Kelly, Landon, and Zaidi et al. reported the safety, feasibility, and efficacy of neoadjuvant nivolumab (Arm A) or nivolumab plus relatlimab (Arm B) combined with chemoradiotherapy in patients with resectable stage II/stage III gastroesophageal cancer. The primary endpoint of safety for Arm A was met, but required an amendment to mitigate toxicity in Arm B. The pCR rate was 40% for Arm A and 21.4% for Arm B, and the 2-year OS rates were 82.6% in Arm A and 93.8% in Arm B. Circulating tumor DNA (ctDNA) analysis was predictive of tumor regression, RFS, and OS, outperforming pCR and MPR. Neoantigen-specific T cell responses paralleled ctDNA kinetics.
Contributed by Shishir Pant
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 .
Author Info: (1) The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA. ronan.kelly@bswhealth.org. (2) The Sidney Kimmel Comprehensive Cancer Center, Johns Hop
Author Info: (1) The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA. ronan.kelly@bswhealth.org. (2) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (4) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (6) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (9) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (10) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (11) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (12) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (13) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (14) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (17) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (18) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (19) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (20) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. (22) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (23) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (24) Department of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (25) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (26) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (27) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (28) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. (29) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (30) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu. Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu. (31) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vklam@jhmi.edu.
