Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial

Cancer Cell. 2024 Sep 9;42(9):1570-1581.e4. doi: 10.1016/j.ccell.2024.07.004. Epub 2024 Aug 1.

Abstract

Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.

Keywords: PD-1 antibody; combined positive score; complete response; locally advanced rectal cancer; neoadjuvant chemoradiotherapy; proficient mismatch repair.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized* / administration & dosage
  • Antibodies, Monoclonal, Humanized* / adverse effects
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Chemoradiotherapy / methods
  • DNA Mismatch Repair
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Immune Checkpoint Inhibitors / therapeutic use
  • Male
  • Middle Aged
  • Neoadjuvant Therapy* / methods
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Rectal Neoplasms* / drug therapy
  • Rectal Neoplasms* / immunology
  • Rectal Neoplasms* / pathology
  • Rectal Neoplasms* / therapy

Substances

  • Antibodies, Monoclonal, Humanized
  • sintilimab
  • Programmed Cell Death 1 Receptor
  • PDCD1 protein, human
  • Immune Checkpoint Inhibitors