karaindrou - Sidney Kimmel Comprehensive Cancer CenterZineb Belcaid - Sidney Kimmel Comprehensive Cancer CenterJames R. White - Sidney Kimmel Comprehensive Cancer CenterSuqi Ke - Sidney Kimmel Comprehensive Cancer CenterAli I. Amjad - Allegheny Health NetworkBenny Weksler - Allegheny Health NetworkEun Ji Shin - Johns Hopkins MedicineElizabeth Thompson - Johns Hopkins MedicineKellie N. Smith - Johns Hopkins UniversityDrew M. Pardoll - Johns Hopkins UniversityChen Hu - Johns Hopkins UniversityJosephine L. Feliciano - Sidney Kimmel Comprehensive Cancer CenterValsamo Anagnostou - Johns Hopkins UniversityVincent K. Lam - Sidney Kimmel Comprehensive Cancer Center
- Publication Details
- Nature medicine, v 30(4), pp 1023-1034
- Publisher
- Nature Publishing Group US
- Number of pages
- 12
- Grant note
- Cancer Research Institute (CRI) (https://doi.org/10.13039/100000884) CA121113; UG1CA233259; R37 CA251447 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) Conquer Cancer Foundation (Conquer Cancer Foundation of the American Society of Clinical Oncology) (https://doi.org/10.13039/100000982)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Surgery
- Web of Science ID
- WOS:001187561800003
- Scopus ID
- 2-s2.0-85188082169
- Other Identifier
- 991021960648904721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
Highly Cited Paper
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Medicine, Research & Experimental