Short-course-based TNT with or without PD-1 inhibitor for pMMR locally advanced rectal cancer: Phase 2 results of a randomized trial (STELLAR II)

Med. 2025 Nov 14;6(11):100807. doi: 10.1016/j.medj.2025.100807. Epub 2025 Aug 21.

Abstract

Background: The therapeutic efficacy and mode of combining immunotherapy with neoadjuvant chemoradiotherapy in proficient mismatch repair (pMMR)/microsatellite stable (MSS) locally advanced rectal cancer (LARC) remain uncertain.

Methods: In this multicenter, randomized, seamless phase 2/3 trial (ClinicalTrials.gov: NCT05484024), eligible participants were randomly assigned (1:1) to receive short-course radiotherapy (SCRT) (5 Gy × 5), followed by 4 cycles of capecitabine and oxaliplatin or 6 cycles of leucovorin, oxaliplatin, and fluorouracil, with (iTNT group) or without (total neoadjuvant therapy [TNT] group) 4 cycles of sintilimab. Following neoadjuvant therapy, participants underwent surgery or a watch-and-wait strategy based on clinical complete response. The primary endpoints were the complete response (CR) rate for phase 2 and the 3-year disease-free survival (DFS) rate for phase 3.

Findings: 218 patients were randomized to the iTNT group (n = 110) and the TNT group (n = 108). All patients completed SCRT, with 88.2% in the iTNT group and 93.5% in the TNT group completing 4 cycles of neoadjuvant treatment. The CR rate was significantly higher in the iTNT group (45.5% vs. 25.0%; p = 0.003). Grade 3-4 treatment-related adverse events were reported in 34.5% of the iTNT group and 19.4% of the TNT group (p = 0.012), with thrombocytopenia, diarrhea, leukopenia, and neutropenia being the most frequently observed. Grade 3-4 immune-related adverse events occurred in 5.5% of patients in the iTNT group.

Conclusions: The addition of the PD-1 inhibitor sintilimab significantly enhances the CR rate compared to SCRT-based TNT, with favorable tolerability in patients with pMMR/MSS LARC.

Funding: This work was funded by the National Natural Science Foundation of China (82473248) and the Shenzhen Medical Research Fund (C2301001).

Keywords: PD-1 inhibitor; Translation to patients; complete response; rectal cancer; short-course radiotherapy; total neoadjuvant therapy.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase II
  • Multicenter Study
  • Clinical Trial, Phase III

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized* / administration & dosage
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Capecitabine / administration & dosage
  • DNA Mismatch Repair
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Immune Checkpoint Inhibitors* / administration & dosage
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Leucovorin / administration & dosage
  • Male
  • Middle Aged
  • Neoadjuvant Therapy* / methods
  • Oxaliplatin / administration & dosage
  • Rectal Neoplasms* / genetics
  • Rectal Neoplasms* / mortality
  • Rectal Neoplasms* / pathology
  • Rectal Neoplasms* / therapy

Substances

  • Oxaliplatin
  • Capecitabine
  • Immune Checkpoint Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Leucovorin
  • Fluorouracil

Associated data

  • ClinicalTrials.gov/NCT05484024