Neoadjuvant Immunotherapy in Esophageal Cancer: ctDNA Clearance Reflects Neoantigen-Specific T Cell Responses
This phase Ib trial evaluated neoadjuvant nivolumab alone or with LAG-3 inhibitor relatlimab plus chemoradiotherapy in 32 patients with resectable gastroesophageal cancer, achieving pathological complete response rates of 40% and 21% respectively. ctDNA analysis showed that patients with undetectable ctDNA after immune checkpoint induction and postoperatively had significantly longer recurrence-free and overall survival. Critically, ctDNA clearance correlated with neoantigen-specific T cell responses, linking molecular and functional immune monitoring in the neoadjuvant setting.
The original study
Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.
- Authors
- Kelly RJ, Landon BV, Zaidi AH, Singh D, Canzoniero JV, Balan A, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase I, Journal Article
- PMID
- 38504015
Original 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 .