Hironori Yoshida

High-dose crizotinib for brain metastases refractory to standard-dose crizotinib.

Journal of Thoracic Oncology ® • Volume 8, Number 9, September 2013 CASE REPORT A 41-year-old man, a former smoker (20 pack-years), was referred to Kyoto University Hospital, Kyoto, Japan, because of an abnormal chest shadow detected at an annual medical checkup. Positron emission tomography revealed multiple metastases to both the liver and bone. A biopsy of the pulmonary nodule demonstrated adenocarcinoma. Combination chemotherapy with pemetrexed and carboplatin was started, but the disease progressed after six cycles of chemotherapy. He then received multilines of chemotherapy, including gemcitabine, bevacizumab, erlotinib, TS-1, and docetaxel. Two years after the start of treatment, he developed multiple brain metastases and received whole-brain radiation therapy. At that time, molecular testing for echinoderm microtubule-associated protein like 4 (EML4)anaplastic lymphoma kinase (ALK) had just become commercially available in Japan, and his tumor demonstrated ALK rearrangement (Fig. 1). Then crizotinib was started at a dose of 250 mg twice daily. Abdominal computed tomography showed a marked decrease in the size of liver metastases, and magnetic resonance imaging of the brain demonstrated improvement of brain metastases; however, regrowth of brain metastases was detected 8 months after the start of crizotinib. Extracranial disease, including liver metastases, was under control with crizotinib. We therefore decided to increase the dose of crizotinib after a thorough discussion. At first, the dose was escalated to 750 mg/d. The dose was then escalated to 1000 mg/d after we confirmed that no new toxicities had occurred. Brain magnetic resonance imaging reassessed 2 weeks after the start of dose escalation demonstrated the striking improvement of multiple brain metastases; however, his brain diseases rapidly progressed after 1 month from the dose escalation (Fig. 2). After the dose escalation, he developed bradycardia without accompanying any symptoms. Pulse rate before and after the dose escalation were 50/minute and 39/minute, respectively. DISCUSSION Although it was reported that crizotinib is effective for brain metastases, its penetration into cerebrospinal fluid (CSF) is considered to be poor. Costa et al. measured the concentration of crizotinib in both CSF and plasma and reported that the CSF-to-plasma ratio of crizotinib was only 0.0026. Because of this relatively low drug exposure, the brain may be a site susceptible to progression in patients with ALK rearrangement and treated with crizotinib. A similar scenario has been observed also in patients with epidermal growth factor receptor (EGFR) mutation and treated with EGFR tyrosine kinase inhibitors, and the efficacy of high-dose gefitinib was reported in patients with EGFR mutation who developed brain metastases during treatment with a standard dose of gefitinib. Recently, Gandhi et al. reported a patient who was effectively treated with high-dose pemetrexed and high-dose crizotinib in the same situation; however, the escalated dose of crizotinib was only 100 mg/d, and the efficacy mainly seemed to be the result of pemetrexed. Therefore, we believe that this is the first case in which high-dose crizotinib was used alone for refractory brain metastases that developed during treatment with the standard dose of crizotinib. However, in this case, response duration was quite short and CSF concentration was not measured. In addition, 1000 mg/d of crizotinib is above the maximum tolerated dose. High-dose crizotinib cannot be recommended in routine clinical practice because safety data and efficacy are lacking in a prospective cohort. Further research is required in this setting.

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.

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.

Efficacy of Ceritinib After Alectinib for ALK-positive Non-small Cell Lung Cancer

Background: Alectinib is a new standard treatment for treatment-naïve anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC); however, resistance ultimately develops in almost all patients, and data regarding the efficiency of ceritinib for such patients are insufficient. Patients and Methods: Patients with ALK-positive NSCLC treated at the Kyoto University Hospital from January 2012 to March 2017 were reviewed. Patients who were treated with ceritinib after alectinib were identified, and the efficacy of ceritinib after alectinib was retrospectively evaluated. Results: There were 35 patients with ALK-positive NSCLC, nine of whom received ceritinib after alectinib. The overall response rate to ceritinib was 44%. It was 16% in patients who received ceritinib immediately after alectinib, and 100% in patients who received chemotherapy before ceritinib. The median progression-free survival for patients treated with ceritinib was 4.4 months (95% confidence interval(CI)=1.1-6.5 months). Conclusion: Ceritinib demonstrated a modest clinical benefit after failure of alectinib. Ceritinib may be a reasonable treatment option in this setting.

Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting interstitial lung disease: Nivolumab in patients with ILD

The risk of developing lung cancer is high in patients with interstitial lung disease (ILD), as few treatment options are available. Immune checkpoint inhibitors (ICI) are used for the treatment of non‐small cell lung cancer (NSCLC) in clinical practice; however, in patients with preexisting ILD, the risk of ICI‐related pneumonitis is unknown. We evaluated the efficacy and lung toxicity of nivolumab in patients with NSCLC and ILD.