Editor's Note: The neoadjuvant treatment landscape for locally advanced rectal cancer (LARC) continues to evolve, with emerging research indicating that incorporating immunotherapy can significantly enhance the pathological complete response (pCR) rate. However, many unanswered questions remain in the "immunotherapy plus" treatment model, including the selection between short-course and long-course radiotherapy, the sequencing or concurrent administration of therapies, and the advantages and disadvantages of different combination strategies, drugs, and treatment cycles. Further research is needed to address these uncertainties.

At the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2025), the UNION TNT study, led by Dr. Tao Zhang and Dr. Kaixiong Tao from the Multidisciplinary Gastrointestinal Tumor Team at Union Hospital, Huazhong University of Science and Technology, was selected as a poster abstract (Abstract #192). This study explored the efficacy and safety of short-course radiotherapy (SCRT) combined with targeted therapy, immunotherapy, and chemotherapy as a total neoadjuvant therapy for high-risk LARC patients. Oncology Frontier is honored to present an in-depth analysis and expert commentary on this study by Dr. Zhenyu Lin, a key member of the research team.

Dr. Zhenyu Lin：The integration of radiotherapy and immunotherapy in neoadjuvant treatment has been a major focus in rectal cancer research. Several clinical studies, including the Phase II and III UNION trials, have demonstrated that combining chemotherapy and immune checkpoint inhibitors (ICIs) with either short-course or long-course radiotherapy significantly improves pathological complete response rates. Long-term survival data from these studies are still being followed up. As precision medicine continues to guide treatment decisions, it is clear that the “immunotherapy plus” model is particularly suitable for high-risk patients who require tumor downstaging or sphincter preservation. Therefore, one of the key areas of research has been enhancing treatment efficacy for this patient subgroup by optimizing combination strategies.

Anti-angiogenic therapy has emerged as a crucial partner for immunotherapy. By normalizing tumor vasculature, reducing interstitial pressure, improving drug delivery, and modulating the tumor immune microenvironment, angiogenesis inhibitors enhance the effectiveness of immune checkpoint inhibitors. In metastatic colorectal cancer (CRC), multiple clinical studies, including the REGONIVO trial, have demonstrated that combining anti-angiogenic therapy with ICIs improves objective response rates, particularly in patients without liver metastases. This naturally raises the question: can the combination of anti-angiogenic and immunotherapy further improve outcomes in neoadjuvant treatment for locally advanced rectal cancer?

At ESMO GI 2024, a Belgian-led Phase II multicenter trial, the REGINA study, reported interim efficacy results on neoadjuvant anti-angiogenic plus immunotherapy in intermediate-risk stage II and III rectal cancer. Patients received regorafenib in combination with nivolumab and short-course radiotherapy. Among 36 enrolled patients, 30 were evaluable for mismatch repair proficiency (pMMR/MSS). A total of 24 patients underwent surgery, with six achieving pCR (25%) and 14 achieving major pathological response (MPR, 58%). Additionally, five patients with clinical complete response (cCR) opted for a watch-and-wait strategy, leading to an overall CR rate of 36.6%.

At ESMO 2024, a team from West China Hospital led by Professor Zhiping Li presented a study investigating SCRT combined with fruquintinib and toripalimab as neoadjuvant therapy for locally advanced rectal cancer, reporting a pCR rate of 37.5%, closely aligning with the results of the REGINA study. These findings have reinforced our confidence in incorporating an anti-angiogenic and immunotherapy combination into the UNION TNT trial for high-risk patients receiving short-course radiotherapy.

With all patient enrollment now completed, the UNION TNT study includes a high-risk cohort, with over half of patients classified as clinical T4 and 44% as clinical N2, in addition to other adverse prognostic factors. For this high-risk population, total neoadjuvant therapy (TNT) with radiotherapy and chemotherapy is already considered the standard of care. The UNION TNT study builds upon the Phase III UNION trial by incorporating an anti-angiogenic small-molecule TKI (fruquintinib) into the total neoadjuvant regimen.

The preliminary efficacy analysis is highly encouraging. Among 19 patients who underwent surgery, all achieved R0 resection (100%), and the CR rate reached 65% (1 cCR + 12 pCR out of 20 patients). This significantly exceeds the 30% CR rate observed in previous studies of TNT with chemoradiotherapy alone. If validated in larger patient cohorts, this approach could offer an enhanced neoadjuvant strategy for high-risk rectal cancer patients.

Beyond efficacy, it is also crucial to address treatment-related toxicity. The completion rate of neoadjuvant therapy was generally acceptable, indicating that the combination regimen was feasible for clinical implementation. In terms of adverse events, 16 patients (47.06%) experienced Grade 3/4 toxicities, a rate comparable to prior studies such as the TROCH trial. However, it is noteworthy that four cases of bowel perforation were reported, all of whom achieved pCR post-surgery. This finding underscores the potential trade-off between enhanced tumor shrinkage and increased risk of serious adverse events, necessitating careful risk-benefit assessment in clinical practice.

The preliminary results of the UNION TNT study suggest that adding an anti-angiogenic therapy to the established short-course radiotherapy and immunotherapy combination further improves pCR rates in high-risk locally advanced rectal cancer, with an overall manageable safety profile. Ongoing follow-up and further data analysis will be essential to confirm the durability of these findings and determine the long-term benefits of this approach.