Severe renal toxicity following adjuvant envafolimab in a patient with ultra-hypermutated (POLE) stage II colorectal cancer: a case report

Introduction

Colorectal cancer (CRC) ranks as the third most common malignancy globally but stands as the second leading cause of cancer-related mortality. According to GLOBOCAN estimates, over 1.8 million new CRC cases were diagnosed worldwide in 2018, accounting for 10.2% of all cancer diagnoses (1). Global projections estimate over 2.2 million new CRC cases annually by 2030 (2). Recent therapeutic advances have demonstrated that programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors significantly improve prognosis and prolong survival compared to conventional chemotherapy, establishing ICIs as the standard clinical treatment for CRC patients (3,4). Despite their durable clinical benefits, ICIs carry unique toxicity profiles known as immune-related adverse events (irAEs), which predominantly affect the skin, gastrointestinal tract, and lungs (5,6). While mild irAEs generally permit continued immunotherapy with close monitoring, moderate-to-severe irAEs may lead to significant organ dysfunction, quality-of-life impairment, or even fatal outcomes.

Recent studies have established that CRC harboring pathogenic POLE exonuclease domain (ED) mutations represent a distinct molecular subtype characterized by ultra-hypermutation, high endogenous immunogenicity, and exceptionally favorable clinical outcomes (7). A retrospective study has demonstrated that patients with POLE-mutated CRC, including those with Stage II disease, exhibit low recurrence rates, often outperforming conventional deficient mismatch repair (dMMR) tumors (8). Consequently, retrospective studies have suggested that POLE-mutated CRC represents a biologically favorable subgroup with a low risk of recurrence, raising the possibility of treatment de-escalation (9). However, this strategy has not yet been incorporated into major clinical practice guidelines [European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN), or Chinese Society of Clinical Oncology (CSCO)] due to the lack of prospective evidence.

In contrast to this emerging de-escalation hypothesis, the present case underwent adjuvant immune checkpoint inhibitor (ICI) therapy based on ultra-high tumor mutational burden (TMB) and PD-L1 expression, representing a treatment escalation management for POLE-mutated stage II CRC. This clinical decision reflects a real-world dilemma, in which biomarker-driven enthusiasm for immunotherapy may conflict with established risk-adapted treatment strategies. Therefore, this case is not only relevant to the association between TMB and irAEs, but more importantly, highlights the potential risks of off-label immunotherapy and treatment escalation in CRC subgroups with a favourable prognosis. It underscores the need for cautious patient selection, risk-benefit evaluation, and guideline-concordant decision-making when considering immunotherapy in early-stage POLE-mutated CRC. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-268/rc).

Case presentation

Clinical history

A 28-year-old Asian male with no family history of malignancy and a 7-year history of tobacco use (10 cigarettes/day) and alcohol consumption presented with intermittent abdominal pain, hematochezia, and increased stool frequency (4–5 times/day) in September 2022. Colonoscopy in March 2023 revealed a circumferential ulcerated mass near the hepatic flexure of the transverse colon with luminal stenosis (endoscope barely passable), pathologically confirmed as adenocarcinoma. Subsequent contrast-enhanced computed tomography (CT) at Shandong Provincial Hospital demonstrated segmental bowel wall thickening with mild enhancement, luminal narrowing accompanied by multiple enlarged lymph nodes, consistent with colonic malignancy.

The patient underwent laparoscopic radical right hemicolectomy on March 27, 2023, with uncomplicated postoperative recovery (discharged on postoperative day 6). Final histopathology confirmed a pT4N0M0 stage IIB [American Joint Committee on Cancer (AJCC) eighth edition] ulcerative moderately differentiated adenocarcinoma of the colon with MSS phenotype (intact nuclear expression of MLH1, MSH2, and MSH6 by immunohistochemistry).

Genomic profiling (Table 1) in April 2023 revealed:

• Exceptionally high TMB: 717.0 Muts/Mb;
• 32,830 tumor neoantigens;
• Microsatellite stable (MSS) status;
• POLE/POLD1 mutations;
• PD-L1 combined positive score (CPS) of eight.
• Wild-type status for KRAS, NRAS, and BRAF V600E.

Treatment and response

The genetic testing results demonstrated a high TMB (Figure 1) of 717.0 Muts/Mb and a PD-L1 CPS of 8. Although retrospective evidence suggests that Stage II POLE-mutated CRC may represent a low-risk subgroup in which treatment de-escalation could be considered, immunotherapy was considered in this case as an off-label treatment based on the patient’s ultra-high TMB and PD-L1 expression. This treatment was not administered as part of a registered clinical trial and was initiated after a multidisciplinary discussion and a detailed informed consent process. The treating physician counseled the patient regarding the benefits of subsequent immunotherapy and the potential risks of irAEs. Following a comprehensive discussion regarding the risks and benefits, the patient opted to proceed with the recommended immunotherapy and executed the informed consent form, acknowledging full understanding of potential irAEs. Before initiation of immunotherapy, baseline renal function was within normal range, with a serum creatinine (Scr) level of 73.3 µmol/L and an estimated glomerular filtration rate (eGFR) of 128 mL/min. The patient commenced therapy with envafolimab (150 mg/week via subcutaneous injection) on July 21, 2023. Following five treatment cycles (Aug 25, 2023), the patient developed acute kidney injury (AKI) with Scr (Figure S1) elevation to 106 µmol/L and eGFR (Figure S2) of 82 mL/min, accompanied by hyperuricemia (serum uric acid 694 µmol/L). Despite cessation, renal dysfunction persisted without significant improvement. In September 2023, conservative therapy with Jinshuibao tablets [Jinshuibao tablet is a traditional Chinese medicine preparation derived from Cordyceps sinensis, commonly used for renal protection and immunomodulation in chronic kidney disease in China were administered as adjunctive supportive therapy (10)] and methylprednisolone (20 mg daily) was initiated.

Figure 1 TMB distribution characteristics chart. The patient’s TMB exceeds that of 99% of samples. MSK, Memorial Sloan-Kettering Cancer Center; SDPH, Shandong Provincial Hospital; TMB, tumor mutational burden.

To clarify the cause of AKI, a systematic differential diagnosis was performed. Contrast-induced nephropathy was considered unlikely because no contrast-enhanced imaging was performed within four weeks prior to the onset of renal dysfunction. The patient had no history of dehydration, diarrhea, or hypotensive episodes. There were no clinical or laboratory signs of infection. The patient denied the use of nonsteroidal anti-inflammatory drugs, aminoglycosides, or other known nephrotoxic medications during immunotherapy. Comprehensive diagnostic evaluation including renal artery Doppler and urogenital ultrasound (October 15, 2023) excluded organic renal disease. Given the temporal association with immunotherapy and clinical history, irAE was suspected.

Renal biopsy was not performed due to the patient’s refusal of invasive procedures and the gradual improvement of renal function after immunotherapy discontinuation and corticosteroid treatment. The diagnosis of immune-related AKI was based on clinical presentation, temporal association with PD-L1 inhibitor exposure, and exclusion of alternative etiologies, which represents an important limitation of this case. Despite discontinuation of immunotherapy and the addition of drug therapy (September 2023), laboratory monitoring showed progressive deterioration of renal function. Renal function reached its nadir in October 2023, with a peak Scr level of 163 µmol/L and an eGFR of 49 mL/min. After initiation of systemic corticosteroid therapy and supportive treatment (piperazine ferulate combined with prednisone, October 15, 2023), renal function gradually improved. At the last follow-up in March 2024, Scr decreased to 104.8 µmol/L with an eGFR of 82 mL/min, indicating near-complete recovery (Table S1). Regular tumor marker surveillance demonstrated no abnormalities, with follow-up through April 2024 showing no evidence of tumor recurrence. The patient currently maintains good status (Figure 2).

Figure 2 Clinical timeline of diagnostic and therapeutic management (September 2022 to March 2024). AKI, acute kidney injury; CPS, combined positive score; CT, computed tomography; eGFR, estimated glomerular filtration rate; PD-L1, programmed cell death ligand 1; Scr, serum creatinine; TMB, tumor mutational burden.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

TMB, defined as the number of nonsynonymous mutations per megabase of sequenced genomic region, serves as a critical biomarker for assessing tumor genomic variability. In clinical practice, the threshold for TMB-high (TMB-H) is typically defined as ≥10 Muts/Mb (11). Previous studies have established that elevated TMB enhances tumor immunogenicity through increased production of neoantigens, thereby improving response rates to ICI therapy (12,13). This mechanism has been validated across multiple solid tumors, including melanoma and non-small cell lung cancer (12,13). Notably, we present a rare case of a 28-year-old CRC patient exhibiting an exceptionally high TMB of 717 Muts/Mb, far exceeding conventional TMB-H thresholds. Genetic testing revealed a pathogenic variant in POLE/POLD1. These genes encode the catalytic subunits of the Polε and Polδ enzyme complexes, which proofread error detection (ED) and are essential for synthesizing leading and lagging DNA strands during replication (14,15). Pathogenic variants in POLE/POLD1 impair replication fidelity by increasing nucleobase substitution rates or causing replication fork collapse, ultimately leading to double-strand DNA breaks (Figure 3) (16). A Chinese study demonstrated that carriers of damaging POLE/POLD1 variants consistently exhibit significantly elevated TMB (17). In this case, the patient’s ultra-high TMB is likely attributable to POLE/POLD1 mutations.

Figure 3 Schematic diagram of acute kidney injury pathogenesis mediated by POLE/POLD1 gene mutations. DSB, double-strand break; TMB, tumor mutational burden.

The patient developed AKI following treatment with a PD-L1 inhibitor. This phenomenon suggests that hyper-TMB may possess dual biological properties - serving as both a therapeutic response predictor and a toxicity warning signal. Current evidence suggests that reliable biomarkers for predicting irAEs remain elusive. While some studies propose TMB as a potential predictive biomarker for irAEs, robust clinical validation is currently lacking (18,19). This exceptional case provides novel clinical evidence supporting the hypothesis that high TMB may serve as a predictive biomarker for severe irAEs. However, it should be acknowledged that the association between TMB and irAEs remains controversial. Recent comprehensive analyses have reported no significant correlation between TMB and irAE incidence (20). For example, a meta-analysis of 117 ICI trials involving over 12 000 patients found no significant association between TMB and toxicity incidence despite earlier hypotheses linking high-TMB tumor types (such as melanoma and NSCLC) with increased irAE risk (18,20). Therefore, current evidence does not support the use of TMB as an independent or universal predictor of immune-related toxicity.

POLE ED-mutated CRC represents a subgroup with a favorable prognosis, characterized by exceptionally low recurrence rates and excellent survival outcomes. Several retrospective studies have suggested that stage II POLE-mutated endometrial cancer patients exhibit excellent outcomes and may derive limited benefit from adjuvant systemic therapy, although no prospective randomized trials have validated this observation in CRC (21,22). In this context, the occurrence of severe renal toxicity in the present case highlights the potential harm of treatment escalation in patients with an intrinsically favorable prognosis. The risk-benefit balance becomes particularly critical when the expected absolute survival benefit of adjuvant immunotherapy is uncertain or minimal. This case supports a more conservative and guideline-adherent approach when considering immunotherapy in early-stage, high-TMB, POLE-mutated CRC. Biomarker-driven enthusiasm should not override established risk-adapted treatment principles, especially in the absence of prospective evidence supporting adjuvant immunotherapy in this population. Although current guidelines do not recommend routine adjuvant immunotherapy for stage II POLE-mutated CRC, the optimal management of ultra-hypermutated tumors in the adjuvant setting remains undefined. This case emphasizes the need for clearer clinical consensus on how to integrate ultra-high TMB into treatment decision-making and cautions against extrapolating metastatic treatment paradigms to non-metastatic disease.

This case also provides practical recommendations for the monitoring of renal toxicity during PD-L1 inhibitor therapy. Baseline renal function assessment, including Scr, eGFR, and urinalysis, should be routinely performed before initiation of ICIs, particularly in patients with ultra-high TMB or early-stage disease receiving off-label treatment.

Given the pharmacokinetic profile of subcutaneous PD-L1 inhibitors such as envafolimab, which may result in sustained drug exposure, more frequent renal function monitoring during the early treatment phase is warranted. We recommend monitoring Scr and eGFR every 1–2 weeks during the first two months of therapy. Any unexplained elevation in Scr should prompt early evaluation, temporary treatment interruption, and multidisciplinary consultation. Early corticosteroid intervention may be considered when immune-mediated nephritis is suspected.

Conclusions

This case highlights a clinical paradox in biomarker-driven immunotherapy. Although high TMB is a predictive biomarker for ICIs efficacy, our patient with an ultra-high TMB developed severe immune-related renal toxicity after adjuvant PD-L1 inhibitor therapy, suggesting a potential association between ultra-high TMB and irAEs that warrants further validation.

POLE-mutated CRC represents a biologically favorable subgroup with low recurrence risk, and the benefit of adjuvant systemic therapy remains uncertain. The severe renal toxicity observed in this case underscores the potential harm of treatment escalation in patients with an intrinsically favorable prognosis.

This case is hypothesis-generating and emphasizes the need for prospective studies to clarify the role of ultra-high TMB in adjuvant treatment decisions and toxicity risk stratification. Careful patient selection and close toxicity monitoring are warranted when immunotherapy is considered in II-stage POLE-mutated CRC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-268/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-268/prf

Funding: This work was supported by National Natural Science Foundation of China (No. 82203854), Key Research and Development Program of Shandong Province (No. 2021CXGC011104), Special Foundation for Taishan Scholars Program of Shandong Province (Nos. ts20190978 and tsqn202408363), and Shandong Medical Association Clinical Research Fund (Qilu Special Project) (No. YXH2022ZX02122).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-268/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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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/.

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