Katsuya Hirano

Prior radiotherapy does not predict nivolumab response in non-small-cell lung cancer: a retrospective cohort study

Nivolumab is one of the standard therapy for previously treated advanced non-small-cell lung cancer (NSCLC) [1]. Durable responses are observed in NSCLC patients treated with nivolumab, but there are fewer than half of patients who will benefit [1]. Immunotherapy administration after radiotherapy may provide synergistic effects (i.e. abscopal effect) [2, 3]. However, it is unclear whether past radiotherapy especially to lung is predictive or not in NSCLC who receive immune checkpoint inhibitor. We conducted a multicenter retrospective cohort study. We included consecutive patients treated with nivolumab between January 2016 and October 2016 after the second line systemic chemotherapy outside of a clinical trial. Variables were retrieved from the medical records before the administration of nivolumab. All variables were dichotomized based on previous study or median [4, 5]. Primary endpoint was progression-free survival (PFS) defined by response evaluation criteria in solid tumors (RECIST) 1.1. Two researchers evaluated the endpoint independently. Any disagreements were resolved by discussion. Cox proportional hazards models were used to assess the impact of pretreatment markers on PFS. One hundred forty-six patients were included. Median observation period were 153 days. Patients characteristics were as follows: median age 69 years, female 36 (25%), never smoker 28 (19%), performance status<2 110 (75%), non-squamous histology 107 (73%). The main results are shown in Table 1. No difference of progression free survival between those without past radiotherapy and received in past 6 months was noted [adjusted hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.37–1.14]. Ten patients (7%) suffered pneumonitis. Two patients received radiotherapy to the lung before one year. Eight patients did not received radiotherapy to the lung (risk ratio 1.34; 95% CI 0.30– 5.90). Past radiotherapy was not a predictive factor. Our study had limited sample size (146 patients with 112 events). Assuming a two-sided a of 0.05, the power to detect the HR of 0.65 was 0.63. So, the conclusion might change with the larger sample size. The results do not deny the additional effect of concurrent radiotherapy with immune checkpoint inhibitor in NSCLC. Further investigation of concurrent radiotherapy is warranted.

Are All ALK Inhibitors Really Necessary

In Response: We thank Dr. Kim for insightful comments and fully agree that the current practice in the United States, supported by the National Comprehensive Cancer Network guidelines, is not evidence based. Indeed, the European Organization for Research and Treatment of Cancer randomized trial that showed improvement in overall survival with the addition of prophylactic cranial irradiation (PCI) did not use brain magnetic resonance imaging (MRI) before treatment or during follow-up. From Dr. Kim’s letter, it is evident that on the basis of the results of the Japan Clinical Oncology Group (JCOG) randomized trial, our Japanese colleagues do not routinely use PCI in extensive stage SCLC but instead follow patients by close monitoring with brain MRI imaging at regular intervals and offer whole brain radiation therapy to patients who develop brain metastases. Our main concern with the JCOG trial is that was presented in 2014 but has not yet been published, either in Japan or elsewhere. A trial that has not been published within 2 years of initial presentation raises significant suspicions and should not dictate the standard of care. Until the JCOG trial is published, clinicians will not know the true benefit (or harm) of PCI in patients who are screened with brain MRI before starting the treatment, and a new clinical trial is greatly needed to answer this question. Our goal with this survey study was to highlight the disconnect between the clinical evidence and practice in the United States and, it is hoped, incite interest in conducting a new randomized trial for patients with extensive stage SCLC.

Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non–small cell lung cancer

OBJECTIVES Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m2) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL-1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation. RESULTS In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m2, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2-85.9%), median progression-free survival was 11.8 months (60% CI, 10.6-16.2 months; 95% CI, 8.2-20.8 months), and median overall survival was not reached. CONCLUSION Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.

Concordance between the response evaluation criteria in solid tumors version 1.1 and the immune-related response criteria in patients with non-small cell lung cancer treated with nivolumab: a multicenter retrospective cohort study

PurposeThe immune-related response criteria (irRC) were proposed to incorporate pseudo-progression. However, the association between the irRC and overall survival (OS) has yet to be evaluated in non-small cell lung cancer (NSCLC). Therefore, the purpose of this study is to evaluate the concordance between the response evaluation criteria in solid tumors (RECIST) version 1.1 and the irRC in patients with NSCLC treated with nivolumab, as well as, to determine the relationship between these two response criteria and OS.MethodsWe conducted a retrospective cohort study of 143 patients at three tertiary care hospitals in Japan between January and December 2016 (UMIN000022014).ResultsThe weighted kappa statistic for the two response criteria was 0.72 (95% confidence interval (CI) 0.66–0.76). The Harrell’s C-index was 0.74 (95% CI 0.68–0.80) for the RECIST and 0.74 (95% CI 0.68–0.80) for the irRC, respectively. The difference between the two criteria was − 0.002 (95% CI − 0.05 to 0.04). The Moreau, O’Quigley, and Lellouch statistic was 0.03 for the RECIST and 0.17 for the irRC, respectively.ConclusionWe demonstrated a good concordance between the RECIST and the irRC for predicting OS in patients with NSCLC treated with nivolumab.

Influence of social determinants of health on patients with advanced lung cancer: a prospective cohort study

Introduction Socioeconomic factors with an influence on human health are known as social determinants of health (SDH). There are some SDH studies in patients with lung cancer, but important exposures such as social isolation and loneliness have not been adequately investigated. This study will assess the influence of SDH, particularly social isolation and loneliness, on patients with advanced lung cancer in Japan. Methods and analysis The inclusion criteria for this prospective cohort study will be as follows: a diagnosis of advanced lung cancer; unsuitability for curative surgery; and willingness to participate. The primary outcome will be the initial choice of treatment and the secondary outcomes will be overall survival, changes in disease staging or performance status, route to diagnosis and place of death. The exposures will be social isolation, loneliness, employment, insurance type, education and dementia. The study enrolment period will be 1 year and the follow-up duration will be 2 years. The log-rank test will be used to compare overall survival between patients when grouped according to the study exposures and multivariate analysis will be performed using Cox proportional hazards regression. The Χ2 test will be used to compare the initial treatment, changes in disease stage and place of death, and logistic regression will be used for multivariate analysis of these factors. A p value <0.05 will be considered statistically significant. Ethics and dissemination This study has been approved by the Institutional Review Board at Hyogo Prefectural Amagasaki General Medical Center (No 29-164). A manuscript summarising the outcome of this study will be submitted to a peer-reviewed journal and the data will be presented at conferences. Trial registration number UMIN000031810.