Effect of Neoadjuvant Chemoradiotherapy with or without PD-1 Antibody Sintilimab in PMMR Locally Advanced Rectal Cancer: A Randomized Clinical Trial

Oncology Life Sciences Immunology Gastroenterology Medicine
neoadjuvant chemoradiotherapy PD-1 antibody locally advanced rectal cancer sintilimab complete response rate

The Role of Neoadjuvant Chemoradiotherapy Combined or Not Combined with PD-1 Antibody Sintilimab in pMMR Locally Advanced Rectal Cancer: Results of a Randomized Clinical Trial

Background and Significance

The management of rectal cancer and organ preservation has always been quite challenging, especially in cases of locally advanced rectal cancer (LARC), due to complex anatomical structures, high rates of postoperative complications, and significantly increased risks of local recurrence and distant metastasis. Traditionally, LARC patients often receive neoadjuvant chemoradiotherapy (NACRT) based on fluoropyrimidine and oxaliplatin to reduce local recurrence risks. In recent years, the emerging total neoadjuvant therapy (TNT) aims to improve the rate of clinical complete response (CCR) and enhance the success rate of organ preservation strategies. The addition of PD-1 inhibitors has shown significant effects in dMMR (Mismatch-Repair Deficient) and high microsatellite instability (MSI-H) rectal cancers. However, in pMMR (Proficient Mismatch Repair) patients, the efficacy of PD-1 antibodies as monotherapy is limited. Therefore, the combination of immune checkpoint inhibitors (ICIs) with radiotherapy has become a current research hotspot, and multiple small single-arm clinical trials and randomized controlled trials (RCTs) are underway.

Study Source

This study, led by Xiao Wei-Wei and Chen Gong from the Sun Yat-sen University Cancer Prevention Center in China, was published in the September 2024 issue of the journal “Cancer Cell.” The team at Sun Yat-sen University conducted a Phase II randomized clinical trial to evaluate the efficacy and safety of the PD-1 antibody Sintilimab combined with NACRT in treating pMMR LARC patients.

Study Methods

This study adopted a single-center, open-label, randomized controlled design. A total of 134 pMMR LARC patients were enrolled and randomly assigned to the NACRT treatment group (control group) and the NACRT + Sintilimab treatment group (experimental group). The primary outcome was the clinical complete response (CR) rate, with CR rates of 44.8% in the experimental group and 26.9% in the control group, showing a significant difference (p=0.031). To explore the potential predictive role of biomarkers, RNA sequencing was performed on tumor tissues before and after treatment to analyze gene expression and immune microenvironment changes.

Study Process and Experimental Design

  1. Patient Enrollment and Characteristics: From June 2020 to July 2022, 134 patients were enrolled in the study, with balanced distributions in terms of gender, age, and tumor staging between the two groups.

  2. Treatment Process: Patients in the experimental group received four cycles of oxaliplatin and capecitabine chemotherapy along with four doses of Sintilimab, and all patients completed the prescribed radiotherapy doses. Treatment compliance was high, with 94% of patients completing all therapy sessions.

  3. RNA Sequencing Analysis: RNA sequencing was conducted on tumor tissues from the experimental and control groups, revealing a significant enrichment of CD8+ T cells, NK cells, and other immune cells in the experimental group post-treatment, suggesting positive regulation of the immune microenvironment.

Study Results

  1. Clinical Response Rate: The CR rate in the experimental group was 44.8%, significantly higher than the 26.9% in the control group. Among patients with different PD-L1 expression levels, those with PD-L1 CPS ≥2 showed a significantly higher response to experimental treatment compared to the control group.

  2. Immune Microenvironment Analysis: RNA sequencing indicated a significant increase in immune scores and CD8+ T cells in tumor tissues of patients in the experimental group after treatment. Additionally, positive PD-L1 expression correlated with increased tumor-infiltrating lymphocytes, further supporting the immune activation mechanism of this therapy.

  3. Resistance Mechanism Exploration: Further analysis revealed that high expression of PDGFA and IL2RG genes in non-CR patients was closely related to treatment resistance, and these genes were associated with increased immunosuppressive cells, providing potential targets for subsequent combinations of anti-tumor drugs.

Adverse Reactions and Safety

Most adverse reactions in the experimental group were grade 1-2, with a few grade 3-4 adverse reactions, including neutropenia, diarrhea, and elevated liver enzymes. Although there were immune-related adverse reactions, overall tolerability was good, and no treatment-related deaths occurred.

Research Conclusion

The results of this Phase II RCT indicate that the combination of PD-1 antibody Sintilimab with NACRT significantly improves the CR rate in pMMR LARC patients with manageable safety. PD-L1 CPS scoring may become a predictive marker for the efficacy of this combined therapy, providing guidance for subsequent personalized treatment. Meanwhile, the active expression of PD-L1 in the immune microenvironment and the significant increase in CR rate among patients with high CPS underscore the clinical value of this marker in pMMR LARC.

Academic Value and Outlook

This study is the first to verify through RCT the efficacy of combining PD-1 antibody with NACRT in pMMR LARC patients, offering new hope for the immunotherapy of non-dMMR rectal cancer. By analyzing the immune microenvironment and resistance gene expression through RNA sequencing, the study aids in understanding the synergistic mechanisms of PD-1 inhibitors and radiotherapy. Future efforts should aim to confirm these findings through Phase III RCTs and explore the combination of anti-PDGFA and IL2RG targeting drugs with NACRT to further enhance efficacy. This research provides strong evidence for the application of PD-1 inhibitors in pMMR rectal cancer, holding significant clinical translational importance.

Research Highlights

  1. Significantly Increased CR Rate: The addition of Sintilimab raised the CR rate to 44.8%, showing a notable advantage compared to the 26.9% achieved by NACRT alone.
  2. Potential Predictive Value of PD-L1 as a Biomarker: PD-L1 CPS scoring provides a reference for selecting benefiting patients, with CPS ≥2 patients showing higher CR rates in the experimental group.
  3. Discovery of Resistance Genes and Immune Microenvironment Changes: The study revealed the roles of PDGFA and IL2RG in treatment resistance, and the regulation of the immune microenvironment provides directions for further research.

Future Research Directions

Considering this study as a Phase II clinical trial, further multicenter Phase III randomized controlled trials are needed to validate the efficacy of PD-1 antibodies in pMMR LARC patients. Additionally, based on current findings, the exploration of combining anti-angiogenic drugs or Treg inhibitors with PD-1 antibodies is warranted to achieve higher CR rates. Moreover, the different impacts of radiotherapy regimens on the immune microenvironment and their adaptability with ICI combined therapy merit in-depth investigation.