Title: Liver Metastasis Is Associated with Poor Progression-Free Survival in Patients with Non–Small Cell Lung Cancer Treated with Nivolumab
Abstract: Nivolumab, an anti–programmed death 1 antibody, has been approved for the treatment of NSCLC. Although nivolumab improves overall survival (OS) more than docetaxel when used as second-line therapy, the rate of objective response remains at approximately 20%. There are currently no precise biomarkers for nivolumab; therefore, biomarkers that predict treatment responses to nivolumab need to be investigated. Between December 2015 and December 2016, 83 consecutive patients with histologically or cytologically confirmed advanced NSCLC were treated with nivolumab. Of these patients, 79 (all of whom were registered at Kyoto University Hospital) participated in the present study. The remaining four patients were excluded because three refused to give informed consent and one had a history of double cancer. This study aimed to investigate differences in the progression-free survival (PFS) of patients receiving nivolumab according to their baseline characteristics. Median PFS in this group was 67 days (95% confidence interval: 54–99). Median PFS was significantly longer in patients without liver metastasis than in patients with liver metastasis at baseline imaging (100 versus 42 days [p = 0.0002, log-rank test]) (Fig. 1). Disease control rates were significantly higher in patients without liver metastasis (60% versus 27% [p = 0.0126, Fisher’s exact test]). No significant differences were observed in other clinical characteristics, including age, sex, smoking status, Eastern Cooperative Oncology Group performance-status score, number of chemotherapy cycles, histologic type, and EGFR mutation status, between patients with and without liver metastasis. CheckMate 057, a randomized phase III study, suggested that docetaxel is a more favorable treatment than nivolumab for subgroups of patients receiving third-line therapy, those who had never smoked, and those with EGFR mutation–positive status.1Borghaei H. Paz-Ares L. Horn L. et al.Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N Engl J Med. 2015; 373: 1627-1639Crossref PubMed Scopus (6814) Google Scholar In the present study, never smoking was also observed to be a poor predictive factor for PFS (51 versus 91 days [p = 0.0079]); however, no significant differences were observed in other characteristics, including second-line versus more than third-line therapy (126 versus 57 days [p = 0.0539]) and EGFR mutation status (82 versus 57 days [p = 0.0914]). In a previous study, OS was shorter in patients with NSCLC who had liver metastasis than in those with different metastatic locations excluding the liver.2Castañón E. Rolfo C. Viñal D. et al.Impact of epidermal growth factor receptor (EGFR) activating mutations and their targeted treatment in the prognosis of stage IV non-small cell lung cancer (NSCLC) patients harboring liver metastasis.J Transl Med. 2015; 13: 257Crossref PubMed Scopus (26) Google Scholar Liver metastasis has been identified as a poor predictive factor for PFS in patients with NSCLC treated with first-line cytotoxic chemotherapy.3Hoang T. Dahlberg S.E. Sandler A.B. Brahmer J.R. Schiller J.H. Johnson D.H. Prognostic models to predict survival in non-small-cell lung cancer patients treated with first-line paclitaxel and carboplatin with or without bevacizumab.J Thorac Oncol. 2012; 7: 1361-1368Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar In patients with stage IV lung adenocarcinoma treated with first-line gefitinib, liver metastasis was associated with worse PFS and OS.4Wu K.L. Tsai M.J. Yang C.J. et al.Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib.Lung Cancer. 2015; 88: 187-194Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar In patients with advanced melanoma who received pembrolizumab or nivolumab, liver metastasis was a poor predictive factor for responses to anti–programmed death 1 monotherapy.5Nosrati A. Tsai K.K. Goldinger S.M. et al.Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy.Br J Cancer. 2017; 116: 1141-1147Crossref PubMed Scopus (94) Google Scholar In conclusion, the results present here suggest that liver metastasis is a poor predictive factor for the efficacy treatment with nivolumab. To the best of our knowledge, the relationship between the efficacy of nivolumab and liver metastasis has never before been examined in patients with NSCLC. Because this was a retrospective study with a small sample size, further investigations are needed to confirm the results obtained.