Partial Remission of Hepatic Metastatic Lesion but Complicated with Secondary and Refractory Fever Lead by Nivolumab in a Patient with Lung Adenocarcinoma Presenting Gefitinib Acquired Resistance

To the Editor: Nivolumab, an antibody that blocks the immune-checkpoint inhibitor programmed cell death protein 1 (PD-1), has recently shown some promising results in clinical trials for all nonsmall cell lung cancer subtypes.[12] It is required that clinic practice about anti-PD-1 antibodies provided real data never observed in previously known clinical trials. In addition, It is also needed to assess the role of nivolumab in the subsequent therapy of tyrosine kinase inhibitor (TKI) acquired resistance. A 60-year-old Chinese woman having a 1 month history of a dry cough was taken to the outpatient of the First Hospital of Taicang City. A chest computed tomography (CT) scan revealed a mass lesion (3 cm × 2 cm) on the right hilus. An abdominal CT showed multiple solid lesions in the liver [Figure 1a]. Clinically, bronchoscope biopsy and histopathological examination revealed lung adenocarcinoma (Stage IV). Chemotherapy, in which the regimen included pemetrexed at 500 mg/m2 in combination with cisplatin at 75 mg/m2, was administered with standard premedication. Due to the poor clinical status, gefitinib was alternatively administered at a daily dose of 250 mg. A good response to gefitinib was observed in lung, but the liver metastasis had clearly increased after 30 months of TKI therapy [Figure 1b]. At that point, we decided to treat the patient with nivolumab. After two courses of a single dose of nivolumab treatment at 2 mg/kg, radiographic examinations demonstrated a significant improvement in the liver lesions [Figure 1c].Figure 1: (a) Metastatic hepatic carcinoma at diagnosis. (b) The liver metastasis had clearly increased after 30 months of TKI therapy. (c) Anti-PD-1 antibody lead to partial remission of hepatic metastatic carcinomas. (d) Within the window of follow-up (n = 35 days), secondary fever was presented in the case after receiving anti-PD-1 antibody therapy. TKI: Tyrosine kinase inhibitor; PD-1: Programmed cell death protein 1.However, about 1 week after the first course of nivolumab treatment, continual fevers were recorded. The co-infection was ruled out based on the negative microbiological testing and the absence of infectious symptoms. Hematologic and biochemical tests were in the normal range. A CT scan identified bilateral pleural effusion but no consolidation or progression of the primary tumor. The results of pleural effusion tests were indicative of transudate. Patient's serum levels of anti-native DNA, anti-nuclear, and anti-cardiolipin antibodies were within the normal range. Taking into account the result of extensive medical tests, we applied methylprednisolone (1.5 mg/kg) for 1 week, followed by oral prednisone at a dosage of 0.5 mg/kg of body mass a day. However, the fever of the patient was not improved during the follow-up [Figure 1d]. Immunotherapy is rapidly being integrated into oncology practice and is poised to alter the therapeutic landscape for a variety of malignancies. However, there are still some reports which pointed out that a certain proportion of Grade 3 or 4 immune-related adverse events (irAEs) of PD-1/PD-L1 inhibitors occurred.[3] Taken together, it was a rare case that exhibited the efficacy of nivolumab on progressive hepatic metastatic carcinomas resulting from TKI acquired resistance in the real world. As an irAEs, the patient suffered from adverse event shortly after administration of nivolumab and manifested with refractory and continual fever even treatment withdrawal. Financial support and sponsorship This work was supported by a grant from Key Talent of Suzhou Health (2015, to Cheng Chen). Conflicts of interest There are no conflicts of interest. Acknowledgments We thanked Prof. Jim Xiang (Cancer Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Canada) for providing constructive criticism for this manuscript.

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