Successful rechallenge of immune checkpoint inhibitors after severe immune-related hepatitis, thyroiditis and hypophysitis in TMB-high NSCLC: a case report

Abstract

Background

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are frequently associated with immune-related adverse events (irAEs), which complicate treatment decisions. Patients who experience severe irAEs are often excluded from further immunotherapy due to concerns of recurrence. However, rechallenging ICIs in selected patients under close monitoring may offer long-term benefits, although evidence remains limited and heterogeneous.

Case Description

We report a case of a 65-year-old man with stage IVB pulmonary adenocarcinoma harboring TP53 mutation and high tumor mutational burden. He initially received pembrolizumab-based chemoimmunotherapy but developed grade 4 hepatitis, requiring immunosuppressive treatment and discontinuation of ICIs. Subsequent tumor progression led to a rechallenge with ICIs alongside prophylactic tocilizumab. Although the patient experienced further grade 2 thyroiditis and grade 2 hypophysitis, all toxicities were manageable with hormone replacement and corticosteroids. A pacemaker was implanted for unrelated sick sinus syndrome. Despite intermittent symptoms, pembrolizumab monotherapy was maintained over a prolonged period, achieving durable tumor control with no progression noted at 4-year follow-up.

Conclusions

This case highlights that ICI rechallenge can be a viable and effective treatment strategy in selected patients with prior high-grade irAEs, especially when initial toxicities are well controlled and alternative causes of symptoms are carefully excluded. The prophylactic use of agents like tocilizumab may reduce the risk of irAE recurrence. This underscores the need for individualized risk-benefit assessment and close clinical monitoring in rechallenge scenarios.

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Key findings

• This case illustrates that immune checkpoint inhibitor (ICI) rechallenge after severe immune-related adverse events (irAEs), including grade 4 hepatitis, can be feasible and lead to long-term tumor control when managed with close monitoring and supportive care.

What is known and what is new?

• ICI rechallenge poses a risk of recurrent irAEs, and current guidelines often recommend discontinuation after grade 4 toxicities. However, some retrospective studies suggest that rechallenge may be safe in selected patients.

• This report provides real-world evidence that ICI rechallenge, combined with prophylactic tocilizumab and individualized irAE management, resulted in sustained disease control in a patient with advanced non-small cell lung cancer (NSCLC) and multiple prior irAEs.

What is the implication, and what should change now?

• Careful patient selection, differentiation between true irAEs and unrelated symptoms, and use of prophylactic agents like tocilizumab may reduce toxicity risks and allow continued ICI therapy. Clinical practice should consider rechallenge in high-risk patients under strict supervision. Prospective trials are needed to guide safer and more effective ICI rechallenge strategies.

Introduction

Immune checkpoint inhibitors (ICIs) are gaining prominence in the treatment of a diverse range of cancers, leading to a rising incidence of immune-related adverse events (irAEs). Patients with a history of severe irAEs are susceptible to recurrent toxicities upon ICIs rechallenge in clinical practice (1). Although several studies have investigated the safety and efficacy of ICI rechallenge, they provide limited or heterogeneous evidence (1-3). Therefore, achieving a balance between clinical benefit and treatment-related toxicities for individual patients presents a formidable challenge. Here, we report a case of an advanced non-small cell lung cancer (NSCLC) patient who experienced sequential immune-related grade 4 hepatitis, grade 2 thyroiditis, and grade 2 hypophysitis during chemo-immune combination therapy. Additionally, we share our successful experience in resuming ICIs to achieve long-term survival. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-341/rc).

Case presentation

A 65-year-old male patient presented to the hospital with right-sided back pain and intermittent cough in March 2021 (Figure 1). Chest computed tomography (CT) scan revealed a 5.7 cm × 5.6 cm mass at the right hilum, multiple lymph node metastases, and positron emission tomography-computed tomography (PET-CT) results demonstrated osteoblastic changes and increased metabolic activity in the left ilium and right ischium, suggestive of metastasis. The patient underwent bronchoscopic biopsy and was diagnosed with stage IVB pulmonary adenocarcinoma (cT4N3M1c) with a TP53 mutation and tumor mutation burden (TMB) 16.95/Mb. The patient was initially treated with pembrolizumab, carboplatin and pemetrexed. After one week, he experienced neutropenic fever with a Tmax of 38.2 ℃, treated with antibiotics. Considering the neutropenia, carboplatin was discontinued, but he experienced fever again after one week. His liver function test (LFTs) results indicated that alanine aminotransferase (ALT) elevated to 2,912.17 U/L and aspartate aminotransferase (AST) elevated to 1,100.5 U/L, reflecting grade 4 immune-related hepatitis. Consequently, the pembrolizumab was discontinued, and he was treated with methylprednisolone in conjunction with intravenous immunoglobulin (IVIG). With the gradual reduction of glucocorticoids, his liver function gradually returned to normal.

Figure 1.

Clinical events and imaging findings during patient treatment. (A) Timeline of primary disease and treatment-related adverse events in a patient with advanced NSCLC, who sequentially developed immune-related grade 4 hepatitis, disease progression, grade 2 thyroiditis, sick sinus syndrome, and grade 2 hypophysitis. (B) Representative chest computed tomography scan obtained during the course of treatment. AC, pemetrexed plus carboplatin; C3/C5/C6, 3/5/6 treatment cycles; K, pembrolizumab; NSCLC, non-small cell lung cancer; PC, paclitaxel plus carboplatin.

The chest CT showed tumor progression in May 2021. Although he was then treated with CryoCare™ targeted cryoablation therapy, the chest CT showed tumor progression again in October 2021, with the right hilum mass measuring 8 cm × 5.3 cm. Due to the continuous tumor progression, the patient began treatment with paclitaxel, carboplatin and pembrolizumab again, and he was concurrently administered tocilizumab 240 mg once as prevention for irAEs. The patient had a relatively poor tolerance of chemotherapy, and he developed neutropenic fever and infectious shock again after the treatment. Consequently, paclitaxel and carboplatin were discontinued. In February 2022, the patient reported fatigue, poor appetite, nausea, vomiting, and sinus bradycardia. Thyroid function tests revealed an increase of thyroid stimulating hormone (TSH) to 16.173 µIU/mL, with a slight decrease in FT4 (0.68 ng/dL) and T4 (4.10 µg/dL). He was diagnosed with grade 2 immune-related thyroiditis, and treated with daily levothyroxine. On February 20 2022, the chest CT suggested that the tumor was in partial remission, therefore the patient was treated with pembrolizumab monotherapy for maintenance. The patient experienced intermittent chest tightness and fatigue in March 2022, and laboratory tests revealed a slight elevation of cardiac troponin I (cTnI) (0.087 ng/mL) and normal CK levels. Holter electrocardiogram results showed sinus bradycardia and sinus arrest, then a comprehensive evaluation excluded immune-related myocarditis and considered sick sinus syndrome, cured after the permanent pacemaker implantation (DDDR). The patient began experiencing fatigue, itching and nausea from April 2022, which resolved with oral prednisone treatment. When the steroid was gradually tapered and discontinued, the laboratory tests showed lower 8 AM serum cortisol (<0.50 µg/dL) and adrenocorticotropic hormone (ACTH) (<1.50 pg/mL) value, which is considered as an immune-related pituitary inflammation resulting in secondary adrenal insufficiency, and his symptoms improved after a daily supplementation of hydrocortisone. In April 2023, a follow-up PET-CT revealed residual lesions in the hilar lymph nodes. In order to prevent disease recurrence, pembrolizumab monotherapy was retained until August 2024. The chest CT showed no progression of the tumor in February 2025 (Table 1). 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 publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.

Table 1. Clinical summary of treatment-related adverse events and management.

Characteristics	Onset time
	2021-03	2021-04	2021-10	2022-02	2022-03	2022-04
Adverse events	Fever	Hepatitis	Fever	Thyroiditis	Sick sinus syndrome	Hypophysitis
ICI-related	No	Yes	No	Yes	No	Yes
Grade	3	4	2	2	1	2
Clinical management	Antibiotics	MP, IVIG	Antibiotics	L-T4	DDDR	Pred
Hospitalization	No	Yes	No	No	Yes	No
Outcomes	Recovery	Recovery	Recovery	Recovery	Recovery	Recovery

DDDR, permanent pacemaker implantation; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; L-T4, levothyroxine; MP, methylprednisolone; Pred, prednisone.

Discussion

This report describes the clinical course of a patient who underwent ICIs rechallenge after experiencing immune-related grade 4 hepatitis, grade 2 thyroiditis, and grade 2 hypophysitis, achieving long-term survival. Numerous clinical practice guidelines address the management of irAEs, but no definitive guidelines have been issued regarding the decision to rechallenge with ICIs (4,5). The general recommendations from the Society for Immunotherapy of Cancer (SITC) for grade 3 or 4 irAEs patients are to adjust the possibility of rechallenge based on the expected benefit against the risk of potential toxicity (4). Additionally, the European Society for Medical Oncology (ESMO) recommends permanent discontinuation of ICIs in cases of grade 4 toxicities, except for endocrinopathies (5).

The findings from this case indicate that the patients who experience high-grade immune-related hepatitis face a significant risk of recurrence upon ICIs rechallenge yet it may present as a viable and effective treatment approach for some patients. Despite disease progression following initial immunotherapy, the decision to rechallenge with ICIs was based on the observation that the patient with high-grade irAEs exhibited favorable treatment responses. Under stringent monitoring and prophylactic measures, this approach yielded positive clinical outcomes in this patient.

Emerging evidence increasingly supports the potential safety of ICI rechallenge when conducted with appropriate clinical oversight. For example, a retrospective analysis of patients with ICI-induced grade 3–4 hepatitis reported that although 48% developed recurrent irAEs upon rechallenge, only 19% required permanent discontinuation, and no irAE-related deaths occurred (6). Another study involving stage IV NSCLC patients found that although 60% experienced recurrent or new irAEs, no grade 4 toxicities or fatal events were observed (7). Similarly, a large cohort study involving over 6,000 patients demonstrated that the recurrence of irAEs upon rechallenge varied by the type of the initial toxicity, but most cases were not severe (8). Notably, recurrent irAEs were generally of reduced intensity, and patients who tolerated rechallenge often had better survival outcomes.

Despite these findings, the therapeutic efficacy of ICI rechallenge remains uncertain. While some studies suggest that rechallenge may confer survival benefits, the overall clinical gain remains modest, and evidence supporting its effectiveness remains limited (8). High-quality, prospective studies are needed to clearly define the risk–benefit profile of this approach and to establish evidence-based guidelines for patient selection.

In this case, the patient received a single prophylactic dose of tocilizumab prior to ICI rechallenge. Tocilizumab, an IL-6 receptor antagonist, has been shown to be effective in managing steroid-refractory irAEs and may facilitate faster resolution of inflammation, particularly in patients with pre-existing autoimmune conditions (9). A recent study also suggests that concurrent administration of tocilizumab with immunotherapy may reduce irAE severity without impairing anti-tumor efficacy (9). Therefore, prophylactic use of tocilizumab may represent a potential strategy to prevent irAE recurrence in high-risk patients, although this approach requires further validation in prospective clinical trials.

Throughout ICI treatment, clinicians frequently ascribe various clinical discomfort symptoms to irAEs, possibly overlooking alternative explanations. For example, the fever and infection were complications of chemotherapy, unrelated to ICIs. Similarly, the sick sinus syndrome was deemed as primary condition. Many elderly cancer patients often have underlying cardiovascular disease, distinct from the cardiotoxicity associated with ICIs. Consequently, we chose not to discontinue ICIs, resulting in a favorable therapeutic outcome. In cases of adverse effects in patients receiving ICIs, it is important not to automatically attribute all adverse effects to irAEs, which helps prevent overlooking other significant medical conditions and reducing the potential for erroneous ICIs discontinuation.

Conclusions

ICIs rechallenge is a possible option with manageable risks for patients who discontinue treatment owing to irAEs. Favorable control of initial irAEs is associated with a low risk of second irAEs.

Supplementary

The article’s supplementary files as

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 publication of this case report and accompany images. A copy of the written consent is available for review by the editorial office of this journal.