Early-Onset KEAP1- and ERBB2-Mutant Lung Adenocarcinoma after CAR T-cell Therapy: A Case Report Suggesting a Potential Contribution of Host Immune Exhaustion

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell lymphomas. However, the emerging risk of secondary primary malignancies and the efficacy of subsequent immune checkpoint inhibitor (ICI) therapy in the unique post-CAR-T immune milieu remain poorly understood. A 59-year-old man with a history of heavy smoking achieved complete remission (CR) of diffuse large B-cell lymphoma after CD19-targeted CAR-T-cell therapy. Four months post-CR, a pleural-based mass emerged in the right upper lobe. Biopsy and immunohistochemistry confirmed a primary poorly differentiated lung adenocarcinoma (LCA−, CK20−, Calretinin−, Ber-EP4+, and TTF-1−). Despite high PD-L1 expression (tumor proportion score ≥ 75%) and high tumor mutational burden of 24 mut/Mb, the patient exhibited primary resistance to pembrolizumab. Comprehensive genomic profiling (CGP) subsequently identified an ERBB2 (c.929C>A (p.Ser310Tyr)) mutation and a KEAP1 (c.596_597insT) frameshift mutation. Although trastuzumab deruxtecan is reimbursed under insurance in Japan, its use was deferred due to the risk of severe hematological toxicity. Furthermore, the patient was deemed ineligible for clinical trials of a novel HER2-tyrosine kinase inhibitor due to a history of lymphoma. The patient received steroid therapy for grade 3 radiation pneumonitis following palliative radiotherapy. The failure of ICI therapy despite favorable "hot" biomarkers suggests a potential synergy between host-side T-cell exhaustion and tumor-side genomic resistance mediated by KEAP1 and ERBB2 mutations. This case emphasizes the need for early CGP and integrated immune profiling in CAR-T survivors.