Yoshiko Takeuchi

Phase II study of pemetrexed plus intermittent erlotinib combination therapy for pretreated advanced non-squamous non-small cell lung cancer with documentation of epidermal growth factor receptor mutation status

INTRODUCTION Erlotinib and pemetrexed have been approved for the second-line and maintenance treatment of non-small cell lung cancer (NSCLC). With the recommended doses determined by our previous phase I study, we conducted a phase II study to evaluate the efficacy and safety of combination of the two agents in pretreated non-squamous NSCLC patients. METHODS This study was performed in patients with stage IIIB/IV or post-surgically recurrent non-squamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m(2) of intravenous pemetrexed every 21 days and 150 mg of oral erlotinib on days 2-16 until disease progression, unacceptable toxicity, or withdrawal of consent. The expected response rate and threshold were defined as 33.5% and 10%, respectively. Assuming a one-sided alpha of 5%, a power of 80%, the possible deviation from assessment, 26 patients were necessary. RESULTS A total of 27 patients, 16 males and 11 females were recruited. Patients had the median age of 70 years (range, 48-80 years) and included 21 stage IV diseases, 22 adenocarcinomas. Epidermal growth factor receptor (EGFR) mutations were examined in all patients. One patient had positive EGFR mutation, but the other 26 patients had wild-type EGFR. The median number of treatment courses was 3 (range, 1 to over 19). The best overall response rate and disease control rate were 11.1% and 63.0%, respectively. The median progression-free survival and overall survival were 2.8 months (95% confidence interval (CI); 1.9-7.5 months) and 15.8 months (95% CI; 9.3 months to not available), respectively. Dermal, hepatic, gastrointestinal and hematological disorders were the frequently observed adverse events. One patient experienced grade 3 drug-induced interstitial lung disease. CONCLUSIONS We could not demonstrate the add-on effect of intermittent erlotinib on pemetrexed in a second-line setting for patients with non-squamous NSCLC without EGFR mutations.

Combination chemotherapy with intermittent erlotinib and pemetrexed for pretreated patients with advanced non-small cell lung cancer: a phase I dose-finding study

BackgroundErlotinib and pemetrexed have been approved for the second-line treatment of non-small cell lung cancer (NSCLC). These two agents have different mechanisms of action. Combined treatment with erlotinib and pemetrexed could potentially augment the antitumor activity of either agent alone. In the present study, we investigated the safety profile of combined administration of the two agents in pretreated NSCLC patients.MethodsA phase I dose-finding study (Trial registration: UMIN000002900) was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m2 of pemetrexed intravenously every 21 days and erlotinib (100 mg at Level 1 and 150 mg at Level 2) orally on days 2–16.ResultsTwelve patients, nine males and three females, were recruited. Patient characteristics included a median age of 66 years (range, 48–78 years), stage IV disease (nine cases), adenocarcinoma (seven cases) and activating mutation-positives in the epidermal growth factor receptor gene (two cases). Treatment was well-tolerated, and the recommended dose of erlotinib was fixed at 150 mg. Dose-limiting toxicities were experienced in three patients and included: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required reduction of the second dose of pemetrexed and grade 3 diarrhea. No patient experienced drug-induced interstitial lung disease. Three patients achieved a partial response and stable disease was maintained in five patients.ConclusionsCombination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated, with promising efficacy against pretreated advanced nonsquamous NSCLC.

Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma

Cancer immunotherapy that blocks immune checkpoint molecules, such as PD-1/PD-L1, unleashes dysfunctional antitumor T-cell responses and has durable clinical benefits in various types of cancers. Yet its clinical efficacy is limited to a small proportion of patients, highlighting the need for identifying biomarkers that can predict the clinical response by exploring antitumor responses crucial for tumor regression. Here, we explored comprehensive immune-cell responses associated with clinical benefits using PBMCs from patients with malignant melanoma treated with anti-PD-1 monoclonal antibody. Pre- and post-treatment samples were collected from two different cohorts (discovery set and validation set) and subjected to mass cytometry assays that measured the expression levels of 35 proteins. Screening by high dimensional clustering in the discovery set identified increases in three micro-clusters of CD4+ T cells, a subset of central memory CD4+ T cells harboring the CD27+FAS-CD45RA-CCR7+ phenotype, after treatment in long-term survivors, but not in non-responders. The same increase was also observed in clinical responders in the validation set. We propose that increases in this subset of central memory CD4+ T cells in peripheral blood can be potentially used as a predictor of clinical response to PD-1 blockade therapy in patients with malignant melanoma.

Development of microscopic polyangiitis-related pulmonary fibrosis in a patient with autoimmune pulmonary alveolar proteinosis

BackgroundAutoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by the autoantibody against granulocyte-macrophage colony stimulating factor (GM-CSF). The clinical course of aPAP is variable; in severe cases, patients develop lethal respiratory failure due to pulmonary fibrosis. However, the pathogenesis of pulmonary fibrosis in aPAP has never been delineated.Case presentationHere, we describe a rare case of aPAP that was subsequently complicated by microscopic polyangiitis-related pulmonary fibrosis. The patient was a 75-year-old Japanese man diagnosed with aPAP based on the crazy-paving appearance on high-resolution computed tomography (HRCT), “milky” appearance of broncho-alveolar lavage fluid (BALF), and elevated serum levels of the anti-GM-CSF antibody. The patient was followed-up without aPAP-specific treatment for 3 years. During this period, both hematuria and proteinuria appeared; in addition, serum myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) turned positive and increased markedly. The second BAL performed one year after the diagnosis, showed that the “milky” appearance had resolved. The HRCT showed that fibrotic changes had developed and that the crazy-paving appearance had disappeared. These data suggest an association between pulmonary fibrosis that developed during the natural course of aPAP and ANCA-related systemic vasculitis.ConclusionThis is the first case report that suggests the existence of a pathogenetic relationship between ANCA-associated systemic vasculitis and aPAP-related pulmonary fibrosis. The link between ANCA-associated systemic vasculitis and aPAP-related pulmonary fibrosis requires further investigation.

Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer

Small-cell lung cancer (SCLC) easily recurs with multidrug resistance phenotype. However, standard therapeutic strategies for relapsed-SCLC remain unestablished. Human epidermal growth factor receptor 2 (HER2) expression correlates with poor prognosis in extensive disease-SCLC. We have reported previously that HER2 expression is upregulated when HER2-positive SCLC cells acquire chemoresistance, and also demonstrated that trastuzumab exerts significant antitumor activity toward HER2-upregulated chemoresistant SCLC, mainly via antibody-dependent cell-mediated cytotoxicity mechanism. Based on these preclinical data, we treated two patients with HER2-positive SCLC by combination of trastuzumab (6 mg/kg, day 1) and irinotecan (80 mg/m(2), days 1 and 8) every 21 days as the third-line chemotherapy following two prior regimens, first-line carboplatin plus etoposide and second-line amrubicin. One patient achieved partial response after the first cycle and received 6 cycles in total without disease progression for 4.5 months. The other also received 4 cycles and kept stable disease for 3.5 months. This treatment can be continued safely at an outpatient clinic without any severe adverse event. In conclusion, trastuzumab plus irinotecan chemotherapy is promising and feasible against HER2-positive relapsed SCLC. Further clinical studies are encouraged to confirm the antitumor efficacy of trastuzumab in SCLC.

Dapsone Hypersensitivity Syndrome-related Lung Injury without Eosinophilia in the Bronchoalveolar Lavage Fluid

A 73-year-old man was admitted in respiratory failure that had subacutely progressed after five weeks of dapsone treatment for a skin rash. He also presented with fever, systemic erythroderma and liver dysfunction. Chest computed tomography showed diffuse reticular shadows with ground-glass opacity and bilateral mediastinal lymphadenopathy. Lymphocytes, but not eosinophils, were increased in the bronchoalveolar lavage fluid. Moreover, reactivation of human herpes virus-6 was confirmed on a paired serum test. Finally, we diagnosed the patient with dapsone hypersensitivity syndrome (DHS), a rare adverse event of this drug. Lung injury unaccompanied by eosinophilia in the bronchoalveolar lavage fluid is even more rare as a DHS-related lung manifestation.

Abstract 4506: Targeting stepwise HER2 and VEGF can overcome multidrug resistance in small cell lung cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Small-cell lung cancer (SCLC) accounts for approximately 15% of primary lung cancer and has the poorest outcome of all its histological types. One of the major reasons of extreme aggressiveness of SCLC is that it recurs shortly after initial therapy with multidrug resistance (MDR) phenotype. However, standard therapeutic strategy for relapsed-SCLC has not been established yet. As one of the targetable receptor tyrosine kinases, human epidermal growth factor receptor 2 (HER2) was reported to be a negative prognostic factor in extensive-disease SCLC (Micke et al. Int J Cancer. 2001;92:474-9). We found that HER2 was more frequently overexpressed in SCLC cell lines of Japanese origin (6/10) compared to those of Caucasian origin (0/3). We also detected HER2 expression in SCLC tissues in 7 out of 25 patients tested by our highly sensitive immunohistochemistry system. Moreover, we found that HER2 was upregulated when HER2-positive SCLC cells acquired MDR. Trastuzumab, a humanized monoclonal antibody against HER2, exerted differential levels of killing effect on HER2-positive parental and chemoresistant SCLC cells only when Fcγ receptor-positive natural killer (NK) cells coexisted. This result suggests that trastuzumab-induced SCLC cell-killing effect was caused mainly via antibody-dependent cell-mediated cytotoxicity (ADCC) but not via direct inhibition of HER2 signal. Among these cell lines, etoposide-resistant SCLC cells were most susceptible to trastuzumab in vitro and in vivo, and the antitumor effects of trastuzumab were not only dependent on the amount of HER2 expression on SCLC cells. We focused on cell-cell contact between SCLC cells and NK cells to determine the molecule affecting trastuzumab-mediated ADCC other than HER2. We found that intercellular adhesion molecule (ICAM)-1 was abundantly expressed on etoposide-resistant SCLC cells, and trastuzumab-mediated ADCC was canceled in the presence of an ICAM-1 functional blocking antibody. These results indicate that ICAM-1 expression on SCLC cell surface is indispensable to augment trastuzumab-mediated ADCC. Thus, trastuzumab could overcome etoposide-resistance in SCLC. On the contrary, irinotecan-resistant SCLC cells were still refractory to trastuzumab. The reason for this was thought that they not only lacked ICAM-1 expression but also came to produce abundant vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF, treatment could significantly inhibit the in vivo growth of irinotecan-resistant xenografts through decreasing microvesseles in mice. These results suggest that bevacizumab-mediated antiangiogenesis is a promising therapeutic strategy to salvage irinotecan-resistance. Collectively, targeting stepwise HER2 and VEGF could overcome MDR in SCLC and bring about a favorable outcome for patients with relapsed-SCLC. Citation Format: Toshiyuki Minami, Takashi Kijima, Osamu Morimura, Yuhei Kinehara, Masayoshi Higashiguchi, Kotaro Miyake, Haruhiko Hirata, Yoshiko Takeuchi, Kiyoharu Fukushima, Yoshitomo Hayama, Koji Inoue, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Atsushi Kumanogoh. Targeting stepwise HER2 and VEGF can overcome multidrug resistance in small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4506. doi:10.1158/1538-7445.AM2014-4506