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Diagnostic challenge of delayed immune-related hepatitis during zongertinib treatment after nivolumab plus ipilimumab in a 52-year-old man with HER2-mutant non-small cell lung cancer: a case report

Year: 2026

Type: article

Abstract: Background: Delayed immune-related hepatitis after discontinuation of immune checkpoint inhibitors (ICIs) is increasingly recognized, but attribution is difficult when liver injury develops during subsequent tyrosine kinase inhibitor (TKI) therapy. This diagnostic dilemma has not been well described during human epidermal growth factor receptor 2 (HER2)-selective TKI treatment after dual ICI therapy. Case Description: A 52-year-old Japanese man with HER2 exon 20 insertion-positive stage IVB non-small cell lung cancer received nivolumab plus ipilimumab from February 28 to November 13, 2025, and developed grade 2 oral mucositis, grade 2 adrenal insufficiency, and grade 1-2 skin toxicity. Zongertinib was initiated on November 26. Routine testing on January 6, 2026 showed grade 3 hepatocellular injury, and zongertinib was withheld. Despite drug withdrawal, liver injury progressed, and he was admitted with mild fatigue on January 20, when aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase levels were 774, 1,386, 156, and 160 U/L, respectively. Total bilirubin remained approximately 1.0 mg/dL. Viral and autoimmune testing and imaging disclosed no alternative cause. Liver biopsy showed active hepatitis with lymphocyte-predominant portal and lobular inflammation and interface activity, findings compatible with an immune-mediated hepatitis pattern but not specific for the causative agent. Prednisolone 40 mg/day (approximately 0.5 mg/kg/day) produced rapid biochemical improvement with resolution of fatigue. Zongertinib was resumed on February 11 and continued without recurrent hepatitis through June 2026. Conclusions: The progression of liver injury despite zongertinib withdrawal, multiple prior immune-related adverse events, exclusion of competing causes, compatible histology, corticosteroid responsiveness, and absence of recurrence after zongertinib rechallenge collectively favored delayed immune-related hepatitis, although zongertinib-associated drug-induced liver injury could not be completely excluded. In similar cases, a structured etiological assessment, including liver biopsy when the result may alter cancer treatment, can help guide management.

Source: Translational Lung Cancer Research

DOI: 10.21037/tlcr-2026-0856