Yoshihiko Taniguchi

Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non–small cell lung cancer

Programmed death‐ligand 1 (PD‐L1) expression status is inadequate for indicating nivolumab in patients with non–small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation‐related parameters) on progression‐free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27–87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin <3.7 g/dL, neutrophil‐to‐lymphocyte ratio ≥4, and ALI <18 were significantly associated with poor PFS and early progression on univariate analysis. Multivariate analyses revealed that pretreatment ALI <18 was independently associated with inferior PFS (median, 1.4 vs. 3.7 months, P < 0.001) and a higher likelihood of early progression (odds ratio, 2.76; 95% confidence interval 1.44–5.34; P = 0.002). The pretreatment ALI was found to be a significant independent predictor of early progression in patients with advanced NSCLC receiving nivolumab, and may help identify patients likely to benefit from continued nivolumab treatment in routine clinical practice.

Severe acute interstitial lung disease after nivolumab in three non-small cell lung cancer patients with imaging findings of airway obstruction adjacent to lung tumors

Nivolumab has been associated with unique adverse events known as immune-related adverse events. Although interstitial lung disease (ILD) is a life-threatening immune-related adverse event, the risk of ILD during nivolumab treatment is unclear. In this report, we encountered three patients with stage IV non-small cell lung cancer with signs of lung obstruction caused by tumor-mediated compression on imaging who developed acute ILD within 10 days of commencing nivolumab treatment. The first case involved a 74-year-old Japanese female never-smoker, the second a 67-year-old Japanese female never-smoker, and the third a 75-year-old Japanese female current-smoker. The first patient was administered nivolumab as third-line chemotherapy, the second was administered nivolumab as fifth-line chemotherapy, and the third was administered nivolumab as second-line chemotherapy. Regardless of aggressive treatments for ILD, 2 of 3 patients died. The findings of these cases suggest that obstructive findings in the lungs, which easily cause infections, may be an important risk factor for nivolumab-induced ILD.

Analysis of early death in Japanese patients with advanced non-small cell lung cancer treated with nivolumab

Micro‐Abstract In the first 3 months of nivolumab treatment, 38 (18.6%) of 201 patients with non–small‐cell lung cancer died (early death). An Eastern Cooperative Oncology Group performance status score ≥ 2, pretreatment of C‐reactive protein‐to‐albumin ratio > 0.3, and poor response to prior treatment were risk factors of early death. The major reasons for early death were disease progression and/or immune‐related adverse events. Background: The increased risk for early death owing to anti‐programmed cell death 1 inhibitors is a major disadvantage that requires special management. We evaluated the frequency, causes, and risk factors of early death during nivolumab treatment for non‐small cell lung cancer (NSCLC) in a Japanese clinical setting. Patients and Methods: The medical records of patients with NSCLC who started receiving nivolumab between December 17, 2015 and July 31, 2016 in 3 Japanese institutes were collected. Early death was defined as any death within 3 months from the start of nivolumab treatment, irrespective of its cause. Treatment response was evaluated using the Response Evaluation Criteria In Solid Tumors criteria, version 1.1. Results: A total of 201 patients with NSCLC were enrolled, and 38 (18.9%) died within the first 3 months. Thirty‐one (81.6%) patients who experienced early death developed progressive disease, whereas 14 (36.8%) patients who experienced early death demonstrated nivolumab‐induced immune‐related adverse events, which required corticosteroid intervention, including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic regression demonstrated that an Eastern Cooperative Oncology Group performance status score ≥ 2 (odds ratio [OR], 5.66; 95% confidence interval [CI], 2.01‐15.61; P < .001), C‐reactive protein‐to‐albumin ratio > 0.3 (OR, 10.56; 95% CI, 3.61‐30.86; P < .001), and the response to prior treatment (OR, 2.07; 95% CI, 1.03‐4.14; P = .041) were independent predictors for early death. Conclusion: Disease progression and immune‐related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology Group performance status score ≥ 2, pretreatment C‐reactive protein‐to‐albumin ratio > 0.3, and poor response to prior treatment were associated with early death.

Association Between Imaging Findings of Airway Obstruction Adjacent to Lung Tumors and the Onset of Interstitial Lung Disease After Nivolumab

Background: Compared to conventional cytotoxic chemotherapy, immune checkpoint inhibitors have shown a significant efficacy in the treatment of lung cancer. Although interstitial lung disease (ILD) is an important adverse event in immunotherapy, risk factors for ILD remain unclear. Patients and Methods: In this multicenter cohort study (UMIN000025908), 201 patients who were treated with nivolumab were retrospectively reviewed. Associations between the incidence of ILD and patient characteristics were evaluated. ILD grade and progression-free survival were analyzed according to the presence or absence of imaging findings of airway obstruction adjacent to lung tumors (IAOT). Results: In the multivariate analysis, the odds ratio (OR) of ILD for patients with a history of radiation pneumonitis or IAOT was 3.96 (p=0.012) and 6.59 (p=0.004), respectively. ILD occurred in six (37.5%) out of 16 patients with IAOT and 19 (10.3%) out of 185 patients without IAOT. Three out of the six patients with ILD and IAOT had ILD of grade 4 or more. The median progression-free survival of patients with and without IAOT was 0.9 and 3.2 months, respectively (p<0.001). Conclusion: IAOT was strongly associated with the occurrence of ILD after therapy with nivolumab.

Metastatic site as a predictor of nivolumab efficacy in patients with advanced non-small cell lung cancer: A retrospective multicenter trial

Purpose 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. Methods 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. Results 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. Conclusion Liver and lung metastases and a poor performance status are independent predictors of nivolumab efficacy in patients with advanced non-small cell lung cancer.

Impact of metastatic status on the prognosis of EGFR mutation‑positive non‑small cell lung cancer patients treated with first‑generation EGFR‑tyrosine kinase inhibitors

The aim of the present study was to analyze the impact of metastatic status on the prognosis of epithelial growth factor receptor (EGFR) mutation-positive patients with non-small cell lung cancer (NSCLC) treated with first-generation EGFR-tyrosine kinase inhibitors (TKIs). A total of 178 EGFR mutation-positive patients with stage IIIB-IV and relapsed NSCLC who were treated with gefitinib or erlotinib as the first-line treatment were enrolled in the present study. Metastatic status, progression-free survival (PFS), overall survival (OS) and treatment-response rates were investigated. The association between the number of metastatic organ sites and patient prognosis was also investigated. The median age at the time of treatment was 72 (range, 39-91) years. A total of 168 patients had adenocarcinoma; 156 were treated with gefitinib. Patients with brain metastases, bone metastases, liver metastases and pleural effusion exhibited a significantly reduced PFS and OS time in the univariate analysis, compared with patients without each of these symptoms. In the multivariate analysis, bone metastasis was associated with a poorer PFS (hazard ratio, 2.11; 95% confidence interval, 1.44-3.09; P<0.001) and brain metastasis was associated with a poorer OS (hazard ratio, 2.41; 95% confidence interval, 1.46-3.95; P<0.001). No association was observed between metastatic status and treatment response rates. Higher numbers of different sites of organ metastases were associated with significantly poorer PFS and OS. Bone, brain metastasis and higher numbers of metastatic organ sites are negative prognostic factors for EGFR mutation-positive NSCLC patients treated with first-generation EGFR-TKIs.

Combination of virtual bronchoscopic navigation, endobronchial ultrasound, and rapid on-site evaluation for diagnosing small peripheral pulmonary lesions: a prospective phase II study.

BACKGROUND The diagnostic yield of peripheral pulmonary lesions (PPLs) by flexible bronchoscopy (FB) is still insufficient. To improve the diagnostic yield of bronchoscopy, several techniques such as endobronchial ultrasound (EBUS), virtual bronchoscopic navigation (VBN), and rapid on-site evaluation (ROSE) have been examined. The primary purpose of the present study was to evaluate the usefulness of combining EBUS, VBN, and ROSE for diagnosing small PPLs. METHODS Patients with PPLs 30 mm or less on chest computed tomography (CT) were prospectively enrolled. We determined the responsible bronchus for the target lesions using VBN before bronchoscopy was performed. EBUS and ROSE were performed during the examination to determine whether the bronchus and specimen were adequate. On the basis of previous studies, we assumed that the diagnostic yield of 85% among eligible patients would indicate potential usefulness, whereas, the diagnostic yield of 75% would indicate the lower limit of interest. The required number of patients was estimated as 45 for a one-sided α value of 0.2 and a β value of 0.8. The primary study endpoint was the diagnostic yield. RESULTS Between June 2014 and July 2015, we enrolled 50 patients in the present study, and we excluded 5 patients. The total diagnostic yield of 45 PPLs was 77.7%. In cases of lung cancer, the diagnostic yield was 84.2%. The sensitivity, specificity, positive predictive value, and negative predictive value of ROSE were 90.6%, 92.3%, 96.7%, and 80.0%, respectively. The diagnostic yield of PPLs from 20 to 30 mm was 87.5%, and the diagnostic yield of PPLs less than 20 mm was 66.7%. PPLs for which the probe was located within the lesion had the highest diagnostic yield. CONCLUSIONS We could not demonstrate usefulness for diagnosing small PPLs by combining EBUS, VBN, and ROSE. However, combining these techniques may be useful for diagnosing lung cancer.

Comparing Gefitinib and Erlotinib With Regard To Brain Metastases Recurrence in EGFR-Mutant Non-Small Cell Lung Cancer Patients

Brain metastases of lung cancer are associated with a poor prognosis. Little research has been conducted to directly compare erlotinib with gefitinib regarding the frequency of central nerve system recurrence. This is the first study to directly compare erlotinib with gefitinib in terms of brain metastases recurrence rates in patients with EGFR-mutant NSCLC who had no brain metastasis at the time of starting TKI treatment. This was a single-center retrospective study. Advanced or recurrent non-small cell lung cancer patients with no brain metastases at the time of starting initial tyrosine kinase inhibitor treatment who received either gefitinib or erlotinib monotherapy were selected. The primary endpoint was the incidence of brain metastases, and secondary endpoints included the objective response rate, progression-free survival, overall survival, and Post-Progression Survival in subgroups based on tyrosine kinase inhibitor treatment and the occurrence of brain metastases. There were 119 patients in the gefitinib group and 13 patients in the erlotinib group. Brain metastases at disease progression were observed in 16 patients in the gefitinib group, and in no patients in the erlotinib group (13.5% vs. 0%, p=0.37). The median overall survival was 29.2 months in the gefitinib group and was not reached in the erlotinib group (p=0.14). The median PPS was 15.5 months in the gefitinib group and 23.7 months in the erlotinib group (p=0.11). Based on the occurrence of brain metastases, Post-Progression Survival was significantly longer in the no brain metastases group (8.0 months vs. 17.9 months, p=0.01). These data showed the possibility of a lower central-nerve-system recurrence rate with erlotinib compared with gefitinib. Post-Progression Survival in patients with brain metastases was significantly shorter than that of patients without brain metastases.