Date Published: February 22, 2018
Publisher: Public Library of Science
Author(s): Motohiro Tamiya, Akihiro Tamiya, Takako Inoue, Madoka Kimura, Kei Kunimasa, Kenji Nakahama, Yoshihiko Taniguchi, Takayuki Shiroyama, Shun-ichi Isa, Kazumi Nishino, Toru Kumagai, Hidekazu Suzuki, Tomonori Hirashima, Shinji Atagi, Fumio Imamura, Aamir Ahmad.
To conduct a retrospective multicenter trial to determine the significance of metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer.
This study was conducted across three medical centers in Japan. We retrospectively reviewed all patients who commenced nivolumab treatment at these centers between December 17, 2015 and July 31, 2016. Clinical data were collected, including age, sex, smoking status, Eastern Cooperative Oncology Group performance status, and metastatic site (lymph nodes, liver, brain, bone, lungs [intrapulmonary metastasis], and malignant pleural effusion) at the time of commencing nivolumab treatment. Patients were followed-up until March 31, 2017.
Two hundred and one patients were enrolled. The median age at the time of commencing nivolumab treatment was 68 (range, 27–87) years. One hundred and thirty-five patients were male, 157 patients had a history of smoking, 153 patients had a performance status of 0–1, and 42 patients had squamous cell carcinoma. The median progression-free survival of all patients was 2.5 months. In the univariate analysis, a performance status of ≥2 (hazard ratio [HR]: 1.89, 95.0% confidence interval [CI]: 1.33–2.69; p < 0.001) and liver (HR: 2.09, 95.0% CI: 1.35–3.25; p < 0.001) and lung (HR: 1.57, 95.0% CI: 1.14–2.16; p < 0.01) metastases correlated with a significantly shorter progression-free survival in nivolumab-treated patients. In the multivariate analysis, a performance status of ≥2 (HR: 1.54, 95.0% CI: 1.05–2.25; p < 0.05) and liver (HR: 1.90, 95.0% CI: 1.21–2.98; p < 0.01) and lung (HR: 1.41, 95.0% CI: 1.00–1.99; p < 0.05) metastases were independently correlated with a significantly shorter progression-free survival in nivolumab-treated patients. Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.
Lung cancer is the leading cause of cancer-related deaths worldwide . Until recently, effective treatments have been limited for patients with non-small cell lung cancer (NSCLC) whose disease progresses after first- or second-line chemotherapy. Docetaxel is associated with a longer survival time than best supportive care  and erlotinib has been shown to improve overall survival compared with placebo as a second-line chemotherapy for advanced NSCLC . Newer agents (e.g., pemetrexed) have better side effect profiles and have shown non-inferiority to docetaxel. However, these agents have not demonstrated superiority to docetaxel with respect to overall survival when used as a second-line treatment . Recently, combined docetaxel and ramucirumab, a fully humanized immunoglobulin G1 monoclonal antibody that specifically binds with high affinity to the extracellular domain of vascular endothelial growth factor receptor 2, has been shown to improve survival compared with docetaxel alone as a second-line chemotherapy . However, the combination of docetaxel and ramucirumab proved to be more toxic and the benefits were modest. Therefore, novel therapeutic approaches are required.
This study was conducted across three medical centers in Japan. The study design was approved by the Institutional Review Board of each participating institution. Research was conducted in accordance with the Declaration of Helsinki and the World Health Organization’s Guidelines for Good Clinical Practice. All study participants have provided informed written consent of receiving nivolumab treatment. The study is registered with the University Hospital Medical Information Network Clinical Trials Registry in Japan (UMIN000025908).
Two hundred and one patients were treated with nivolumab and enrolled in this study (S1 Table). The median follow up time of this study was 12.2 months. At the time of commencing nivolumab treatment, the median age was 68 (range, 27–87) years. One hundred and thirty-five patients were male, 157 patients had a history of smoking, 153 patients had an ECOG PS of 0–1, the median number of previous treatment was 2, 42 patients had SQ carcinoma, and 37 patients had EGFR mutation. Intrapulmonary metastasis, thoracic LNs metastasis, MPE, bone metastasis, brain metastasis, and liver metastasis were observed in 115 (57.2%), 105 (52.2%), 89 (44.3%), 66 (32.8%), 51 (25.4%), and 29 (14.4%) patients, respectively (Table 1).
Previous studies have shown that among patients receiving third line therapy, those who had never smoking status, those with central nerve system metastases, those with EGFR mutation, and those with poor PS [11,12]. Moreover, the PFS may be shorter in a clinical setting than in a clinical trial. In this study, we particularly focused on between metastatic site and effect of nivolumab.
Liver and lung metastases and a poor ECOG PS are independently correlated with a shorter median PFS in nivolumab-treated patients with NSCLC in a real-world setting. Nivolumab-treated patients with NSCLC who have liver and lung metastases and a poor ECOG PS will require careful monitoring.