Hiroaki Ozasa

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.

Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells

The c‐MET receptor tyrosine kinase is the receptor for hepatocyte growth factor. Recently, activation of the c‐MET/hepatocyte growth factor signaling pathway was associated with poor prognosis in various solid tumors and was one of the mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib. But the link between c‐MET activation and the cytotoxic anticancer drug has not been fully examined. Here, we found that the enhanced expression and activation of c‐MET in cytotoxic anticancer agent‐resistant small‐cell lung cancer cells. Downregulation of c‐MET expression by siRNA against the c‐MET gene or inhibition of c‐MET activation by SU11274, a c‐MET inhibitor, in the resistant cells altered resistance to the cytotoxic anticancer agent. These results indicated that c‐MET overexpression might play an important role in acquired resistance to cytotoxic anticancer drugs. Furthermore, the number of c‐MET gene loci was increased in the resistant cells compared to the parental cells. In conclusion, increased c‐Met expression through an increase in the number of c‐MET gene loci is one of the mechanisms of acquired resistance to cytotoxic anticancer drugs. Our results add a new strategy, the targeting of c‐MET, for overcoming resistance to cytotoxic agents in small‐cell lung cancer.

Disease flare after discontinuation of crizotinib in anaplastic lymphoma kinase-positive lung cancer.

We report the case of a 50-year-old male former smoker. He was diagnosed as having lung adenocarcinoma and treated with induction chemoradiation therapy followed by surgery and adjuvant chemotherapy. Molecular testing revealed that his tumor had an echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement. Therefore, he was treated with crizotinib when his disease recurred. He achieved a partial response, which persisted for 10 months until progressive disease was confirmed. Crizotinib was continued for 1 month and the tumor size increased slightly. At that time, crizotinib was discontinued and he participated in a clinical trial of erlotinib ± Met inhibitor; however, his disease progressed rapidly after discontinuation of crizotinib, and the diagnosis of disease flare was made. Readministration of crizotinib was started immediately; however, his disease progressed rapidly, and he died 2 days after starting crizotinib retreatment. Currently, the incidence of disease flare is unknown and it is impossible to predict who will experience it. Therefore, continuing crizotinib after disease progression may be a reasonable option to avoid disease flare.

Phase II Study of Pemetrexed and Erlotinib in Pretreated Nonsquamous, Non-Small-Cell Lung Cancer Patients without an EGFR mutation

Background: Preclinical data indicated that the combination of erlotinib and pemetrexed is synergistic when erlotinib is administered after pemetrexed. Patients and Methods: This was a phase II study of pemetrexed and erlotinib in patients with pretreated advanced non-squamous non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR). Chemotherapy consisted of pemetrexed (500 mg/m2) on day 1 and erlotinib (150 mg/body) on days 2-15 every 3 weeks. The protocol treatment was repeated until disease progression or intolerable toxicities occurred. Results: Seventeen patients were enrolled between January 2010 and January 2013, and 15 patients were evaluable for both safety and efficacy. The study was terminated due to slow patient accrual. There was 1 complete response. There was a partial response in 3 patients, stable disease in 4 and progressive disease in 7. The response rate was 27% and disease control rate was 53%. The median progression-free survival and overall survival were 2.5 months and 6.7 months, respectively. Conclusions: Statistical interpretation could not been made due to the early termination of the study. Further studies are needed to clarify the efficacy of this regimen in NSCLC patients without EGFR mutation (UMIN-CTR No. 0000024531).

Organic cation transporter OCT6 mediates cisplatin uptake and resistance to cisplatin in lung cancer

PurposeThe purposes of this study were to determine whether organic cation transporters (OCTs) can mediate platinum uptake, and whether OCT down-regulation confers resistance against cisplatin (CDDP) in cancer cells.MethodsTwo lung cancer cell lines, PC-6 and PC-14, and their CDDP-resistant derivatives, PC-6/CDDP and PC-14/CDDP, were analyzed. OCT expression levels were assayed using quantitative RT-PCR and Western blotting. Additionally, the effect of OCT6 overexpression, induced by transfection of the OCT6 gene SLC22A16 using a forced expression vector, on cellular sensitivity to CDDP and on intracellular platinum accumulation was measured using PC-14/CDDP cells.ResultsBoth gene and protein expression of OCT6 were decreased in both CDDP-resistant cell lines compared with their expression in their respective parental cells. Intracellular accumulation of platinum was decreased in PC-14/CDDP cells compared with the parental cells after CDDP treatment. Furthermore, OCT6 overexpression induced by transfection of the OCT6 gene (SLC22A16) forced expression vector-sensitized PC-14/CDDP cells to CDDP and oxaliplatin (L-OHP) concomitant with increased intracellular concentration of platinum.ConclusionOCT6 is a mediator of platinum uptake in cancer cells, and down-regulation of OCT6 is possibly one of the mechanisms of resistance against cisplatin in lung cancer.

Successful treatment with carboplatin and nanoparticle albumin-bound paclitaxel in a patient with pulmonary spindle cell carcinoma

Introduction Pulmonary spindle cell carcinoma (SpCC) is a rare subtype of non-small-cell lung cancer (NSCLC) and, in general, is chemoresistance. Case A sixty-five year-old male patient with metastatic pulmonary SpCC was initially treated with cisplatin and docetaxel, but his disease progressed. Then, he received a combination chemotherapy with carboplatin and nab-PTX followed by maintenanced chemotherapy with nab-PTX. Fluorodeoxyglucose (FDG) positron-emission CT revealed a substantial decrease of FDG accumulation in the primary tumor, and the response continued for more than 7 months. Discussion Preclinical models suggested that nab-PTX may reach the tumor microenvironment more efficiently than solvent-based paclitaxel (sb-PTX) and be preferentially taken up by cancer cells. Considering that there is no effective treatment for patients with pulmonary SpCC, nab-PTX may merit further investigation in patients with pulmonary SpCC.

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.

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.

Response to chemotherapy with carboplatin plus albumin‑bound paclitaxel in a patient with lymphoepithelioma‑like thymic carcinoma: A case report

Thymic carcinoma is a rare neoplasm with a poor outcome due to its aggressive characteristics. For patients who are not operable, radiation therapy and/or palliative chemotherapy are indicated. However, no optimal chemotherapy regimen has been established. The present study reports the case of a 22-year-old man with advanced lymphoepithelioma-like thymic carcinoma refractory to conventional chemotherapy with carboplatin plus solvent-based paclitaxel (sb-PAC) treatment. The patient was subsequently treated with carboplatin plus nanoparticle albumin-bound paclitaxel (nab-PAC). The treatment resulted in a partial response following three cycles of chemotherapy. Since only grade 3 neutropenia, but no other severe adverse effects, was observed, no dose reduction was required. To the best of our knowledge, the current study is the first to present the response to chemotherapy with carboplatin plus nab-PAC in a patient with lymphoepithelioma-like thymic carcinoma. Considering that no standard treatment has been established in thymic carcinoma, nab-PAC may merit further investigation in this rare, but aggressive disease.

Abstract 5045: Overexpression of ABC transporters through HGF/c-MET activation results in anti-cancer drug resistance in SCLC

Upregulation of hepatocyte growth factor (HGF)/c-MET pathway causes drug resistance to anti-cancer agents such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in non-small lung cancer (NSCLC) with EGFR mutation and cytotoxic agents in small cell lung cancer (SCLC), but the roles and mechanisms of c-MET in drug-resistant cancer cells are not clarified. We studied to reveal the role of c-MET overexpression in the resistant lung cancer cell lines and to demonstrate whether MET-inhibition could restore drug sensitivity in anti-cancer drug resistant cell lines via ABC transporters down-regulation. In this study we used the 7-ethyl-10-hydroxycamptothesin (SN-38)-resistant cell line (PC-6/SN-38) that was derived from the human SCLC cell line PC-6. We compared the expression levels of the purposed genes by quantitative real-time PCR (qRT-PCR) and western blotting (WB). MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay was used to measure cell viability of the resistant cells compared with the parental cells. Inhibition of c-MET activation was performed by c-MET inhibitors, PHA665752 and Crizotinib or small interfering RNA against c-MET. We found MET inhibitors (4 or 8μM) reduced cell growth and restored drug sensitivity (2μM) of resistant cells, PC-6/SN38, compared to parental cells. To reveal the mechanisms of c-MET in drug resistance we examined ATP-binding cassette (ABC) transporters expression in PC-6/SN-38 compared to the parental cells by qRT-PCR, and found the mRNA level of ABCG2, which effluxes SN-38 as substrate, in PC-6/SN-38 cells was extremely increased and another ABC transporters that do not efflux SN-38 were not. Recently we reported PC-6/SN-38 cells had c-MET overexpression, and c-MET inhibition in resistant cells such PC-6/SN-38 resulted in restoration drug resistance. Based on this report we examined c-MET inhibition by c-MET inhibitor and small interfering RNA against c-MET in PC-6/SN38, and qRT-PCR and WB were performed to investigate alteration of ABCG2 expression, and found both two c-MET inhibition reduced ABCG2 expression. In addition, to demonstrate c-MET upregulation in resistant cells is addicted to the ligand HGF, PC-6 cells were incubated with HGF treated for 3 weeks and made PC-6/HGF, then continued to incubate with HGF and SN-38 was added two times in a week. Although c-MET expression is equal in PC-6 and PC-6/HGF, after SN-38 treatment c-MET was overexpressed. Furthermore, serum HGF level in SCLC patients correlated with clinical course. We demonstrated upregulation of ABC transporters via HGF/c-MET signaling activation might be one of the mechanisms of acquired resistance to cytotoxic anticancer agents in lung cancer cells. Decreased ABC transporters expression through inhibition of c-MET activation might overcome drug resistance to cytotoxic agents. Citation Format: Yoshitaka Yagi, Hiroaki Ozasa, Takahiro Tsuji, Yuichi Sakamori, Takeshi Nomizo, Hiroki Nagai, Young Hak Kim, Ken Maeno, Tetsuya Oguri, Michiaki Mishima. Overexpression of ABC transporters through HGF/c-MET activation results in anti-cancer drug resistance in SCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5045.