Toxic Epidermal Necrolysis in a Patient with Hepatocellular Carcinoma Receiving Pembrolizumab Plus Regorafenib: A Case Report.

Introduction

Background
Programmed cell death protein 1 (PD-1) inhibitors constitute a cornerstone of immune checkpoint inhibitor (ICI) therapy. They function by blocking the PD-1 pathway, thereby reactivating T-cell-mediated antitumor immunity and have demonstrated remarkable efficacy and durable clinical responses across a wide spectrum of malignancies.1,2 However, this enhanced immune activity is not tumor-specific and can lead to unintended off-target tissue damage, manifesting as immune-related adverse events (irAEs). Cutaneous irAEs are the most common; typical manifestations include maculopapular eruptions, pruritus, and psoriasiform or lichenoid rashes. While often manageable, these conditions can significantly impair patients’ quality of life and may necessitate dose modification or temporary cessation of immunotherapy.3

Rationale and Knowledge Gap
Toxic Epidermal Necrolysis (TEN) is a rare, life-threatening cutaneous adverse reaction with an estimated annual incidence of 1–7 cases per million individuals.4 It is characterized by widespread blistering and extensive epidermal detachment, resembling a severe burn, and is frequently accompanied by systemic complications that confer a high mortality rate.5 Although traditionally associated with drugs such as anticonvulsants, antibiotics, and NSAIDs, the emergence of novel immunotherapies has introduced new potential triggers. Indeed, cases of pembrolizumab monotherapy-induced TEN have been documented,6,7 highlighting the capacity of ICIs to trigger this extreme reaction. Separately, the multi-kinase inhibitor regorafenib is known to induce dose-dependent cutaneous toxicities, such as hand-foot skin reaction,7 through mechanisms distinct from the immune-mediated pathogenesis of TEN. The pathogenesis of TEN involves a complex interaction between drug exposure and individual genetic susceptibility, leading to a massive keratinocyte apoptosis. While the overall incidence of TEN with ICIs remains low, its severity and the expanding use of combination regimens—which may alter the risk and presentation of irAEs—highlight a critical knowledge gap. Specifically, reports of TEN occurring in the context of PD-1 inhibitor and tyrosine kinase inhibitor combinations are exceedingly scarce. There is a pressing need to better understand the risk profiles, clinical course, and optimal management strategies for severe cutaneous irAEs, particularly TEN, in the context of modern immuno-oncology therapies.

Objective
This article aims to report a detailed case of TEN occurring in a patient receiving combination therapy with pembrolizumab (a PD-1 inhibitor) and regorafenib (a multi-kinase inhibitor). The primary objective is to enhance early recognition and promote standardized, multidisciplinary management of this severe adverse drug reaction. By elucidating the diagnostic challenges, therapeutic interventions, and clinical outcome in this case, we seek to contribute to the collective clinical experience, ultimately supporting the safe and continued use of effective anticancer immunotherapies. We present this case in accordance with the CARE reporting checklist.

Case Presentation
A 34-year-old woman (height 155 cm, weight 40 kg) with no significant past medical history experienced unexplained right upper quadrant discomfort in December 2023. Abdominal ultrasonography in January 2024 identified a hypoechoic hepatic mass, leading to a diagnosis of hepatocellular carcinoma. A subsequent contrast-enhanced magnetic resonance imaging (MRI) confirmed the diagnosis of hepatocellular carcinoma (HCC), revealing a solid mass measuring approximately 5.5×4.2 cm in the right lobe with multiple intrahepatic metastatic foci and no major vascular invasion. The patient’s clinical profile was further characterized by a markedly elevated serum alpha-fetoprotein (AFP) level of 2582 ng/mL, impaired liver function graded as Child-Pugh class B, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Collectively, these findings supported a clinical stage of China Liver Cancer Staging (CNLC) IIb. Following an initial session of Transarterial Chemoembolization (TACE), she began combination therapy with oral lenvatinib (8mg qd) and intravenous pembrolizumab (200mg q3w) on April 10, 2024. Despite an additional TACE procedure in May 2024, follow-up imaging by December 2024 indicated disease progression. Consequently, the targeted agent was switched to regorafenib (160mg qd) and continued pembrolizumab immunotherapy every three weeks. The final dose of pembrolizumab was administered on February 16, 2025. In February 2025, the patient developed bilateral lower extremity weakness and sensory loss below the trunk. Spinal imaging confirmed metastatic lesions at the T4–T5 level. A course of palliative radiotherapy to the spinal metastases was planned, with a prescription dose of 30 Gy in 8 fractions. A planned radiotherapy course (8 sessions) was initiated but discontinued after two sessions due to poor mobility. All procedures performed in this study comply with the Declaration of Helsinki and its subsequent amendments. And the study was approved by the Ethics Committee of People’s Hospital of Guanghan City (Approval Number: LS202405). Written informed consent was obtained from the patient to publish this case report and accompanying images.
On February 22, 2025, the patient was hospitalized with an acute onset of high-grade fever (39.3°C) and a generalized, non-pruritic blanching rash, accompanied by chills, dry itchy throat, anorexia, fatigue, and lumbar pain. Notably, no significant respiratory, cardiovascular, or gastrointestinal symptoms were observed. Her general condition had significantly deteriorated, characterized by poor appetite, sleep disturbance, lethargy, and recent urinary/fecal incontinence, with a total weight loss of 15 kg since the initial symptom onset. Physical examination upon admission revealed tachycardia (138 bpm), tachypnea (22 breaths/min), hypotension (87/62 mmHg), and fever (39°C), with a Performance Status (PS) score of 2. Key laboratory findings are presented in Table 1.
After admission, the patient was instructed to discontinue anti-tumor therapy, and supportive treatments such as anti-infection (amoxicillin and clavulanate potassium), anti-allergy (dexamethasone sodium phosphate + calcium gluconate), and electrolyte and fluid replacement were administered. Dermatology consultation raised suspicion of a viral rash, leading to the addition of desloratadine 5 mg po qd, topical zinc oxide lotion applied 3–4 times daily, and acyclovir 0.5 g ivgtt q12h. The patient’s skin symptoms and special treatment are shown in Figure 1.
Between February 24 and 28, 2025, the patient’s cutaneous condition deteriorated progressively. Initial diffuse erythema evolved into flaccid blisters with clear fluid and partial ulceration (Figure 2A), followed by widespread erythema, erosions, desquamation, and exudative ulceration. The most significant epidermal detachment involved the lower back, buttocks, and posterior thighs and legs (Figure 2B). On February 28, she developed dyspnea, respiratory distress, and hypoxemia, leading to a diagnosis of respiratory failure and severe exfoliative dermatitis affecting >30% of her body surface area—a serious immune-related adverse event. Based on the extent of epidermal detachment (>30% BSA) and the presence of mucosal involvement, a definitive diagnosis of Toxic Epidermal Necrolysis (TEN) was established. The SCORTEN severity-of-illness score was calculated as 4, indicating a high mortality risk (20–40%). Given the life-threatening nature of her condition, she was transferred to and managed in the Intensive Care Unit (ICU). Acyclovir and dexamethasone were discontinued. Management included non-invasive ventilation with BIPAP for respiratory support, amoxicillin-clavulanate for infection prophylaxis, intravenous methylprednisolone (80 mg daily), oral antihistamines (olopatadine and cetirizine), and topical care with fluticasone cream, burn ointment, povidone-iodine cleansing, and amikacin spray, alongside nutritional support.
Between March 1 and 4, intravenous immunoglobulin (IVIG) was administered for immunomodulation. On March 1, the patient was alert but lethargic, and afebrile. She exhibited mild tachypnea, cough with sputum, and a dry, sore throat, which limited oral intake. Dermatological examination showed generalized mild erythema, with scattered vesicles below the right ear and waist. Significant epidermal detachment was noted over the lower back, buttocks, and posterior thighs and legs, exposing erythematous dermis with considerable exudate but no active bleeding. By March 5, her mental status had improved slightly, vesicles and ulcerations persisted, but exudate had diminished. IVIG and nutritional infusions were discontinued, while anti-infective, immunosuppressive, and supportive care continued.
Between March 10 and 19, the patient’s cutaneous condition entered a recovery phase. On March 10, mild skin edema was observed, along with scattered ulcerations and exudate below the right ear and waist. Epidermal detachment persisted over the lower back, buttocks, and posterior thighs and legs, presenting a fish‑flesh appearance with exudate and scattered bleeding points. Areas of nascent epidermal regeneration were visible, with no signs of purulent discharge or suppurative foci, prompting the discontinuation of antibiotics. By March 19, partial crusting had formed in the affected regions, accompanied by granulation tissue formation, minimal exudate, and no active bleeding; mild lower limb edema remained (Figure 2C). As the patient’s clinical status continued to improve, the methylprednisolone dose was gradually tapered. The intravenous methylprednisolone dose was maintained at 80 mg/day for the first week. During the second week, the dose was tapered by 10 mg every 2 days, gradually decreasing to 40 mg/day. In the third week, the tapering regimen was adjusted to a 10-mg reduction every 3 days, with the final intravenous dose being 8 mg/day. The tapering process was uneventful, and no symptom rebound was observed throughout the entire course.
On March 25, approximately four weeks after the acute onset and diagnosis of TEN, regorafenib monotherapy was reintroduced, and no recurrent cutaneous adverse reactions were observed. By March 27, the dermatitis had significantly resolved, with new epidermis visible over the previously denuded areas and only minimal exudate at bilateral iliac lesions (Figure 2D). Intravenous corticosteroids were discontinued and transitioned to oral prednisolone (10 mg qd). The patient was discharged one week later.

Discussion

Key Findings
This report describes a case of Toxic Epidermal Necrolysis (TEN) involving more than 30% of the body surface area in a young female patient with hepatocellular carcinoma, occurring two months after initiation of combination therapy with pembrolizumab and regorafenib. Causality assessment using both the ALDEN8 and Naranjo9 scales indicated a “ probable” association for each drug. Pembrolizumab scored 5 (ALDEN) and 6 (Naranjo), while regorafenib scored 5 on both scales. However, the patient tolerated regorafenib rechallenge without recurrence, and consideration of the distinct pharmacological profiles of the two agents strongly implicates pembrolizumab as the primary causative drug. This case underscores that although severe cutaneous adverse reactions are rare, they represent potentially life-threatening complications of combination immuno-targeted therapy.

Strengths and Limitations
A key strength of this case analysis lies in its comprehensive causality assessment, which integrated the clinical timeline, drug rechallenge data, and standardized scoring systems, thereby providing compelling evidence for drug association. The detailed documentation of clinical management and outcomes offers practical insights for clinicians. However, as a single case report, the generalizability of these findings is limited. In addition, the absence of histological confirmation via skin biopsy—though not uncommon in the management of TEN—represents a methodological limitation. This decision was based on a clinical judgment that the risks of biopsy (including pain, potential infection, and delayed wound healing in a critically ill patient with extensive denudation) outweighed its diagnostic benefit, given the classic clinical presentation meeting diagnostic criteria for TEN. Future prospective studies or systematic analyses of pharmacovigilance data are warranted to better quantify the risk and characterize the clinical course of TEN associated with immune checkpoint inhibitor (ICI)-containing regimens.

Comparison with Similar Research
Our findings are consistent with emerging evidence indicating that ICIs can induce severe cutaneous immune-related adverse events (irAEs), including TEN-like reactions, albeit at low frequencies. Previous case reports have documented blistering eruptions and TEN in association with anti-PD-1 monotherapy.6 The present case is notable, however, for its occurrence in the context of combined PD-1 and tyrosine kinase inhibition. Although regorafenib has been independently linked to severe cutaneous reactions,7 the clinical course and successful rechallenge observed here suggest a dominant role for the ICI. This aligns with the established mechanism of ICI-driven, T-cell-mediated cytotoxicity, which differs from the direct epidermal toxicity typically seen with kinase inhibitors.

Explanations of Findings
The development of TEN in this patient likely results from the distinct, yet potentially synergistic, mechanisms of pembrolizumab and regorafenib. Pembrolizumab, as an anti-PD-1 antibody, disrupts immune tolerance. This can unleash autoreactive T-cell responses against keratinocytes, possibly via molecular mimicry or epitope spreading.10 In contrast, regorafenib is a multi-kinase inhibitor. By blocking multiple signaling pathways, it may compromise epidermal integrity and vascular homeostasis.11,12 This effect could potentially lower the threshold for severe cutaneous immunotoxicity.
The differing pharmacological profiles of the two drugs support this mechanistic interpretation. Immune-related skin adverse events from pembrolizumab typically arise weeks to months after initiation and may persist due to the prolonged half-life of ICIs.10,13,14 Regorafenib-related cutaneous reactions (eg, hand-foot syndrome) usually occur earlier, are dose-dependent, and often resolve after withdrawal.7,15 The onset of TEN after two months of combination therapy aligns with the characteristic latency of ICI-related irAEs. Furthermore, the lack of recurrence upon regorafenib rechallenge robustly indicates that the sustained immune activation triggered by pembrolizumab was the principal driver in this setting.

Implications and Actions Needed
This case highlights critical lessons for managing severe irAEs in patients receiving combination immuno-oncology therapy. First, it underscores the essential role of clinical pharmacists in early recognition and causality assessment. Pharmacists are pivotal in identifying high-risk drug combinations, applying standardized tools like the ALDEN and Naranjo scales, and differentiating irAEs from other causes.
Second, it validates a structured, multidisciplinary management protocol for patients. Key steps include: Immediate suspension of suspected drugs; Prompt initiation of immunomodulatory therapy16–19 (eg, high-dose corticosteroids and IVIG for life-threatening cases like TEN); Comprehensive supportive care;20,21 Akin to burn management, to prevent complications. Third, it informs difficult rechallenge decisions. The decision to cautiously reintroduce regorafenib monotherapy was based on a careful risk-benefit analysis conducted by the multidisciplinary team, including clinical pharmacy. This analysis considered: 1) the strong mechanistic and clinical evidence pointing to pembrolizumab as the primary culprit; 2) the limited alternative treatment options for advanced HCC; and 3) the imperative to control cancer progression. Rechallenge was deemed justifiable under close monitoring, which in this case was successful and helped confirm the causative agent. Finally, it reinforces the need for proactive strategies. Robust pharmacovigilance systems, thorough patient education about potential skin toxicities, and seamless collaboration between oncology, dermatology, and pharmacy are paramount to optimizing the safety of modern anticancer regimens.

Conclusions
While combining immune checkpoint inhibitors (ICIs) with other therapies has improved oncology outcomes, it also elevates the risk of severe immune-related adverse events (irAEs). This case underscores the need for heightened vigilance and multidisciplinary collaboration—especially as ICI use expands—to enable early detection and management of serious toxicities such as cutaneous irAEs. Crucially, patients with rapidly progressing rashes should be referred for urgent dermatology consultation. Furthermore, clear patient education at the initiation of therapy is imperative, ensuring they understand the need to seek immediate medical attention upon developing any skin symptoms. In this setting, clinical pharmacists assume a critical role in adverse event identification, therapy optimization, and ensuring patient safety through structured pharmaceutical care.