Is preoperative immunotherapy promising for patients with proficient mismatch repair or microsatellite stable locally advanced rectal cancer?—a commentary on TORCH randomized phase 2 trial

For patients with resectable locally advanced rectal cancer (LARC) of clinical (c) stage T3 or T4 without distant metastasis, preoperative chemoradiotherapy (CRT) using radiotherapy (RT) plus concurrent fluoropyrimidine-based chemotherapy followed by total mesorectal excision (TME) has long been the standard treatment (1). Recently, total neoadjuvant therapy (TNT), which incorporates CRT and preoperative oxaliplatin-based chemotherapy before TME, has shown preferred outcomes and is emerging as the new standard for LARC (2-5). Patients achieving a clinical complete response (cCR) after preoperative treatment may avoid surgery through watch and wait or non-operative management (NOM), which spares permanent stoma and postoperative complications, such as voiding, urination, and sexual dysfunction, thereby preserving quality of life (6). The pathological complete response (pCR) rate of TNT surpasses that of CRT, estimated at 22.5–28.0% (2,3,5), with high organ preservation rates, also reported (6). Consequently, TNT holds promise as an organ-sparing therapy for patients with rectal cancer.

Immune checkpoint inhibitors (ICIs), which block cytotoxic T-lymphocyte associated protein-4, programmed cell death protein-1 (PD-1), and programmed death ligand 1 (PD-L1), have become standard therapies for various solid types (7,8). In colorectal cancer (CRC), ICIs have demonstrated considerable benefits for patients with microsatellite instability-high (MSI-H) or mismatch-repair deficient (dMMR) metastatic (m) CRC, whereas their benefits in microsatellite stable (MSS) or mismatch-repair proficient (pMMR) mCRC are limited (9). Approximately 40 trials have investigated neoadjuvant ICIs for early-stage resectable CRC, with some specifying MSI-H/dMMR status for inclusion, some designed exclusively for MSS/pMMR, and others being agnostic for MMR status (10). In resectable LARC, preoperative ICIs have shown promise in achieving high cCR rates, allowing NOM in MSI-H or dMMR cases (11). For MSS or pMMR LARC, several trials have been investigating the safety and efficacy of combining preoperative ICIs with RT (12-16). Although preoperative RT may modulate immune-related (ir) characteristics of LARC and potentially enhance immunotherapy responsiveness (17), the benefits of preoperative ICIs for these patients remain inconclusive (12-16).

Xia et al. conducted a prospective multicenter randomized phase 2 trial comparing short-course radiotherapy (SCRT) followed by consolidation immunochemotherapy with induction immunochemotherapy followed by SCRT and remaining immunochemotherapy (18). The study included 130 adult patients with histopathologically confirmed rectal adenocarcinoma located ≤12 cm from the anal verge and clinical stage II (T3–4, N0) or stage III (any T, N1–2) disease based on magnetic resonance imaging (MRI) using a specified rectal cancer protocol. Patients were randomized 1:1 to receive either SCRT followed by six cycles of consolidation immunochemotherapy with capecitabine, oxaliplatin, and toripalimab (group A) or two cycles of induction immunochemotherapy followed by SCRT and the remaining four cycles (group B). SCRT consisted of 25 Gy in five fractions using intensity-modulated RT to the primary tumor and regional pelvic lymph nodes. Immunochemotherapy included oxaliplatin and capecitabine (CAPOX) and toripalimab (toripalimab 240 mg once on day 1, oxaliplatin 130 mg/m² on day 1, and capecitabine 1,000 mg/m² twice daily on days 1–14), repeated every 21 days. Adjuvant chemotherapy after surgery was not recommended. The primary endpoint was the complete response (CR) rate, calculated as the proportion of patients with a pCR among those who underwent surgery and a cCR for those under NOM, relative to the total number of evaluable patients. Of 121 evaluable patients, 62 were in group A and 59 in group B.

The study demonstrated high CR rates in both groups (56.5% in group A and 54.2% in group B), meeting the predefined statistical hypothesis that immunotherapy-based TNT (iTNT) could raise the CR rate to 40%, compared with an estimated 25% with conventional TNT based on institutional experience with SCRT followed by fluoropyrimidine and oxaliplatin (unpublished). Using a pick-the-winner strategy, the authors concluded that SCRT followed by consolidation immunochemotherapy is promising for future phase 3 trials. NOM was an option for patients achieving cCR, defined as no residual disease on digital rectal examination, MRI, and endoscopy. As a result, 15 patients in each group underwent NOM and remained disease-free. Compliance with treatment was 74.2% in group A and 86.4% in group B, with acceptable adverse event (AE) rates in both arms, compared with previous phase 3 TNT trials (2,3,5). The most common grade 3–4 AEs were thrombocytopenia and neutropenia, whereas the incidence of immunotherapy-specific AEs, such as hypothyroidism, were similar to that in previous reports (13,16,19). AE frequencies during neoadjuvant treatment and surgical complications were comparable between the groups.

The results of this trial offer hope for iTNT in patients with pMMR or MSS LARC. The authors demonstrated a significant improvement in the CR rate with iTNT compared with historical benchmarks or prior phase 3 trials of SCRT-based TNT (2,5), despite differences in the scheduling of SCRT and immunochemotherapy. The most likely explanation for this enhanced tumor regression is the addition of immunotherapy, a hypothesis supported by recent studies. Lin et al. reported that neoadjuvant SCRT followed by camrelizumab plus CAPOX (experimental arm) achieved a significantly higher pCR rate, compared with long-course (L) CRT followed by CAPOX (standard arm), with rates of 39.8% and 15.3%, respectively (20). The surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related AEs occurred in 29.2% and 27.2% of patients, respectively, across the arms. The 3-year event-free survival and overall survival (OS) rates are still maturing. At the 2023 American Society of Clinical Oncology congress, George et al. reported that long-term results from the NRG-GI002 trial (12) investigating pembrolizumab plus CRT vs. standard CRT in a TNT setting showed a significant improvement in 3-year OS with pembrolizumab (95% vs. 87%, P=0.04) despite no significant differences in neoadjuvant rectal scores or 3-year disease-free survival. Although positive results from additional phase 3 trials are necessary to confirm the benefit of preoperative immunotherapy for resectable LARC, the combination of immunotherapy and RT shows great promise as a preoperative approach, compared with standard CRT or TNT with cytotoxic chemotherapy.

In the TORCH trial, consolidation immunochemotherapy showed a slightly higher response rate, compared with induction immunochemotherapy, although the difference was modest. Two factors may explain this outcome. First, the consolidation immunochemotherapy group had a longer interval from the completion of SCRT to the assessment of response, compared with the induction group. As demonstrated in the OPRA and CAO/ARO/AIO-12 trial (4,6), consolidation chemotherapy is more advantageous than induction chemotherapy for organ preservation, and the findings of this study further support this perspective. Second, the tumor microenvironment changes after RT. If immunotherapy is effective in pMMR or MSS CRC—which typically do not respond to immunotherapy—this effect is likely related to RT-induced changes in the tumor microenvironment. Consequently, altering the tumor microenvironment with RT first may have contributed to the improved response seen in the consolidation group compared with the induction group.

Several key considerations must be addressed in developing iTNT. First, the choice between SCRT and LCRT for radiation therapy combined with immunotherapy is critical. Although SCRT raises concerns about local recurrence, as indicated in the long-term results of the RAPIDO trial (21), it may enhance the effects of immunotherapy more effectively, compared with LCRT. Studies have reported that SCRT offers advantages in RT-immunotherapy synergy, such as milder treatment-related lymphopenia, enhanced antigen release, and increased tumor-infiltrating lymphocytes, as noted by Xia et al. (18). However, definitive conclusions require clinical outcome data. Further clinical trials are essential to determine whether SCRT or LCRT is superior when combined with immunotherapy.

Second, biomarker studies are crucial for identifying good responders to iTNT. If preoperative immunotherapy has an add-on effect on pMMR or MSS CRC, which generally do not respond to immunotherapy, there must be underlying reasons. High tumor mutation burden and high PD-L1 expression are recognized as potential biomarkers for immunotherapy; however, they may not be the only promising indicators. There are reports on biomarkers for preoperative immunotherapy combined with CRT for LARC (13,16); however, additional data from other studies is needed. Moreover, biomarker studies can help determine whether SCRT or LCRT is better when paired with immunotherapy, as previously mentioned. Immunotherapy has specific side effects, known as irAEs, which can be prolonged and significantly impact patients’ quality of life. For example, in the TORCH trial, more than 10% of patients developed hypothyroidism, sometimes requiring long-term medication. There has also been a report of a patient requiring total colectomy due to ir-colitis after preoperative immunotherapy (16). These challenges are not unique to preoperative immunotherapy; however, given the likelihood of long-term survival for patients with LARC, minimizing AEs that impair quality of life is critical. Additionally, increasing preoperative treatments can lead to more AEs and higher medical costs, making it essential to provide the most appropriate preoperative treatment to the right patients. Biomarker studies are vital to achieving this goal.

If organ preservation is a goal with iTNT, careful attention must be paid to defining cCR. In the TORCH trial, the frequency of pseudo residual cancer cells was higher than that of conventional CRT: 34.2% of patients who did not meet cCR criteria showed pCR. This underscores the need to reconsider cCR criteria after iTNT, as incorrect tumor response evaluation could deny patients the opportunity for organ preservation. As global experience with NOM increases, research on evaluating the efficacy of conventional CRT and TNT has advanced (22). As more data on preoperative immunotherapy emerges, new insights into tumor response evaluation after iTNT are anticipated in the future.

Combinations of immunotherapies should also be noted. Clinical trials in mCRC have demonstrated the efficacy of combining immunotherapies (e.g., ipilimumab plus nivolumab) (23). A clinical trial in LARC investigating the combination of immunotherapies is currently underway (NCT02948348), the results of which are expected (13,16).

This study has some limitations. First, the observation period was short: the median follow-up from study enrollment to the clinical data cutoff (September 1, 2023) was 19 months. Long-term follow-up is required to assess the precise re-growth rate, long-term prognosis, and late AEs. Second, this paper does not present results from a biomarker study; however, biomarker studies are believed to be ongoing. As previously mentioned, biomarker studies are essential for advancing preoperative immunotherapy, and their results, particularly those accompanying this study, are eagerly awaited.

The study group of the TORCH trial is also investigating preoperative immunotherapy for resectable CRC beyond LARC. The TORCH-C trial is a randomized phase 2 trial targeting patients with MSS locally advanced colon cancer with cT4 tumors or bulky lymph nodes (24). In the control arm, patients will receive four cycles of CAPOX, whereas those in the intervention arm will undergo SCRT followed by four cycles of CAPOX and a PD-1 inhibitor (serplulimab). Both groups will receive curative surgery followed by four cycles of CAPOX. The primary endpoint is the pCR rate. Additionally, the TORCH-E trial is a single-arm phase 2 study targeting cT1-3N0M0 low rectal cancer and aiming for organ preservation (25). Enrolled patients will receive SCRT followed by four cycles of CAPOX and a PD-1 antibody (toripalimab), concluding with surgery or NOM. The primary endpoint is the CR rate, defined as the rate of pCR plus cCR, whereas secondary endpoints include the organ preservation rate. Results from these trials are highly anticipated.

In summary, the TORCH trial demonstrated a high CR rate following preoperative immunochemotherapy combined with SCRT in patients with pMMR or MSS LARC. The findings of this trial inspire hope for the future development of preoperative immunotherapy. Large-scale phase 3 trials and biomarker studies are essential to further clarify the efficacy and appropriate applications of immunotherapy in pMMR or MSS CRC.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-16/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-16/coif).The authors have 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-40. [Crossref] [PubMed]
2. Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:29-42. [Crossref] [PubMed]
3. Conroy T, Bosset JF, Etienne PL, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:702-15. [Crossref] [PubMed]
4. Fokas E, Schlenska-Lange A, Polat B, et al. Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. JAMA Oncol 2022;8:e215445. [Crossref] [PubMed]
5. Jin J, Tang Y, Hu C, et al. Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR). J Clin Oncol 2022;40:1681-92. [Crossref] [PubMed]
6. Verheij FS, Omer DM, Williams H, et al. Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial. J Clin Oncol 2024;42:500-6. [Crossref] [PubMed]
7. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:23-34. [Crossref] [PubMed]
8. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022;386:449-62. [Crossref] [PubMed]
9. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372:2509-20. [Crossref] [PubMed]
10. Veen T, Kanani A, Lea D, et al. Clinical trials of neoadjuvant immune checkpoint inhibitors for early-stage operable colon and rectal cancer. Cancer Immunol Immunother 2023;72:3135-47. [Crossref] [PubMed]
11. Cercek A, Lumish M, Sinopoli J, et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med 2022;386:2363-76. [Crossref] [PubMed]
12. Rahma OE, Yothers G, Hong TS, et al. Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Initial Results From the Pembrolizumab Arm of a Phase 2 Randomized Clinical Trial. JAMA Oncol 2021;7:1225-30. [Crossref] [PubMed]
13. Bando H, Tsukada Y, Inamori K, et al. Preoperative chemoradiotherapy plus nivolumab before surgery in microsatellite stable and microsatellite instability-high locally advanced rectal cancer patients. Clin Cancer Res 2022;28:1136-1146. [Crossref] [PubMed]
14. Shamseddine A, Zeidan YH, El Husseini Z, et al. Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma. Radiat Oncol 2020;15:233. [Crossref] [PubMed]
15. Bando H, Tsukada Y, Ito M, et al. Novel Immunological Approaches in the Treatment of Locally Advanced Rectal Cancer. Clin Colorectal Cancer 2022;21:3-9. [Crossref] [PubMed]
16. Tsukada Y, Bando H, Inamori K, et al. Three-year outcomes of preoperative chemoradiotherapy plus nivolumab in microsatellite stable and microsatellite instability-high locally advanced rectal cancer. Br J Cancer 2024;131:283-9. [Crossref] [PubMed]
17. Seo I, Lee HW, Byun SJ, et al. Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer. J Immunother Cancer 2021;9:e001610. [Crossref] [PubMed]
18. Xia F, Wang Y, Wang H, et al. Randomized Phase II Trial of Immunotherapy-Based Total Neoadjuvant Therapy for Proficient Mismatch Repair or Microsatellite Stable Locally Advanced Rectal Cancer (TORCH). J Clin Oncol 2024;42:3308-18. [Crossref] [PubMed]
19. Li Y, Pan C, Gao Y, et al. Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer. JAMA Surg 2024;159:529-37. [Crossref] [PubMed]
20. 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. [Crossref] [PubMed]
21. Dijkstra EA, Nilsson PJ, Hospers GAP, et al. Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared to long-course chemoradiotherapy and surgery: a five-year follow-up of the RAPIDO trial. Ann Surg 2023;278:e766-72. [Crossref] [PubMed]
22. Custers PA, Beets GL, Bach SP, et al. An International Expert-Based Consensus on the Definition of a Clinical Near-Complete Response After Neoadjuvant (Chemo)radiotherapy for Rectal Cancer. Dis Colon Rectum 2024;67:782-95. [Crossref] [PubMed]
23. André T, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann Oncol 2022;33:1052-60. [Crossref] [PubMed]
24. Zhang H, Li Y, Xia F, et al. Study protocol of short-course radiotherapy combined with CAPOX and PD-1 inhibitor for locally advanced colon cancer: a randomised, prospective, multicentre, phase II trial (TORCH-C). BMJ Open 2024;14:e079442. [Crossref] [PubMed]
25. Chen Y, Wang Y, Zhang H, et al. Short-course radiotherapy combined with chemotherapy and PD-1 inhibitor in low-lying early rectal cancer: study protocol for a single-arm, multicentre, prospective, phase II trial (TORCH-E). BMJ Open 2023;13:e076048. [Crossref] [PubMed]