Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.
Ronan J KellyBlair V LandonBlair A JobeDipika SinghJenna V CanzonieroArchana BalanRussell K HalesK Ranh VoongRichard J BattafaranoBlair A JobeStephen C YangStephen BroderickJinny HaKristen A MarroneGavin PereiraNisha RaoAryan BoroleKaterina KaraindrouZineb BelcaidJames R WhiteSuqi KeAli I AmjadBenny WekslerEun Ji ShinElizabeth ThompsonKellie N SmitDrew M PardollChen HuJosephine L FelicianoValsamo AnagnostouVincent K LamPublished in: Nature medicine (2024)
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 .
Keyphrases
- circulating tumor
- papillary thyroid
- locally advanced
- rectal cancer
- free survival
- cell free
- circulating tumor cells
- squamous cell
- immune response
- lymph node
- randomized controlled trial
- clinical trial
- childhood cancer
- lymph node metastasis
- poor prognosis
- squamous cell carcinoma
- study protocol
- oxidative stress
- small molecule
- young adults
- phase iii
- dendritic cells
- dna methylation
- cancer therapy
- gene expression
- phase ii
- peripheral blood
- tyrosine kinase