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Purpose To evaluate masticatory performance (MP), maximum occlusal force (MOF), maximum tongue pressure (MTP) and oral diadochokinesis (ODK) among community-dwelling elderly patients without posterior occlusal support. Methods This study enrolled community-dwelling elderly patients (≥65 years old) who belonged to Eichner A, B4, C1, C2, and C3. Each oral function was statistically compared among groups. Correlations between MP and other variables were examined in Eichner B4 and C patients. Results MP and MOF values in Eichner B4 and C patients were significantly lower than in Eichner A patients. There were significant differences in MTP values between Eichner "A and C2, C3", and "B4 and C2, C3". ODK in Eichner C patients showed significantly lower values compared to Eichner A patients in general. Although there were statistically significant correlations of MP with age, the number of remaining teeth and all oral functions were identified, and multiple regression analysis indicated that MOF and MTP were independently related to MP. Conclusion Oral functions in Eichner B4 and C patients were lower compared to Eichner A patients. MP was significantly correlated with MOF and MTP in elderly patients without posterior occlusal support, suggesting the importance of rehabilitation of MOF and MTP in MP.

// Yoko Ueno 1 , Masamichi Mori 1 , Yoshiteru Kamiyama 1 , Rika Saito 1 , Naoki Kaneko 1 , Eriko Isshiki 2 , Sadao Kuromitsu 1 and Masahiro Takeuchi 1 1 Drug Discovery Research, Astellas Pharma, Inc., Ibaraki, Japan 2 Biological Research Division, Astellas Research Technologies Co., Ltd., Ibaraki, Japan Correspondence to: Yoko Ueno, email: yoko.ueno@astellas.com Keywords: acute myeloid leukemia; FLT3 inhibition; internal tandem duplication; combination therapy; apoptosis Received: January 02, 2019 Accepted: March 04, 2019 Published: April 02, 2019 ABSTRACT Activating internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations in Fms-like tyrosine kinase 3 ( FLT3 ) occur in approximately 30% of patients with acute myeloid leukemia (AML), and confer a poor prognosis with standard cytarabine/anthracycline or azacitidine-based chemotherapy regimens. Gilteritinib is a highly-specific, potent FLT3/AXL inhibitor with demonstrated activity against FLT3-ITD and FLT3-TKD mutations. Compared with salvage chemotherapy, treatment with once-daily oral gilteritinib demonstrated a clinical benefit in patients with FLT3 -mutated relapsed/refractory AML, which led to its recent approval in Japan and the United States. We investigated the effects of gilteritinib combined with cytarabine plus daunorubicin/idarubicin, or combined with azacitidine in human FLT3-ITD –positive ( FLT3-ITD + ) AML cell lines and xenografted mouse models. Gilteritinib induced G 1 arrest and apoptosis in a dose-dependent manner. The addition of cytarabine, daunorubicin, idarubicin, or azacitidine potentiated apoptosis. Gilteritinib alone or combined with cytarabine, daunorubicin, idarubicin, or azacitidine, inhibited anti-apoptotic protein expression in MV4-11 cells. In xenografted mice, administration of cytarabine, idarubicin, or azacitidine in combination with gilteritinib had little impact on plasma or intratumor PK profiles of gilteritinib, cytarabine, idarubicin, or azacitidine. Gilteritinib combined with chemotherapy reduced tumor volume to a greater extent than either gilteritinib or chemotherapy alone. Of note, the addition of cytarabine plus daunorubicin/idarubicin led to tumor regression in mice, with complete regression observed in six out of eight mice in both triple combination groups. These findings support the investigation of gilteritinib combined with chemotherapy in patients with FLT3-ITD + AML, including those who are ineligible for intensive chemotherapy.

This study aimed to explore the competencies of health care practitioners who promote shared decision-making (SDM)-based care for women facing an unplanned pregnancy in Japan. We conducted semistructured interviews with 12 care providers who are pioneers in care for women facing an unplanned pregnancy and adopted a modified grounded theory approach for data analysis. A three-step model for shared decision making in practice (team talk, option talk, and decision talk) was used as a reference. The answers given by the care providers were analyzed to identify the competencies involved in shared decision making. We identified three stages: (i) building trust and promoting women's expression; (ii) discussing women's real needs; and (iii) exploring the intentions and goals expressed by women and finding the best choices while promoting women's autonomy in decision-making. The coordination between the support of partners, families, and professionals, and the care provided to strengthen women's identities facilitated shared decision making. Women facing an unplanned pregnancy can benefit from interventions designed to improve shared decision making. A key component of shared decision making-based care relates to practitioners' raised awareness toward their roles and responsibilities: developing good communication skills and fostering collaboration between all stakeholders.

e16078 Background: Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets Claudin 18.2 (CLDN18.2), a tight junction protein that is normally confined to gastric mucosa but is retained in G/GEJ. A phase 2 (NCT01630083, FAST) trial demonstrated significantly prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. Two global phase 3 studies are ongoing, comparing zolbetuximab + chemotherapy vs chemotherapy as first-line treatment in CLDN18.2-positive G/GEJ. This study assessed the influence of ethnic differences and chemotherapy on the pharmacokinetics (PK) of zolbetuximab in patients (pts) with G/GEJ and the potential effect of zolbetuximab on chemotherapy PK. Methods: In the Japanese phase 1 and global phase 2 studies, adult pts with CLDN18.2-postitive G/GEJ received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 1 (Cycle 1 Day 3 in Cohort 2 of phase 2) then 600 mg/m2 Q3W. Phase 1 and Cohort 1A of the phase 2 study assessed zolbetuximab monotherapy in 21-day cycles. Cohort 2 of the phase 2 study assessed zolbetuximab + mFOLFOX (5-FU, folinic acid, oxaliplatin; 4 cycles) in 42-day cycles (Q2W from Cycle 1 Day 1). Blood samples for zolbetuximab PK following single and multiple doses, and for chemotherapy (5-FU and oxaliplatin) PK alone or with zolbetuximab were collected. Maximum serum drug concentration (Cmax) and area under the concentration-time curve from 0-21 days (AUC0-21) were assessed. Potential ethnic differences in zolbetuximab exposures across Japanese, other Asian (Korean and Taiwanese), and Western pts, and the potential drug-drug interaction between zolbetuximab and chemotherapy were evaluated. Results: Zolbetuximab concentration profiles and PK parameters were generally comparable across Japanese, other Asian, and Western populations (Table). Zolbetuximab PK properties were similar between monotherapy and combination therapy cohorts (Table). Chemotherapy PK was comparable with and without zolbetuximab. Conclusions: The analyses suggest no apparent ethnic differences in zolbetuximab PK across Japanese/Asian and Western pts and no PK interactions between zolbetuximab and mFOLFOX6. These results support the use of zolbetuximab and mFOLFOX without the need for dose adjustment in global phase 3 trials. Clinical trial information: NCT03505320, NCT03528629. [Table: see text]

Background and objectives: In an aging society, the maintenance of the oral function of the elderly is of importance for the delay or prevention of frailty and long-term care. In the present study, we focused on the maximum tongue pressure (MTP) value and analyzed the relationship between MTP and age, occlusal status, or body mass index (BMI). Materials and Methods: This one-center observatory study was conducted using a cohort consisting of 205 community-dwelling outpatients over 65 years old. The MTP values of all subjects were measured using a commercially available tongue pressure measurement device and statistically analyzed. In addition, the correlation between MTP value and BMI was analyzed. Results: The MTP value decreased with age, especially in subjects classified as Eichner B and C. The difference in occlusal status did not show any statistically significant influence on MTP value. The correlation between BMI and MTP value was indicated in the tested groups other than an age of 65&ndash, 74 and Eichner A groups. Conclusions: Although MTP value decreased with age, the difference in occlusal status did not have an impact on MTP value. The correlation between BMI and MTP value was not shown in the youngest group or a group with sufficient occlusal units. The results presented in the present study may imply that, even if MTP is low, younger age and/or better occlusal status compensate for the inferior MTP value in the cohort studied.

Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non–small cell lung cancer (NSCLC). Echinoderm microtubule–associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-molecule ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concentrations >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body weight. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality. Mol Cancer Ther; 13(2); 329–40. ©2014 AACR.

A 28-year-old woman presented with right flank pain. A large, firm, fixed mass was palpable in the right side of the abdomen. Computed tomography revealed a solid mass of the right kidney with extension into the renal vein and inferior vena cava. The patient underwent right radical nephrectomy with en bloc resection of the inferior vena cava containing tumor thrombus and right adrenalectomy. Histologically the tumor consisted of small tumor cells with rosette formation. Immunohistochemical staining was positive for CD99 and NSE. Analysis with polymerase chain reaction (PCR) demonstrated the EWS/FLI1 fusion products resulting from a chromosomal translocation. These findings were consistent with primary renal primitive neuroectodermal tumor (PNET). Two months after surgery, multiple lung, liver and lymph node metastases were found. The patient received 2 cycles of chemotherapy with cisplatin, ifosfamide, etoposide, resulting in a partial remission. She subsequently received 1 cycle chemotherapy with paclitaxel and carboplatin, resulting in no response. The metastatic lung and liver diseases progressed and she died 5 months after diagnosis.

We report a rare case of squamous cell carcinoma in the renal pelvis of a horseshoe kidney. An 80-year-old woman was referred to the National Nagano Hospital for the examination of occult blood in her urine. Microscopic hematuria was found, but pyuria was not seen. Computed tomography and magnetic resonance imaging showed a mass in the left renal pelvis of the horseshoe kidney. No renal stone or hydronephrosis was found. Cytopathological examination in the voided urine specimen was positive. Left nephroureterectomy with the splitting of the isthmus of the horseshoe kidney was performed without renal pedicle clamping using a microwave tissue coagulator. No bleeding was encountered after separating the isthmus. A final pathological diagnosis of squamous cell carcinoma with a tumor thrombus was made. Lymph node metastasis had developed and rapidly progressed and the patient died of disseminated malignancy 4 months after the operation. We reviewed 24 cases of renal pelvic tumor in horseshoe kidneys previously reported in Japan. Seven cases (30%) included components of squamous cell carcinoma. The incidence is higher than that of renal pelvic tumors in the general population.

Background FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Activating mutations in FLT3 such as internal tandem duplications (ITD) at the juxtamembrane domain are present in approximately 25-30% of newly diagnosed AML cases. Patients with AML harboring the FLT3-ITD mutation have poorer prognosis following the current induction chemotherapy treatment of cytarabine (AraC) and an anthracycline (daunorubicin [DNR] or idarubicin [IDR]). Azacitidine (Aza) is a treatment option for AML patients who are not eligible for intensive chemotherapy. Gilteritinib, a novel, small molecule inhibitor of the tyrosine kinases FLT3/AXL, is in Phase 3 development for treatment of FLT3 mutation-positive AML, including patients with FLT3-ITD mutations. In previous preclinical studies, gilteritinib has demonstrated superior antitumor effects when given in combination with AraC and either DNR or IDR compared with combination chemotherapy. Here, we report preclinical antileukemic activity of gilteritinib in combination with Aza against FLT3-ITD mutation-positive AML. Methods: The antitumor effects of gilteritinib alone and in combination with Aza were investigated in MV4-11 cells harboring the FLT3-ITD mutation. Apoptosis was detected using annexin V staining via flow cytometry; PARP cleavage was evaluated via Western blot analysis. Anti-apoptotic protein expression was evaluated by Western blot. Furthermore, the combination antitumor effects were evaluated in MV4-11-xenografted nude mice administered once-daily, oral gilteritinib at 3 mg/kg for 21 days alone and concomitantly with once-daily intravenous Aza at 3 mg/kg for 5 days. Pharmacokinetic parameters were also investigated in MV4-11 xenografted nude mice. Statistical differences in antitumor effects of combination therapy versus gilteritinib alone and combination therapy versus Aza alone were assessed on Day 21 using the Student's t-test. Results: Gilteritinib treatment for 48h resulted in an induction of apoptosis in MV4-11 cells as determined by an increase in annexin V-positive cells. When used in combination, gilteritinib augmented the Aza-induced increase in annexin V-positive cells. Gilteritinib also decreased the expression of anti-apoptotic proteins such as MCL-1, BCL2L10, and survivin, which are reported to be important in chemotherapy sensitivity, following 24h treatment. In combination with annexin results, an increase in PARP cleavage was also observed in MV4-11 cells following gilteritinib treatment; cells co-treated with gilteritinib and Aza showed a further increase in PARP cleavage. In mice xenografted with MV4-11 cells, oral gilteritinib (3 mg/kg/day) inhibited the tumor growth by 71%; Aza alone did not suppress tumor growth. The tumor volume in the doublet combination group (94% growth inhibition) was significantly smaller than in each single treatment group on Day 21 (Figure). No obvious influences on body weight, behavior, or diarrhea were noted in the combination group. Plasma concentrations for either gilteritinib or Aza were not considerably increased by their use in combination therapy when compared with the concentrations observed with single treatment. Conclusions: Gilteritinib treatment augmented Aza-induced apoptosis in part by reductions of anti-apoptotic protein expressions in vitro. In the non-clinical models used, gilteritinib, in combination with Aza, showed superior antitumor efficacy compared with each single agent alone. These findings support the development of gilteritinib in combination with Aza as a potential treatment of FLT3-ITD mutation-positive AML. Figure Antitumor Effect of Gilteritinib in Combination with Azacitidine in Mice Xenografted with MV4-11 Cells ***P Disclosures Ueno: Astellas Pharma Inc: Employment. Mori:Astellas Pharma Inc: Employment. Kamiyama:Astellas Pharma Inc: Employment. Kaneko:Astellas Pharma Inc: Employment. Isshiki:Astellas Pharma Inc: Employment. Takeuchi:Astellas Pharma Inc: Employment.

We experienced a 78-year-old man in whom transient pulmonary hypertension was documented during epileptic seizure. A Swan-Ganz catheter demonstrated that pulmonary arterial pressure rose immediately after the initiation of the seizure, which was followed by systemic hypertension. The plasma level of angiotensin II increased in pulmonary circulation during the seizures; however, catecholamines did not change from the baseline. The patient responded well to treatment with an antiepileptic drug and losartan potassium.

EML4-ALK translocation has been validated as a therapeutic target in a subset of non-small-cell lung cancer (NSCLC) patients. In clinical settings, crizotinib has shown promising response rates in patients with EML4-ALK-positive NSCLC. However, disease relapse has been observed after an initial favorable response and several resistance mechanisms, including the gatekeeper L1196M mutation, have been reported to date. We have discovered ASP3026, a selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity with an IC50 value of 3.5 nmol/L and showed more selective inhibition in a Tyr-kinase panel than crizotinib. Using NCI-H2228, a human NSCLC cell line endogenously expressing EML4-ALK, we determined the anti-proliferative effect of ASP3026. ASP3026 inhibited the in vitro proliferation with an IC50 value of 64.8 nmol/L and induced dose-dependent anti-tumor effects starting at 1 mg/kg with marked regression at 10, 30 and 100 mg/kg in a subcutaneous tumor model. Body weights were unaffected. ASP3026 at 100 mg/kg also showed tumor regression against EML4-ALK-driven tumor model with gatekeeper mutation while crizotinib at 100 mg/kg was ineffective. In an NCI-H2228 orthotopic lung model, ASP3026 at 30 mg/kg induced sustained tumor regression during the experimental period. In contrast, crizotinib at 30 mg/kg induced initial regression during the first 7 days but regrowth of the tumor was observed despite continuous crizotinib administration. After tumor regrowth had been established in crizotinib-treated mice, substantial tumor regression was achieved by subsequent administration of ASP3026 at 30 mg/kg. Taken together, these results suggest that ASP3026 in the non-clinical setting shows superior efficacy to crizotinib in crizotinib-resistant models.

7070 Background: Activating mutations in FLT3 receptor tyrosine kinase, characterized by internal tandem duplication (ITD) and tyrosine kinase domain point mutations near position D835, have been i...

7071 Background: Patients with AML harboring internal tandem duplication (ITD) of FLT3 have a poor prognosis following the current chemotherapeutic treatment of cytarabine (AraC) and anthracycline ...

The recent breakthrough identifying the onco-driver fusion mutant of ALK kinase and its inhibitor crizotinib commercially termed as Xalkori has brought significant benefit to a portion of non-small cell lung cancer (NSCLC) patients. However, a number of clinical issues in ALK-positive lung cancer remain, involving resistance to crizotinib caused by secondary mutation, amplification of the ALK gene, activation of alternative pathways, and metastatic resistance, etc. Among these mechanisms, brain metastasis is a critical issue because of its poor prognosis. We have recently identified ASP3026 as a novel type of ALK inhibitor under development, and have reported that ASP3026 shows antitumor activities in several crizotinib-refractory models including gate keeper mutants. Here, we report the first PET imaging of an ALK inhibitor using [11C]ASP3026. The study has revealed that ASP3026 shows a brain tumor permeability in an intracranial xenograft model of H2228-luc ALK fusion positive cells. In this model, significant growth inhibition of H2228 intracranial tumor was observed by treatment with ASP3026 (10 mg/kg, q.d.), but not with crizotinib (10 mg/kg, q.d.) as determined by a bioluminescent imaging technique. Pharmacokinetic measurements of ASP3026 and crizotinib indicated that ASP3026 showed a four-fold better brain penetration than crizotinib on AUC0-24 base analysis, with a brain/plasma ratio=0.72 and 0.18 for ASP3026 and crizotinib, respectively. Further, we synthesized positron-labeled [11C]ASP3026 and performed PET imaging to clarify penetration of ASP3026 into cranial tumors. Quantitative analysis of [11C]ASP3026-PET data indicated that ASP3026 showed higher uptake into cranial tumors (SUV=3.0) than brain parenchyma (SUV=0.8). Moreover, comparison of pharmacokinetic profiles in several tumor models showed that tumor uptake of ASP3026 was higher than that of surrounding tissue, suggesting that tumor accumulation of ASP3026 was dependent on the microenvironment of tumor. Taken together, these results suggest that ASP3026 has favorable properties that may be useful for the treatment of brain metastases in ALK-positive NSCLC patients. Thus, PET imaging using 11C-labeled ASP3026 may allow the tumor penetration of ASP3026 to be clarified in any primary or metastatic tumor site. Citation Format: Hiroshi Fushiki, Rika Saito, Makoto Jitsuoka, Itsuro Shimada, Yutaka Kondoh, Hideki Sakagami, Yukiko Funatsu, Akihiro Noda, Yoshihiro Murakami, Sousuke Miyoshi, Yoko Ueno, Satoshi Konagai, Takatoshi Soga, Shintaro Nishimura, Masamichi Mori, Sadao Kuromitsu. First demonstration of in vivo PET imaging for ALK inhibitor using [11C]ASP3026, a novel brain-permeable type of ALK inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2678. doi:10.1158/1538-7445.AM2013-2678

EML4-ALK translocation has been validated as a therapeutic target in a subset of non-small cell lung cancer (NSCLC) patients. In clinical settings, crizotinib has shown promising response rates in patients with EML4-ALK positive NSCLC, while disease relapse has been observed in several sites, including the lungs. Our previous studies found that ASP3026, a selective ALK inhibitor, had higher kinase selectivity than crizotinib and induced regression of tumors expressing EML4-ALK with a gate-keeper mutation that confers resistance to crizotinib. Here, we evaluated the antitumor activity of ASP3026 and crizotinib against orthotopic lung and intrapleural tumors in mice using luciferase-expressing NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK. In an orthotopic lung model, implanted cells were monitored using bioluminescent imaging (BLI) of the chest area. ASP3026 and crizotinib were administered orally at once daily doses ranging from 3 to 30 mg/kg (starting after confirmation of tumor growth). ASP3026 at 30 mg/kg induced tumor regression by 27 days after the start of administration; in contrast, crizotinib at 30 mg/kg induced regression during the first 7 days of administration, although tumors subsequently regrew despite continuous drug administration. After tumor regrowth had been established by the first cycle treatment of crizotinib, substantial regression was achieved by subsequent administration of ASP3026 at 30 mg/kg against the crizotinib-refractory tumors. In an intrapleural xenograft model, disease-related mortality was observed in tested animals, with a median survival time (MST) of 39 days in vehicle-treated control mice and 71 days in crizotinib-treated animals at 30 mg/kg. In contrast, no mice receiving ASP3026 treatment at 30 mg/kg died during the experimental period (90 days). These effects were accompanied by change in the bioluminescent emissions, with crizotinib-treated mice showing increased emissions following the initial reduction, while ASP3026-induced reduction continuing throughout the experimental period. The mean bioluminescent emission in the group treated with ASP3026 was significantly lower than in the crizotinib-treated group, indicating that ASP3026-treated animals exhibited lower tumor burden than crizotinib-treated ones.Taken together, these results suggest that ASP3026 is effective in producing shrinkage of tumors refractory to crizotinib and shows superior efficacy to crizotinib against intrapleural metastatic tumors with respect to prolonging survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 866. doi:1538-7445.AM2012-866

EML4-ALK is an oncogenic fusion kinase, which was first identified in non-small cell lung cancer (NSCLC), and is regarded as an attractive therapeutic target for treating a subpopulation of NSCLC patients. Crizotinib, which is inhibitor for MET and ALK, was recently approved by FDA (26 August 2011) for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. We synthesized and screened chemical compounds utilizing an ALK kinase inhibition assay aimed at the EML4-ALK target for drug discovery, and found ASP3026, a novel and selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity and was more selective than crizotinib in a Tyr-kinase panel. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3 and that of 3T3 cells expressing EML4-ALK variant 1, 2 and 3. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor were determined using high-performance liquid chromatography-tandem mass spectrometry. Significant tumor penetration was observed. The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts. ASP3026, (daily oral dosing for 14 days) induced dose dependent anti-tumor effects starting at 1 mg/kg with marked regression at 10, 30 and 100 mg/kg. Body weights were unaffected. Crizotinib, (twice daily oral dosing) was less potent, with growth inhibition at 10 mg/kg, and tumor regression at 30 mg/kg. A dose of 100 mg/kg of crizotinib was poorly tolerated. Resistance mutations in ALK kinase domain against crizotinib were reported following sequence analysis of tumor cells derived from crizotinib-relapsed patients. The position of the mutation is the so-called gatekeeper mutation and is thought to be one of the causes of crizotinib relapse. In an EML4-ALK driven tumor model with gatekeeper mutation, ASP3026 showed potent anti-tumor effects while crizotinib was ineffective even at 100 mg/gk qd. In summary, ASP3026 has a broad safety margin and inhibitory activity at the gatekeeper mutation. Therefore, ASP3026 may still effective in EML4-ALK fusion positive NSCLC patients, that have relapsed to crizotinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A227.