Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.

Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation - or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Fujimoto D ，Yoshioka H ，Kataoka Y ，Morimoto T ，Kim YH ，Tomii K ，Ishida T ，Hirabayashi M ，Hara S ，Ishitoko M ，Fukuda Y ，Hwang MH ，Sakai N ，Fukui M ，Nakaji H ，Morita M ，Mio T ，Yasuda T ，Sugita T ，Hirai T ... -  《-》

Real-world Efficacy and Safety of Nivolumab for Advanced Non-Small-cell Lung Cancer: A Retrospective Multicenter Analysis.

Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non-small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy. A total of 142 patients with advanced non-small-cell lung cancer who were administered nivolumab at Keio University and affiliated hospitals in Japan from January to July 2016 were enrolled. The treatment efficacy and adverse events were retrospectively reviewed, and the clinical characteristics associated with the nivolumab response were evaluated using univariate and stratified analyses and the Cochran-Mantel-Haenszel test. The objective response rate was 17.0% (95% confidence interval [CI], 12.0%-24.0%), the median progression-free survival (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely associated with the treatment response (P < .05), and the difference in PFS for the mutation-positive versus mutation-negative patients was statistically significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P = .029). Previous radiotherapy also had a positive association with the treatment response (P = .012). The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status and previous radiotherapy might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer.

Kobayashi K ，Nakachi I ，Naoki K ，Satomi R ，Nakamura M ，Inoue T ，Tateno H ，Sakamaki F ，Sayama K ，Terashima T ，Koh H ，Abe T ，Nishino M ，Arai D ，Yasuda H ，Kawada I ，Soejima K ，Betsuyaku T ，Keio Lung Oncology Group (KLOG) ... -  《-》

Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: A multicenter, open-label single-arm phase II trial.

The efficacy of nivolumab against metastatic non-small cell lung cancer (NSCLC) has been demonstrated; however, pneumonitis is relatively common and is a potentially life-threatening immune-related adverse event. Patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis and are generally excluded from clinical trials. Additionally, to date, a multicenter prospective trial for previously-treated NSCLC patients with IIP has not been performed. To fulfill this unmet medical need, we conducted a multicenter, open-label single-arm phase II trial to evaluate the efficacy and safety of nivolumab in NSCLC patients with mild IIP. Eligible patients had previously-treated, inoperable NSCLC with mild IIPs. Mild IIP was defined as a predicted vital capacity of at least 80% and possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern by chest high-resolution computed tomography. Primary end point was the 6 months PFS rate and secondary end point was the safety of this therapy. Eighteen patients were enrolled in this trial. Six months PFS rate was 56%, response rate was 39%, and disease control rate was 72%. There were no treatment-related deaths. One drug-related grade 3/4 nonhematologic event (grade 3 neurotoxicity) was observed. Two patients had grade 2 pneumonitis which improved by corticosteroid therapy. Nivolumab could be an effective therapy for NSCLC patients with mild IIPs.

Fujimoto D ，Yomota M ，Sekine A ，Morita M ，Morimoto T ，Hosomi Y ，Ogura T ，Tomioka H ，Tomii K ... -  《-》

Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan.

To describe the treatment patterns and determine the effectiveness and safety of nivolumab treatment for non-small cell lung cancer (NSCLC) in real-world setting in Japan. Japanese patients with NSCLC who received nivolumab were analyzed retrospectively. Patients who had started nivolumab treatment between April 2016 and December 2016 were enrolled. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness and safety of nivolumab treatment and that of treatments just before and after nivolumab treatment, and programmed death-ligand 1 (PD-L1) expression status, if available, were collected. Factors associated with nivolumab effectiveness identified by univariate and multivariate analyses were further investigated for plotting Kaplan-Meier curves of epidermal growth factor receptor (EGFR) gene mutation status, PD-L1 expression status, and Eastern Cooperative Oncology Group performance status (ECOG PS). In this study, 901 NSCLC patients were enrolled. Nivolumab was used the most as a second line treatment with a median number of nivolumab doses of five. The median overall survival (OS) was 14.6 months, one-year survival rate was 54.3 %, and median progression-free survival (PFS) was 2.1 months. The objective response rate was 20.5 % and disease control rate was 57.4 %. According to multivariate analyses, better OS and PFS were associated with favorable ECOG PS and absence of liver metastasis. Better PFS was observed in patients without EGFR mutation and patients with smoking history. PFS and best overall response in PD-L1 expression subgroups were expression level-dependent. The overall incidence of irAEs was 45.8 %, and the incidence of adverse events of grade 3 or higher was 14.0 %. The real-world effectiveness and safety of nivolumab is consistent with that reported by previous clinical trials and other real-world data. Subgroup analysis showed that ECOG PS, EGFR mutation status, smoking status, and PD-L1 were associated with the effectiveness of nivolumab.

Morita R ，Okishio K ，Shimizu J ，Saito H ，Sakai H ，Kim YH ，Hataji O ，Yomota M ，Nishio M ，Aoe K ，Kanai O ，Kumagai T ，Kibata K ，Tsukamoto H ，Oizumi S ，Fujimoto D ，Tanaka H ，Mizuno K ，Masuda T ，Kozuki T ，Haku T ，Suzuki H ，Okamoto I ，Hoshiyama H ，Ueda J ，Ohe Y ... -  《-》

Prognostic value of morphological characteristics assessed by CT scan in patients with non-small cell lung cancer treated with nivolumab.

Nivolumab is known to demonstrate superior overall survival compared with docetaxel in pretreated non-small cell lung cancer (NSCLC) patients. Programmed death-ligand 1 (PD-L1) expression is reported to predict the outcome of treatment by nivolumab in lung cancer patients. However, the significance of the morphological characteristics of chest computed tomography (CT) as predictors of nivolumab efficacy for advanced NSCLC patients remains unknown. We performed a multicenter retrospective trial from April 2013 to March 2017, to assess the significance of CT morphological characteristics as predictors of nivolumab efficacy for advanced NSCLC patients. A total of 78 NSCLC patients pretreated with nivolumab were enrolled. A chest radiologist used chest CT to assess the following morphological characteristics of each patient's main tumor and intrathoracic status prior to nivolumab treatment; interstitial septal thickening, peritumoral ground-glass opacity, spiculated margin, air bronchogram, cavity or necrosis, adjacent organ invasion, bulky lymph node, and accumulation of small lymph nodes. Logistic regression and Cox proportional hazards regression models were used to analyze outcomes. A total of 60 (77%) patients were male and 72 (92%) had a performance status (PS) of 0 or 1. The objective response rates of male patients and heavy smokers were significantly higher than those of female patients and light or never smokers, respectively. Multivariate analysis identified light or never smoking, poor PS, histological type of squamous cell carcinoma, and interstitial septal thickening as independent negative predictors of progression free survival (PFS). Interstitial septal thickening was a significant and independent predictor of PFS in NSCLC patients treated with nivolumab. SIGNIFICANT FINDINGS OF THE STUDY: Interstitial septal thickening is an independent predictor of progression free survival in non-small lung cancer patients treated with nivolumab. The current study reveals the significance of morphological characteristics obtained via chest computed tomography as a predictor of nivolumab efficacy for advanced non-small cell lung cancer patients.

Minemura H ，Moriya H ，Imai H ，Sugiyama T ，Yamada Y ，Higuchi M ，Kaira K ，Ozaki Y ，Kanazawa K ，Yokouchi H ，Kasai T ，Kaburagi T ，Suzuki H ，Minato K ，Shibata Y ... -  《-》