BACKGROUND. The PD-1–blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events.METHODS. To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non–small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up.RESULTS. Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2–15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response.CONCLUSIONS. Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment.TRIAL REGISTRATION. University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623.FUNDING. This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).
Pleomorphic carcinoma (PC) of the lung is a rare type of non‐small cell lung cancer, exhibiting aggressive behavior and resistance to chemotherapy and radiotherapy. A previous study reported that PCs expressed high levels of PD‐L1, suggesting the potential efficacy of immune checkpoint inhibitors in these tumors. We retrospectively reviewed the clinical records of three patients with PC of the lung treated with nivolumab: a 59‐year‐old woman (Case 1), a 66‐year‐old man (Case 2), and an 83‐year‐old man (Case 3). PD‐L1 was highly expressed in their tumor cells. Two cases showed a partial response with long progression‐free survival. However, in Case 2, brain and bone metastases progressed during nivolumab treatment in spite of high PD‐L1 expression. This case series indicates that nivolumab is effective to some extent for PC of the lung. However, the clinical course of patients treated with nivolumab should be carefully observed, even when PD‐L1 is highly expressed.
Abstract. 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.
Although small cell lung cancer (SCLC) is initially sensitive to chemotherapy, it recurs in most cases. Standard regimens for salvage chemotherapy have not been established, and the prognosis of relapsed SCLC remains poor. In the present study, we investigated the clinical efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimens for the treatment of relapsed SCLC.In this retrospective multicenter analysis, 14 patients (3 women and 11 men; median age 71 years) with relapsed SCLC received nab-paclitaxel alone or in combination with carboplatin between February 2013 and July 2014. The safety and efficacy of the regimens were evaluated.The response rates, disease control rates, and median overall survival for the total patient population were 36%, 64%, and 7.8 months, respectively. Response rates, disease control rates, and the median overall survival were 11%, 44%, and 4 months, respectively, in the monotherapy group; and 80%, 100%, and 10.6 months, respectively, in the combination therapy group. The most common adverse events were hematological toxicities such as neutropenia and anemia. Severe neutropenia appeared in some patients, although it was resolved by treatment in all. The most common nonhematological toxicity was anorexia (64%), followed by neurotoxicity and constipation. All nonhematological toxicities were mild and manageable.Our results suggest that chemotherapy with nab-paclitaxel regimens for relapsed SCLC exhibits moderate clinical efficacy and is well-tolerated. Further clinical trials in relapsed SCLC patients are warranted.
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