The UNION trial: open the door to immune checkpoint inhibitors for proficient mismatch repair/microsatellite stability rectal cancer?
Editorial Commentary

The UNION trial: open the door to immune checkpoint inhibitors for proficient mismatch repair/microsatellite stability rectal cancer?

Yoshinori Kagawa1 ORCID logo, Jun Watanabe2 ORCID logo, Koji Ando3 ORCID logo

1Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan; 2Department of Colorectal Surgery, Kansai Medical University, Hirakata, Japan; 3Department of Surgery and Science, Kyushu University, Fukuoka, Japan

Correspondence to: Yoshinori Kagawa, MD, PhD. Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan. Email: yoshinori.kagawa@oici.jp.

Comment on: Lin ZY, Zhang P, Chi P, et al. Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial. Ann Oncol 2024;35:882-91.

Keywords: Immune checkpoint inhibitor; locally advanced rectal cancer (LARC); total neoadjuvant therapy (TNT); radiotherapy; proficient mismatch repair or microsatellite stable

Received: 24 November 2024; Accepted: 27 February 2025; Published online: 07 May 2025.

doi: 10.21037/actr-24-253

In recent years, locally advanced rectal cancer (LARC) has been treated with total neoadjuvant therapy (TNT) to improve short- and long-term outcomes, such as local recurrence, distant metastasis, disease-free, and overall survival (1). Patients who achieve a clinical complete response (cCR) with TNT can be managed with nonoperative management (NOM), which avoids surgery, preserves the rectum, and maintains quality of life (QoL), without compromising long-term prognosis.

However, the current TNT achieves a modest cCR rate of 47–53% in OPRA trial; therefore, ongoing research aims to enhance further tumor regression and preserving organ function while prolonging survival.

Monoclonal antibodies targeting the programed death receptor 1 (PD-1) and its ligand 1 (PD-L1) have shown considerable efficacy for treating several malignant tumors (2).

Tumor tissues of the MSI-H type (high microsatellite instability) exhibit a substantial mutational burden due to the occurrence of deficient mismatch repair (dMMR) and an increase in short tandem repeat DNA sequences. This results in high immunogenicity of tumor antigens and an increased immune response, which in turn facilitates the infiltration of CD8+ T cells into the tumor microenvironment. PD-L1 and other immune checkpoints in the tumor microenvironment prevent and inhibit immune suppression, resulting in better response to PD-1/PD-L1 monotherapy. However, microsatellite stability (MSS) tumors exhibit limited sensitivity to PD-1/PD-L1 monotherapy with PD-1/PD-L1 monoclonal antibodies due to the absence of the characteristics (3).

In light of these considerations, the question of how to increase the efficacy of immunotherapy for proficient mismatch repair (pMMR) rectal cancer has emerged as an important area of research.

Preclinical studies have shown that radiotherapy can increase the body’s antitumor immunity (2). The cellular stress induced by regional radiotherapy (RT) in the primary tumor will result in the formation of an inflammatory milieu comprising of cytokines and damage-associated molecules, as well as the release of tumor peptides. Dendritic cells loaded with tumor peptides will cross-present them to naïve CD8+ T cells within the tumor microenvironment, thereby inducing their activation. The activated CD8+ T cells will mediate local and distant tumor cytotoxicity (2). It has also been shown to promote the infiltration of tumor-infiltrating lymphocytes, expand the immune reservoir of T cells to promote vaccine effects in situ, and generate “abscopal responses” by attacking activated T cells (4). Radiotherapy can also induce the upregulation of PD-L1 expression in tumor tissues, promote the normalization of tumor vasculature, and facilitate the delivery of immunotherapeutic monoclonal antibodies, which can lead to the transformation of “cold” tumors into “hot” tumors (5).

Camrelizumab, which was launched in China on May 29, 2019, is used to treat complicated or refractory classical Hodgkin’s lymphoma after at least second-line chemotherapy. Subsequently, camrelizumab was approved in China as second-line treatment for advanced hepatocellular carcinoma on March 4, 2020. Camrelizumab is currently being investigated in clinical trials for treating advanced solid tumors, including liver, gastric, esophageal, and lung cancers, all of which have demonstrated clinical efficacy.

A phase III study of camrelizumab, a humanized anti-PD-1 monoclonal antibody, as a TNT enhancer for LARC was published in 2024 (6). Lin et al. conducted a multicenter, randomized, open-label phase III study, the UNION trial, to assess the efficacy and safety of combining camrelizumab with CAPOX (capecitabine + oxaliplatin) (two cycles) following short-course radiotherapy (SCRT) (a total of 25 Gy over 5 days) compared with CAPOX alone following long-course chemoradiotherapy (a total dose of 50.4 Gy over 28 days with concomitant oral capecitabine) in patients with LARC (6).

Radical surgery, according to the principles of total mesorectal excision, was mandatory within 10 weeks of the end of preoperative radiotherapy. Postoperative adjuvant chemotherapy was administered 4–6 weeks after surgery. In the camrelizumab + CAPOX group, patients received 6 cycles of combination therapy with camrelizumab and CAPOX, followed by camrelizumab monotherapy (up to 17 times in total). Patients in the CAPOX alone group received 6 cycles of CAPOX.

The pathological complete response (pCR) rate was significantly higher in the camrelizumab + CAPOX group than in the CAPOX alone group (39.8% vs. 15.3%). The addition of two cycles of camrelizumab + CAPOX after SCRT demonstrated high efficacy in patients with pMMR/MSS LARC. This treatment offers patients with LARC the opportunity to preserve their organs through NOM. No unexpected toxicities were observed, and the safety profile was manageable (6).

The UNION trial compared SCRT followed by immune checkpoint inhibitor (ICI) + chemotherapy with course radiotherapy (CRT) followed by chemotherapy, meaning there were two key differences between the treatment arms—immunotherapy use and radiotherapy type. This makes it difficult to isolate the effect of immunotherapy alone on treatment outcomes.

Preliminary data have shown that low-dose chemotherapy is generally more effective in stimulating the immune system compared to high-dose chemotherapy. Chemotherapy can selectively kill antitumor immune cells, which can further weaken the response to ICI (2).

The NRG-GI002 trial, a randomized controlled study on TNT for LARC, compared CRT with or without ICI after eight cycles of FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin regimen 6 cycles). The trial showed a pCR rate of CRT plus pembrolizumab vs. control (31.9% vs. 29.4%), with no evidence of ICI efficacy (7). Therefore, FOLFOX for six cycles before ICI administration may have had a killing effect on immune cells, such as CD8+ T cells. High doses of cytotoxic drugs can inactivate immune cells, limiting the efficacy of immunotherapy (8). In this UNION trial, CAPOX was administered only twice, suggesting the potential for nonintensive chemotherapy to enhances the effects of immunotherapy. Further research is required to account for confounding factors.

Radiotherapy can effectively activate the tumor’s immune microenvironment through several mechanisms, including inducing tumor antigen release, increasing tumor cell immunogenicity, activating immune cells, secreting immune factors, and promoting the presentation of tumor-related antigens (9). This phenomenon can be explained in the literature as a consequence of the transformation of inherently “cold” tumors (pMMR/MSS) into “hot” tumors (MSI-H/dMMR), which can subsequently benefit from ICI therapy. In VOLTAGE-A, nivolumab was administered 14 days after long-term CRT for five cycles, with a pCR rate of 30% (10). In the NECTAR trial, tislelizumab administered concomitantly with the start of long-term CRT resulted in a higher rate of pCR (40%) (11). In the STARS-RC03 trial, six cycles of CAOPOX plus sintilimab after a long course of CRT resulted in a cCR rate of 51.4%, a pCR rate of 26.1%, and an NOM rate of 32.4% (12). The synergistic effects of radiotherapy and ICI are superior with SCRT than those of LCRT in terms of milder treatment-related lymphopenia, accelerated antigen release, and increased tumor-infiltrating lymphocytes. In the Averectal trial, six cycles of FOLFOX plus avelumab after SCRT resulted in a pCR rate of 37.5% (13). In the UNION trial, two cycles of camrelizumab along with CAPOX after SCRT resulted in a pCR of 39.8% (6). The TORCH trial, which evaluated SCRT and CAPOX + ICI sequencing, compared SCRT followed by six cycles of CAPOX and toripalimab vs. two cycles of CAPOX and toripalimab followed by SCRT followed by four cycles of CAPOX and toripalimab (14). The pCR rate was 50% in both arms, and the cCR rate was 43.5% vs. 35.6%. Six cycles of CAPOX and toripalimab after SCRT were superior in terms of cCR and thrombocytopenia rates. In the PRECAM trial, two cycles of CAPOX and six cycles of envafolimab were administered after SCRT, resulting in an unprecedented pCR rate of 62.5% (15). This outcome was likely due to minimizing the number of chemotherapy cycles and allowing sufficient time for restaging after SCRT.

The latest guidelines recommend an MMR status-oriented approach for patients with LARC (16). Immune checkpoint inhibitor monotherapy in patients with LARC and dMMR achieved cCR, preserved organ function, and sustained QoL (17). Furthermore, the OPRA trial illustrated the potential for approximately 50% NOM following TNT in patients with pMMR/MSS, indicating that morbidity could be avoided while maintaining disease control in LARC. Therefore, biomarkers that can more accurately predict the efficacy of immunotherapy are useful as a guide for treatment strategies at the time of diagnosis and/or disease stage. To facilitate precision oncology in LARC, international collaborations have been established to integrate multiomics data from ongoing TNT clinical trials. This collaboration will cover multiomics data, including genomics, transcriptomics, proteomics, pathomics, radionics, clinical features, and QoL data. The implementation of an artificial intelligence (AI)-based model for the precise and targeted treatment of LARC with a supercomputing system will facilitate the provision of precision medicine for individual patients (1).

The combination of TNT and immunotherapy has promising potential for treating LARC from the results of clinical trials (6,7,10-25) (Table 1). This approach is expected to overcome challenges associated with immunotherapy and offer opportunities to preserve organ function and maintain QoL in patients with pMMR/MSS LARC. The above findings should be validated in large, randomized, controlled clinical trials (Table 2). These trials should focus on optimizing treatment modalities, evaluating clinical efficacy, and screening for markers. This study aims to translate promising therapeutic efficacy into tangible improvements in patient survival and treatment experience throughout the process.

Table 1

Summary of the efficacy of neoadjuvant radiotherapy combined with immune checkpoint inhibitors for pMMR/MSS LARCs in clinical trials

Trial name and number Phase Case number Patients characteristics Treatment pCR (%) cCR (%) Area Year
UNION (6) NCT04928807 III 231 T3–4/N+ SCRT + (CAPOX + Camreli) × 2, LCRT + CAPOX × 2 39.8, 15.3 41.6, 18.6 China 2024
PRECAM (15) NCT05216653 II 32 T3–4/N+ SCRT + CAPOX × 2/Envafo (qw) × 6 62.5 NA China 2024
TORCH (14) NCT04518280 II 62, 59 T3–4/N+ SCRT + (CAPOX + Toripali) × 6, (CAPOX + Toripali) × 2 + SCRT + (CAPOX + Toripali) × 4 50, 50 43.5, 35.6 China 2024
Wuhan Concord II (18) NCT04231552 II 30 High-risk T3–4/N+ SCRT + (CAPOX + Camreli) × 2 46 NA China 2021
Averectal (13) NCT03503630 II 40 Stage III 91% SCRT + (FOLFOX + Avelu) × 6 37.5 – Europe 2024
TARZAN (19) NCT04017455 II 38 T3ab, N0–1, MRF− SCRT + Atezo + Bev for 3 cycles – 45 The Netherlands 2024
REGINA (20) NCT04503694 II 36 cT3/T4a and Nany or cT1–2 and N+ SCRT + nivolumab + regorafenib 25 – Belgium 2024
STARS-RC03 (12) NCT04906044 II 30 T3–4/N+ LCRT + (CAPOX + Sintili) × 3 or 6 26.1 51.4 China 2023
DUREC NCT04293419 II 61 T3–4/N+ FOLFOX × 6 + Durva × 6 + LCRT 39 – Spain 2023
PKUCH 04 (21) NCT04340401 II 25 N2 =76%, MRF+ 56% (CAPOX + Camreli) × 3 + LCRT + CAPOX × 2 33.1 48 China 2022
NRG-GI002 (7) NCT02921256 II 90, 96 T3–4/N+ FOLFOX 8 cycles + LCRT/Pem-bro six cycles, FOLFOX 8 cycles + LCRT 31.9, 29.4 13.6, 13.9 USA 2021
NECTAR (11) NCT04911517 II 50 T3–4 92%, N+ 64% LCRT/Tisleli 3 cycles 40 39.1 China 2024
R-IMMUNE (22) NCT03127007 Ib/II 37 Stage III 84% LCRT + Atezo 4 cycles 24 NA North America 2023
AVANA (23) NCT03854799 II 101 Stage III 94% LCRT + Avelu for 6 cycles 23 NA Italy 2021
PANDORA (24) NCT04083365 II 55 T3–4 95%, N+ 80% LCRT + Nivo 3 cycles 34.5 10.9 Italy 2023
NSABP FR-2 (25) NCT03102047 II 45 Stage III 89% LCRT + Durva for 4 cycles 22.2 31.1 USA 2022
VOLTAGE-A (10) NCT02948348 Ib 37 Stage III: 23% LCRT + Nivo 5 cycles 30 NA Japan 2022

Atezo, atezolizumab; Avelu, avelumab; Camreli, camrelizumab; cCR, clinical complete response; CAPOX, capecitabine + oxaliplatin; Durva, durvalumab; Envafo, envafolimab; FOLFOX, fluorouracil + oxaliplatin; LARC, locally advanced rectal cancer; LCRT, long-course chemoradiotherapy; MSS, microsatellite stable; Nivo, nivolumab; pCR, pathological complete response; Pem-bro, pembrolizumab; pMMR, proficient mismatch repair; SCRT, short-course radiotherapy; Sintili, sintilimab; Tisleli, tislelizumab; Toripali, toripalimab.

Table 2

Summary of basic information from ongoing clinical trials on neoadjuvant radiotherapy combined with immune checkpoint inhibitors for pMMR/MSS LARC

Trial name and number Phase Case number Patients’ characteristics Treatment Primary end point Area Year
TIMENT-R NCT05507112 II 100 T3–4/N+ LCRT + 8–12 W Tisleli × 3 + TME, LCRT + 8–12 W + TME pCR China 2022
Ave-Rec NCT03299660 II 37 T3b–4/N1–2 LCRT + Avelu × 4 pCR Australia 2023
Beijing Friendship III NCT05245474 III 186 T3–4/N+ LCRT/Tisleli × 3, LCRT + Tisleli × 3, LCRT pCR China 2023
CHINOREC NCT04124601 II 80 T3–4/N+ LCRT/(Ipili × 1 + Nivo × 3) AEs, mrTRG, pTRG Austria 2022
CHOICE II NCT05215379 II-III 180 T1-3aN0-1M0 LCRT + CAPOX × 2, LCRT/Sintili × 2 + (CAPOX + Sintili) × 2 cCR China 2022
STELLAR II NCT05484024 III 588 T3–4/N+ SCRT + (CAPOX × 4/FOLFOX × 6)/Sintili × 4, SCRT + CAPOX × 4/FOLFOX × 6 CR China 2023
Zhejiang Tumor NCT04663763 II 40 T3–4/N+ SCRT + (CAPOX + Sinitili) × 4 pCR China 2023
N-PRC NCT05576480 II 55 T3–4/N+ (SCRT + Penpuli) + (CAPOX + Penpuli) × 4 pCR China 2023
PRECAM-R NCT05752136 III 108 cT2-4a N+ and cT3/T4a N0 SCRT + CAPOX × 2, SCRT + CAPOX × 2/Evafo × 6 pCR China 2023
PRIME-RT NCT04621370 II 48 cT3b+, N+, and EMVI+ or low rectal tumor (SCRT + FOLFOX × 6)/Durva, (LCRT + FOLFOX × 4)/Durva CR United Kingdom and Northern Ireland 2020
TNTi NCT06229041 III 472 T4b/N2/MRF+/EMVI+/LLND+ TNT + Camreli (details not shown), TNT (details not shown) pCR China 2023
PEMREC NCT04109755 II 25 T3–T4 N0 or T any, or N1–2 SCRT + Pem-bro × 4 pTRG Switzerland 2019

AEs, adverse events; Avelu, avelumab; Camreli, camrelizumab; CAPOX, capecitabine + oxaliplatin; cCR, clinical complete response; Durva, durvalumab; FOLFOX, fluorouracil + oxaliplatin; Ipili, ipilimumab; LARC, locally advanced rectal cancer; LCRT, long-course chemoradiotherapy; mrTRG, MRI-based tumor regression grades; MSS, microsatellite stable; Nivo, nivolumab; pCR, pathological complete response; Pem-bro, pembrolizumab; Penpuli, penpulimab; pMMR, proficient mismatch repair; pTRG, pathological tumor regression grades; SCRT, short-course radiotherapy; Sintili, sintilimab; Tisleli, tislelizumab.

For patients with pMMR/MSS LARC, developing a method for using TNT and immune checkpoint inhibitors could be key to curing the disease without surgery.

Acknowledgments

We are grateful for the support of Yoshimi Shinomiya from the Osaka General Medical Center.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-253/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-253/coif). Y.K. reports payments or honoraria from Lilly, Sanofi, Takeda, Merck, Taiho, MSD, Chugai, Bayer, and Ono. J.W. reports payments or honoraria from Johnson & Johnson, Medtronic, Eli Lilly, and Takeda Pharmaceuticals, TERUMO, and Stryker Japan. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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doi: 10.21037/actr-24-253
Cite this article as: Kagawa Y, Watanabe J, Ando K. The UNION trial: open the door to immune checkpoint inhibitors for proficient mismatch repair/microsatellite stability rectal cancer? AME Clin Trials Rev 2025;3:37.

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