Tomoko Funazo

Clinical Impact of Single Nucleotide Polymorphism in PD-L1 on Response to Nivolumab for Advanced Non-Small-Cell Lung Cancer Patients

This study was intended to determine the efficacy of nivolumab, we evaluated treatment response with respect to PD-1/PD-L1 SNPs among patients with NSCLC. A total of 50 patients with NSCLC were treated with nivolumab and were also evaluated for PD-1/PD-L1 single nucleotide polymorphisms (SNPs) from plasma DNA. We investigated the association among PD-1/PD-L1 SNPs, objective response rate (ORR) and progression-free survival (PFS). Two of seven SNPs studied showed association with ORR and PFS, with maximum evidence at the marker rs2282055. The ORR was 25%, 15%, and 0% for the G/G, G/T and T/T genotypes of PD-L1 rs2282055, respectively. The G allele of PD-L1 rs2282055 was significantly associated with better clinical response compared with the T allele (P = 0.0339 [Cochran-Armitage trend test]). The median PFS time was 2.6 months (95% confidence interval [CI], 1.8 months to 4.3 months) for the G/G and G/T genotypes and 1.8 months (95% confidence interval [CI], 0.4 months to 2.2 months) for the T/T genotype (P = 0.0163). Moreover, the C/C and C/G genotypes of PD-L1 rs4143815 were significantly associated with better ORR and PFS in NSCLC patients treated with nivolumab. These results suggest that rs2282055 and rs4143815 may be a biomarker for the efficacy of nivolumab.

Liver Metastasis Is Associated with Poor Progression-Free Survival in Patients with Non–Small Cell Lung Cancer Treated with Nivolumab

Figure 1. Kaplan–Meier curves of progression-free survival (PFS) (N 1⁄4 79). PFS was longer in patients without liver metastasis (n 1⁄4 57) than in those with it (n 1⁄4 22) (median PFS, 100 versus 42 days, log-rank P 1⁄4 0.0002). HR, hazard ratio; CI, confidence interval. To the Editor: Nivolumab, an anti–programmed death 1 antibody, has been approved for the treatment of NSCLC. Although nivolumab improves overall survival (OS) more than docetaxel when used as second-line therapy, the rate of objective response remains at approximately 20%. There are currently no precise biomarkers for nivolumab; therefore, biomarkers that predict treatment responses to nivolumab need to be investigated. Between December 2015 and December 2016, 83 consecutive patients with histologically or cytologically confirmed advanced NSCLC were treated with nivolumab. Of these patients, 79 (all of whom were registered at Kyoto University Hospital) participated in the present study. The remaining four patients were excluded because three refused to give informed consent and one had a history of double cancer. This study aimed to investigate differences in the progression-free survival (PFS) of patients receiving nivolumab according to their baseline characteristics. Median PFS in this group was 67 days (95% confidence interval: 54–99). Median PFS was significantly longer in patients without liver metastasis than in patients with liver metastasis at baseline imaging (100 versus 42 days [p 1⁄4 0.0002, log-rank test]) (Fig. 1). Disease control rates were significantly higher in patients without liver metastasis (60% versus 27% [p 1⁄4 0.0126, Fisher’s exact test]). No significant differences were observed in other clinical characteristics, including age, sex, smoking status, Eastern Cooperative Oncology Group performance-status score, number of chemotherapy cycles, histologic type, and EGFR mutation status, between patients with and without liver metastasis. CheckMate 057, a randomized phase III study, suggested that docetaxel is a more favorable treatment than nivolumab for subgroups of patients receiving third-line therapy, those who had never smoked, and those with

Successful oral desensitization with crizotinib after crizotinib‑induced hepatitis in an anaplastic lymphoma kinase‑rearranged non‑small‑cell lung cancer patient: A case report

Crizotinib is one of the molecularly-targeted agents targeted against anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Although its effects appear to be promising, crizotinib may cause adverse effects in patients with ALK-rearranged NSCLC. Hepatic laboratory abnormalities are frequently observed with crizotinib and treatment discontinuation is occasionally required. We herein report the case of a 51-year-old woman diagnosed with relapsed ALK-rearranged NSCLC, who received crizotinib as second-line systemic chemotherapy. After 17 days of crizotinib therapy, the patient developed grade >3 hepatotoxicity. Treatment discontinuation improved the laboratory abnormalities and fifth-line oral desensitization with crizotinib achieved successful response without hepatotoxicity. Therefore, oral desensitization with crizotinib may be a viable option following crizotinib-induced hepatitis.

Clinical impact of high serum hepatocyte growth factor in advanced non-small cell lung cancer

Activation of c-MET through hepatocyte growth factor (HGF) increases tumorigenesis, induces resistance, and is associated with poor prognosis in various solid tumors. However, the clinical value of serum HGF (sHGF) in patients with advanced non-small cell lung cancer (NSCLC), especially those receiving cytotoxic chemotherapy, remains unknown. Here, we show that sHGF may be useful to predict tumor response and progression-free survival (PFS) in patients with advanced NSCLC. A total of 81 patients with NSCLC were investigated. sHGF levels were evaluated using ELISA at 4 time-points: at pre-treatment, at response-evaluation (1–2 months after treatment initiation), at the best tumor response, and at disease progression. As a control biomarker, CEA was also evaluated in lung adenocarcinoma. Positive-sHGF at response-evaluation predicted poor PFS compared with Negative-sHGF in both first-line (median, 153.5 vs. 288.0; P < 0.05) and second-line treatment (87.0 vs. 219.5; P = 0.01). In 55 patients that received cytotoxic chemotherapy, multiple Cox proportional hazards models showed significant independent associations between poor PFS and Positive-sHGF at response-evaluation (hazard ratio, 4.24; 95% CI, 2.05 to 9.46; P < 0.01). Lung adenocarcinoma subgroup analysis showed that in patients receiving second cytotoxic chemotherapy, there were no significant differences in PFS between patients with low-CEA compared with those with high-CEA, but Positive-sHGF at pre-treatment or at response-evaluation predicted poor PFS (35.0 vs. 132.0; P < 0.01, 50.0 vs. 215.0; P < 0.01, respectively). These findings give a rationale for future research investigating the merit of sHGF as a potential clinical biomarker to evaluate HGF/c-MET activity, which would be useful to indicate administration of c-MET inhibitors.Activation of c-MET through hepatocyte growth factor (HGF) increases tumorigenesis, induces resistance, and is associated with poor prognosis in various solid tumors. However, the clinical value of serum HGF (sHGF) in patients with advanced non-small cell lung cancer (NSCLC), especially those receiving cytotoxic chemotherapy, remains unknown. Here, we show that sHGF may be useful to predict tumor response and progression-free survival (PFS) in patients with advanced NSCLC. A total of 81 patients with NSCLC were investigated. sHGF levels were evaluated using ELISA at 4 time-points: at pre-treatment, at response-evaluation (1-2 months after treatment initiation), at the best tumor response, and at disease progression. As a control biomarker, CEA was also evaluated in lung adenocarcinoma. Positive-sHGF at response-evaluation predicted poor PFS compared with Negative-sHGF in both first-line (median, 153.5 vs. 288.0; P < 0.05) and second-line treatment (87.0 vs. 219.5; P = 0.01). In 55 patients that received cytotoxic chemotherapy, multiple Cox proportional hazards models showed significant independent associations between poor PFS and Positive-sHGF at response-evaluation (hazard ratio, 4.24; 95% CI, 2.05 to 9.46; P < 0.01). Lung adenocarcinoma subgroup analysis showed that in patients receiving second cytotoxic chemotherapy, there were no significant differences in PFS between patients with low-CEA compared with those with high-CEA, but Positive-sHGF at pre-treatment or at response-evaluation predicted poor PFS (35.0 vs. 132.0; P < 0.01, 50.0 vs. 215.0; P < 0.01, respectively). These findings give a rationale for future research investigating the merit of sHGF as a potential clinical biomarker to evaluate HGF/c-MET activity, which would be useful to indicate administration of c-MET inhibitors.

Retrospective analysis of acute exacerbation of interstitial lung diseases with nanoparticle albumin-bound paclitaxel in patients with advanced lung cancer with preexisting interstitial lung disease

Lung cancer with preexisting interstitial lung disease (ILD) is difficult to treat due to the risk of acute exacerbation of ILD. Nanoparticle albumin-bound (nab-) paclitaxel improves the overall response rate and reduces neuropathy more efficiently compared with conventional solvent-based (sb-) paclitaxel in patients with advanced non-small-cell lung cancer. However, it is not known whether the risk of acute exacerbation of ILD with nab-paclitaxel is higher compared with that with sb-paclitaxel. Advanced lung cancer patients with ILD treated with nab-paclitaxel (n=14) or sb-paclitaxel (n=14) were retrospectively reviewed. Acute exacerbation of ILD developed in 1/14 patients (7.7%) receiving nab-paclitaxel and 3/14 patients (21.4%) receiving sb-paclitaxel; the difference was not statistically significant. To the best of our knowledge, this is the first study to compare the incidence of acute exacerbation of ILD with nab-paclitaxel with that of sb-paclitaxel in patients with advanced lung cancer with preexisting ILD. The results of the present study support conducting a prospective clinical trial to confirm the clinical benefit of this agent.

Successful Treatment with Alectinib for Choroidal Metastasis in Anaplastic Lymphoma Kinase Rearranged Non-small Cell Lung Cancer

Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances.