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457 Background: Axitinib is one of the standard second-line therapies after sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC). The previous study showed that higher exposure and diastolic blood pressure (dBP) were independently associated with better clinical outcomes. However, many factors, such as antihypertensive agents use, usually affect dBP. Therefore, axitinib dose adjustment based on its exposure could be more adequate than that based on dBP. Methods: We conducted a prospective phase II trial of axitinib dose adjustment for Japanese pts with mRCC previously treated with sunitinib. Starting dose of axitinib was 5 mg BID. We assayed blood axitinib levels on day 1 and calculated the area under concentration-time curve from 0 to 12 hours (AUC0-12). We determined the individual sufficient dose (SD) to reach AUC0-12 value at the steady state of 150 ng*hr/mL. After day 15, axitinib dose was adjusted to keep over SD according to adverse drug reaction for each patient. The primary endpoint is 6-month progression-free survival (6m-PFS) rate. Secondary endpoints include toxicity and objective response rate. With power of 80% and one-sided alpha of 10%, thirty-two pts were required to reject 48% of 6m-PFS rate under expected 69% 6m-PFS rate. Results: Between May 2013 to March 2015, 26 pts were enrolled when the trial closed for poor accrual. Pts’ characteristics were: median age 71 years, male 20 (77%), PS 0 19 (73%), and International Metastatic RCC Database Consortium intermediate risk 24 (92%). Median SD of axitinib was 3 mg BID (range 1-16). SD was given at a median of 78% (range 0-100) of total administration day until 6 months. Two pts did not receive the planned SD because their SD was over 10 mg BID. Therefore, the two pts were excluded from safety analysis; meanwhile all pts were included in efficacy analysis. The 6m-PFS rate was 85% (95% CI 66-94, p < 0.01). The median PFS was 10.6 months (95% CI 7.2-16.7). The most common grade 3 to 4 adverse events during the first 6 months were hypertension (79%), decrease appetite (29%), fatigue (13%), and hand-foot syndrome (13%). Conclusions: The individual dose adjustment of axitinib to keep over 150 ng*hr/mL of AUC0-12 on day 1 for sunitinib-pretreated mRCC is feasible. Clinical trial information: UMIN000009579.

Hepatitis C virus (HCV) infection is one of the most common blood-borne infections worldwide. Little is known with respect to changes in HCV status during chemotherapy for colorectal cancer (CRC), and the influence of HCV infection on chemotherapy remains unclear. Between 2001 and 2012, 3,260 patients were diagnosed with CRC in our institute. We studied 77 patients who were positive for anti-HCV antibodies. We retrospectively reviewed changes in HCV load and chemotherapy toxicities. Twenty-four of 77 HCV-infected patients with CRC received chemotherapy. Their median age was 66 years, and four patients had liver cirrhosis. The remaining 20 patients were diagnosed with chronic hepatitis, and their liver function tests and blood cell counts at baseline were normal. Serum HCV ribonucleic acid level before and after chemotherapy was evaluated in ten patients, with medians of 4.0 and 3.05 log IU/ml at baseline before and after chemotherapy, respectively. Two patients demonstrated elevated transaminase levels during chemotherapy. Among the 24 HCV patients received chemotherapy, no patients suffered from febrile neutropenia or treatment delay; two required chemotherapy dose reduction. Our results indicated that chemotherapy for CRC patients with HCV infection can be performed safely without changing the viral load.

For patients with HER2-positive breast cancer, the prognostic impact of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is unclear when stratified by hormonal receptor (HR) status; however, the impact of pCR on survival when stratified by hormonal receptor (HR) status is uncertain.This multicenter retrospective study investigated the predictors of pCR and its prognostic value in Japanese patients 366 HER2-positive breast cancer who received NAC. pCR was defined as no invasive residual tumor in the breast or axilla.Median follow-up was 55 months. Multivariate analysis revealed that HR status (OR, 0.37; p0.001) was one of the independent predictors of pCR. Five-year recurrence-free survival was higher in HR-negative patients with pCR (93%) than in those without pCR (68%), and pCR was independently prognostic (hazard ratio, 0.32; p = 0.005). However, 5-year recurrence-free survival was not different between HR-positive patients with pCR (94%) and those without pCR (84%), and pCR was not significantly prognostic (hazard ratio, 0.53; p = 0.39). In addition, 5-year overall survivals were high and similar (97% in pCR, 94% in non-pCR). Among 204 patients treated with neoadjuvant trastuzumab, pCR was not significantly prognostic in the HR-positive group (hazard ratio, 0.63; p = 0.56).Our study suggested that the HER2-positive HR-positive patients had a good prognosis despite the lower achievement rate of pCR, whose prognostic impact was smaller than that in the HER2-positive HR-negative patients. The treatment strategy for HER2-positive breast cancer can be stratified by HR status.

Objective: FSK0808 is a filgrastim biosimilar. This study assessed the efficacy and safety of FSK0808 in patients with breast cancer. Methods: One hundred and four breast cancer patients undergoing chemotherapy were enrolled in the study. FSK0808 was used to treat the neutropenia experienced by the patients in the course of their chemotherapy. Efficacy was evaluated by the recovery of absolute neutrophil count following FSK0808 administration based on the duration of neutropenia in patients who received pre- or postoperative chemotherapy containing fluorouracil, epirubicin and cyclophosphamide. Adverse events were evaluated in accordance with the Common Terminology Criteria for Adverse Events version 3.0. The incidence of febrile neutropenia and generation of an anti-granulocyte colony-stimulating factor antibody were also evaluated. Results: The average duration of neutropenia in Cycle 2 was 2.2 days with a standard deviation of 1.5 days. The upper limit of the 97.5% one-sided confidence interval was 2.5 days and was confirmed not to exceed 3.0 days, which was defined as the threshold value of absolute neutrophil count recovery. The incidence of febrile neutropenia across all treatment cycles was 34.6%. Observed adverse drug reactions with an incidence of .5% were back pain (60.6%), bone pain (9.6%), alanine aminotransferase increase (8.7%), aspartate aminotransferase increase (5.8%) and arthralgia (5.8%). Production of the anti-granulocyte colony-stimulating factor antibody was not observed in any patient during the study. Conclusions: FSK0808 was safe and well tolerated in breast cancer patients undergoing chemotherapy and effectively stimulated neutrophil recovery.

Alterations in the epidermal growth factor receptor ( EGFR ) gene are associated with carcinogenesis in non-small cell lung cancer. However, the intratumoral distribution of these abnormalities has not been elucidated. This study included patients with surgically resected lung adenocarcinoma. The predominant histological growth pattern was determined. Chromogenic in situ hybridization (CISH) and EGFR -mutation specific-antibodies were used for analysis of changes in gene copy number and EGFR mutations, respectively. EGFR mutation detected immunohistochemistry (IHC) and amplification were identified in 31 (53%) and 30 (52%) cases, respectively. The predominant growth patterns in the 58 tumors evaluated were papillary (28, 48%), lepidic (8, 14%), acinar (15, 26%), and solid (7, 12%). EGFR mutations were the least common in cases with a solid predominant pattern. The incidence of EGFR amplification did not differ among predominant patterns. Analyzing each histological subtype, no differences were noted between the prevalence of EGFR-IHC positive and CISH-positive rates. In the analysis of EGFR amplification, CISH-positive status was more prevalent in IHC-positive cases than in IHC-negative cases. All 19 cases that were both IHC and CISH positive were analyzed. In 17 cases (90%), the IHC-positive area was equal to or larger than the CISH-positive area. Among the histological subtypes of lung adenocarcinoma, the solid predominant subtype was distinguishable by its infrequent EGFR mutations. EGFR gene mutations preceded changes in oncogenic drive, more so than did EGFR gene number alterations during the developmental process of lung adenocarcinoma.

Background: This retrospective study aimed to determine whether adverse events are more common in docetaxel followed by cyclophosphamide (TC) as compared to the reverse infusion order (rTC). Methods: A retrospective analysis was undertaken at a single institution for 92 consecutive cases treated with TC or rTC for stage I-III breast cancer in a neoadjuvant/adjuvant setting between December 2006 and June 2011. TC was administered during the first 2.5 years and rTC in the latter 2 years. Results: Among the 92 cases, 50 were in the TC arm and 42 in the rTC arm. Fatigue (72.0 vs. 23.8%), edema (48.0 vs. 16.7%), peripheral neuropathy (66.0 vs. 14.3%), myalgia (48.0 vs. 9.5%) and stomatitis (48.0 vs. 16.7%) occurred significantly more often in cases receiving TC compared to rTC, respectively. Conclusion: Nonhematological toxicities are less common in cases receiving rTC in comparison to those receiving TC.

Five prognostic factors had been previously identified in patients with metastatic colorectal cancer (MCRC) who received irinotecan-based second-line chemotherapy. Patients were classified into three prognostic groups based on significant differences in median overall survival (OS). This study is conducted to validate this classification in an external validation cohort. This retrospective study included 193 patients of an external validation cohort who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy, with or without bevacizumab at three institutions. Three of the five predefined factors (poorly differentiated adenocarcinoma, LDH ≥400 IU/L, progression-free survival of first-line therapy

3568Background: The programmed death-1 (PD-1)/PD-L1 pathway is a negative feedback mechanism that suppresses the activity of T cells. PD-L1 was expressed on tumor cells (TCs) or tumor-infiltrating ...

3567Background: The objective of this phase II trial wasto compare efficacy of Pmab plus FOLFIRI and Bmab plus FOLFIRI as second-line chemotherapy for patients (pts) with wild-type (WT) KRAS exon 2...

TPS636Background: Combination of pertuzumab (Pmab) with trastuzumab (Tmab) has dramatically improved patients’ outcomes compared to Tmab as 1st line therapy in HER2-positive (+ve) locally advanced ...

611 Background: Programmed death 1 (PD-1)/ PD-L1 pathway is a negative feedback mechanism that suppresses the activity of T cells. Some previous studies showed that positive PD-L1 expression on tumor cells (TC) was poor prognostic factor in patients with colorectal cancer; however, recent studies suggest that IC also play important roles to determine the prognosis in cancer patients. The aim of this study is to investigate the association of clinical and pathological features with PD-L1 expression on TC and IC. Methods: We retrospectively reviewed data of consecutive patients with stage IIIb colorectal cancer (Japanese classification of colorectal carcinoma The 8th Edition), who underwent surgery and received adjuvant chemotherapy in our institution between January 2009 and July 2012. PD-L1 expression was evaluated by immunohistochemistry (IHC) on TC and IC. Specimens were scored as IHC low (L) or high (H), if < 5% or ≥ 5% of cells were PD-L1 positive, respectively. Results: Seventy-four patients were included in this analysis. Median age was 61 years (range 32-84). Thirty-one (41.9%) and 43 (58.1%) patients received fluoropyrimidine and fluoropyrimidine combined with oxaliplatin as adjuvant chemotherapy, respectively. The median follow-up time was 51.3 months (range 4.6-75.9). The number of patients with PD-L1 expression on TC/IC (H/H, H/L, L/H, and L/L) were 0, 12, 11, and 51, respectively. The median disease-free survival (DFS) in patients with high and low PD-L1 expression on TC were 29.9 months and “not reached”, respectively (hazard ratio [HR] 2.02; 95% confidence interval [CI], 0.85-4.30; P = 0.11). The median DFS in patients with high and low PD-L1 expression on IC were “not reached” and 55.1 months, respectively (HR 0.29; 95%CI, 0.05-0.95; P = 0.04). Conclusions: Although high PD-L1 expression on TC is associated with poor prognosis, high PD-L1 expression on IC positively affects the survival in patients with stage IIIb colorectal cancer.

599 Background: It is well known that the loss of BAP1 protein expression in primary site of clear cell type renal cell carcinoma (ccRCC) is prognostic marker. However, the existence of intratumoral heterogeneity in primary site of ccRCC makes it difficult to assess accurate prognosis. The aim of this study is to investigate the heterogeneity of BAP1 expression in metastatic sites and to evaluate the possibility as a prognostic marker. Methods: We collected samples of both primary and matched metastatic sites of the first recurrence in 41 metastatic ccRCC patients. Immunohistochemistry (IHC) for BAP1 and PBRM1 protein expression were performed on at least two tissue microarray (TMA) sections from primary site and at least one TMA sections from metastatic sites. We retrospectively analyzed the association of the IHC with clinical outcomes. Results: 41 primary and metastatic sites were available for this analysis. The most of metastatic sites were lung (68.3%) and lymph node (12.2%). BAP1 protein expression-positive, -negative and -heterogeneity in primary/metastatic sites were 29/29 (70.7/70.7%), 8/11 (19.5/26.8%) and 4/1 (9.8/2.4%), respectively. PBRM1 protein expression-positive, -negative and -heterogeneity in primary/metastatic site were 22/27 (53.7/65.9%), 9/11 (21.9/26.8%) and 10/3 (24.4/7.3%), respectively. The concordance between primary and metastatic site for BAP1 and PBRM1 protein expression was 82.9 and 63.4%, respectively. Median overall survival (OS) from the first recurrence of metastasis in patients with BAP1-positive and -negative in metastatic sites was 97 and 51 months, respectively (p = 0.0275). Median OS from the first recurrence of metastasis in patients with PBRM1-positive and -negative in metastatic sites was 82 and 58 months, respectively (p = 0.44). Conclusions: There is more intratumoral heterogeneity for BAP1 and PBRM1 in primary site than metastatic sites of ccRCC. The loss of BAP1 protein expression by IHC in metastatic sites predicts poor clinical outcome.

To the Editor: Ledermann et al. (April 12 issue)1 report that olaparib as maintenance therapy significantly improved progression-free survival among patients with platinum-sensitive relapsed ovarian cancer who had a response to the most recent platinum-based chemotherapy. In this study, the benefit of olaparib was consistently shown regardless of the BRCA mutational status. Another study showed that the efficacy of olaparib depended on platinum sensitivity even among patients with BRCA-mutated ovarian cancer.2 These studies suggest that platinum sensitivity is more important to predict sensitivity of poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors than the mutational status of BRCA1 and BRCA2 alone. Many genes other than BRCA are involved in platinum-induced DNA damage repair and related to platinum sensitivity.3,4 We believe that such genes, not only BRCA, should be analyzed in clinical trials of PARP inhibitors.

136 Background: Nanoparticle Albumin-Bound Paclitaxel (nab-PTX) is a new solvent free taxane-based anticancer drug. According to CA024 trial, nab-PTX 100mg/m2 demonstrated superior response to docetaxel (DTX) in patients with metastatic breast cancer. Besides, nab-PTX 100mg/m2 was less toxicity. In operable breast cancer, GeparSepto study was reported that the pCR rate were significantly higher with nab-PTX 125/150 mg/m2 compared to paclitaxel. We planned the randomized parallel design phase II trial to evaluate nab-PTX 100mg/m2in early breast cancer. Methods: Stage II-III HER2-negative breast cancer patients were included in this trial and received either 4 cycles of DTX (75 mg/m2 day1) q 3 w or 4 cycles of nab-PTX (100 mg/m2 day1/8/15) q4w followed by 4 cycles of FE100C. The primary end point is pCR (ypT0/is ypN0) rate, and the secondary end points are response rate, histological effect of treatment, breast conservation rate, and toxicity. Results: Between March 2011 to March 2014, 152 eligible patients were enrolled at 6 centers (75 pts were allocated for nab-PTX). Baseline characteristics were well balanced; median age was 51/49 years (DTX/nab-PTX), 61/61% of the patients with ER positive, 38/36% triple negative breast cancer, 57/65% Ki67 > 20%. Clinically response rate was similar to each drug. (53/57%) The pCR rate was 12/17% (p = 0.323). In TNBC group, the pCR rate was 28/30% (p = 0.866). In Ki67 > 20% group, the pCR rate was significantly higher, 16/48% (p = 0.021) with nab-PTX arm. The most common grade3-4 adverse event was neutropenia, which was observed in 40/36% of cases. Non-hematological adverse events of any grade were; 34/32% myalgia (DTX/nab-PTX), 42/35% arthralgia, 55/65% peripheral sensory neuropathy. No Grade3-4 peripheral sensory neuropathy was observed in nab-PTX arm. Infusion reaction of DTX occurred in 1 patient. Conclusions: In this initial effectively analysis, neoadjuvant weekly nab-paclitaxel 100mg/m2 were promising drug in HER2-negative operable breast cancer patients. Larger studies will be needed to evaluate neoadjuvant weekly nab-paclitaxel compared with DTX. Clinical trial information: 000005388.

We report a case of small-bowel perforation due to metastatic carcinoma of the breast during chemotherapy. Partial resection of the small intestine and primary anastomosis were performed. Although the patient made a good recovery from panperitonitis, she died of the disease on the 55th postoperative day. Since perforation during chemotherapy results in an extremely poor prognosis, special caution during chemotherapy is needed for patients with possible gastrointestinal involvement with tumor.

Purpose This study evaluated whether the presence of epidermal growth factor receptor (EGFR) mutations is a predictive marker for survival benefit from gefitinib and/or a prognostic marker in patients with advanced lung adenocarcinoma. Patients and Methods Overall survival (OS) was compared between patients with advanced lung adenocarcinoma who began first-line systemic therapy before and after gefitinib approval in Japan (January 1999 to July 2001 and July 2002 to December 2004, respectively). Deletional mutations in exon 19 or the L858R mutation in exon 21 of EGFR were evaluated using high-resolution melting analysis. Results EGFR mutations were detected in 136 (41%) of the 330 patients included in this study. OS was significantly longer among the EGFR-mutant patients treated after gefitinib approval compared with the OS of patients treated before gefitinib approval (median survival time [MST], 27.2 v 13.6 months, respectively; P < .001), whereas no significant survival improvement was observed in patients without EGFR mutations (MST, 13.2 v 10.4 months, respectively; P = .13). A significant interaction between the presence of EGFR mutations and a survival improvement was seen (P = .045). Among patients treated before gefitinib approval, those with EGFR mutations lived longer than those without EGFR mutations (MST, 13.6 v 10.4 months, respectively; P = .034). The response rates to first-line cytotoxic chemotherapy were not significantly different between patients with and without EGFR mutations (31% v 28%, respectively; P = .50). Conclusion EGFR mutations significantly predict both a survival benefit from gefitinib and a favorable prognosis in patients with advanced lung adenocarcinoma.

Purpose: Epidermal growth factor receptor (EGFR) mutations, especially in-frame deletions in exon 19 (DEL) and a point mutation in exon 21 (L858R), predict gefitinib sensitivity in patients with non–small cell lung cancer (NSCLC). In this study, we verified the accuracy of EGFR mutation analysis in small samples by high-resolution melting analysis (HRMA), which is a rapid method using PCR amplification with a dye to analyze the melting curves in NSCLC. Experimental Design: We designed a prospective study to compare the sensitivity and specificity of HRMA and DNA sequencing with laser capture microdissection. Eligible patients with lung lesions were screened by bronchoscopy or percutaneous needle biopsy to histologically confirm the diagnosis, followed by surgical resection of the NSCLC. Small diagnostic specimens were analyzed for EGFR mutations by HRMA, and the surgically resected specimens were examined for mutations by HRMA and DNA sequencing. Results: The analyses for EGFR mutations were conducted in 52 eligible cases of the 92 enrolled patients. EGFR mutations were detected in 18 (34.6%) patients. The results of HRMA from surgically resected specimens as well as DNA sequencing revealed 100% sensitivity and specificity. On the other hand, the sensitivity and specificity of HRMA from the small diagnostic specimens were 83.3% and 100%, respectively. Conclusions: In this study, we showed that HRMA is a highly accurate method for detecting DEL and L858R mutations in patients with NSCLC, although it is necessary to consider the identification of patients with a false-negative result when the analysis is conducted using small samples.

Epidermal growth factor receptor (EGFR) mutations have been reported as a predictive factor for favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. However, its confounding with sex and smoking makes it unclear whether the EGFR mutation is independently associated with prolonged patient survival. In this study, we analyzed a large-scale database to discriminate the survival impact of EGFR mutations against those of sex and smoking after gefitinib therapy. EGFR mutations in exon19 and exon21 named drug-sensitive EGFR mutations were examined to investigate the impact of EGFR mutation, sex, and smoking status on survival of 362 gefitinib-treated patients with lung adenocarcinoma. Drug-sensitive EGFR mutations were detected in 169 patients (46.7%). The multivariate analysis including EGFR, sex, and smoking status showed that drug-sensitive EGFR mutations were significantly related to longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P < 0.001). In addition, we investigated the impact of sex and smoking status according to EGFR mutation status, and the impact of EGFR mutation status according to sex and smoking status on survival. Sex and smoking status were not significantly associated with longer OS and PFS according to EGFR mutation status. Drug-sensitive EGFR mutations were significantly associated with longer OS and PFS according to sex or smoking status. Our results indicated that drug-sensitive EGFR mutations were the only independent factor for longer survival of patients treated with gefitinib, suggesting that patient selection based on EGFR mutation status for gefitinib therapy will lead to a better outcome for patients with lung adenocarcinoma.

9598 Background: Superiority of palonosetron to granisetron is uncertain, for patients with breast cancer receiving both steroid and NK1 inhibitor against CINV caused by AC regimen. Methods: We con...

11100 Background: The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by the age and genetic composition of patients. Paclitaxel is known to act as a substrate in SLCO1...

126 Background: Five-weekly schedule of S-1 plus CDDP (5-weekly SP) is the standard first-line chemotherapy for the patients (pts) with advanced gastric cancer (AGC) in Japan. Tmab with fluoropyrimidine plus CDDP chemotherapy has shown a survival benefit for pts with HER2-positive AGC and EGJ cancer. However, little information on the efficacy and safety of 5-weekly SP combined with Tmab is available. Methods: We conducted a prospective, single arm, multicenter, phase II trial of 5-weekly SP (S-1 40-60 mg bid for 21 days plus CDDP 60 mg/m2on day 8, every 5 weeks) combined with Tmab (8 mg/kg as a loading dose then 6 mg/kg, every 3 weeks) for pts with HER2-positive (IHC 3+ or IHC 2+ and FISH positive) AGC or EGJ cancer. Primary endpoint was response rate (RR) evaluated by independent review committee, using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. With power of 80% and one-sided alpha of 10%, thirty-five pts were required to reject 40% of RR under expected 60% RR. During the study, protocol was amended based on the favorable accrual rate. Pts were enrolled over 35 to improve precision, until pts enrollment up to 55 (power 85% and alpha 5%) or the end of predetermined accrual period, whichever came first. Results: Between August 2012 to January 2014, 44 pts were enrolled. Pts’ characteristics were: males 34 (77%), median age 62.6 years, PS 0-1 42 (95%), primary tumor site of stomach 37 (84%), histology of diffuse type 18 (41%). IHC 3+ was recorded in 32 (73%) pts. The RR was 64% (95% CI 48-78, one-sided p

HER2 is one of the most important therapeutic targets in breast cancer, and anti-HER2 agents such as trastuzumab, lapatinib, pertuzumab, and T-DM1 have significantly improved the prognosis of patients with HER2-positive breast cancer in both adjuvant and metastatic settings. However, there remain many clinical questions on how to use these agents: optimal sequence of them, clinical significance of “trastuzumab beyond progression”, role of “dual blockade” with two anti-HER2 agents (e.g. trastuzumab + lapatinib, trastuzumab + pertuzumab, and T-DM1 + pertuzumab), appropriate combination with endocrine therapy or chemotherapy, and individualized treatment based on biomarkers. Recently, many biomarkers have been investigated as candidate predictors of sensitivity or resistance to these agents: the expression pattern of HER2 or p95HER2, the expression of other receptors such as EGFR, HER3, and IGF-IR, the activation of the PI3K/Akt/mTOR pathway, the mutational status of PIK3CA, and the expression of HER family ligands. We are now conducting a randomized trial of trastuzumab + capecitabine and lapatinib + capecitabine in HER2-positive metastatic breast cancer patients previously treated with trastuzumab and taxanes (WJOG6110B), which accompanies large-scale comprehensive biomarker analyses including next-generation, high-throughput sequencing of formalin-fixed paraffin-embedded DNA and plasma cell-free DNA. The identification of predictive biomarkers will help us to select appropriate treatment for each patient and to develop strategy to overcome the drug resistance.

Background: Eribulin dose modification is recommended in breast cancer patients with liver dysfunction evaluated by Child-Pugh classification. However, the little information on initial dose modification for the patients with Child-Pugh A liver dysfunction is available. Methods: We retrospectively reviewed breast cancer patients with Child-Pugh A liver dysfunction who received eribulin at Toranomon Hospital between July 2011 and March 2013. Clinicopathological data and toxicity evaluated by Common Terminology Criteria for Adverse Events (version 4.0) was retrieved from medical records. Results: 20 patients were identified as Child-Pugh A liver dysfunction who received eribulin. Median age was 61.5 years (range 36-77), and median number of eribulin administration was 12 doses (1-34). 19 patients (95%) received 1.4mg/m2 of eribulin as initial dose, and the remaining one patient receive 1.1mg/m2. Neutrophil counts at baseline were normal in all patients. Neutrophil counts at day 8 were evaluated in 16 patients. Grade 3 and 4 neutropenia developed in 4 (25%) and 3 (18.8%) patients, respectively. Eribulin was discontinued due to toxicity in 5 patients (15%). Dose delay and reduction occurred in 8 (40%) and 8 patients (40%), respectively. Febrile neutropenia developed in 3 patients (15%) during the overall treatment period. Conclusion: Dose modification of eribulin may be required for breast cancer patients with Child-Pugh A liver dysfunction.

Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor against vascular endothelial growth factor receptors (VEGFR). Sunitinib showed dramatically improved clinical outcome in advanced renal cell carcinoma (RCC); however, it is difficult to manage the balance of toxicity and efficacy of sunitinib. The information on whether the initial response to sunitinib can maintain disease control after temporal cessation of sunitinib is limited. Methods: A retrospective study of patients with metastatic RCC who initiated sunitinib between December 2010 and January 2013 at Toranomon Hospital and NTT Medical Center Tokyo was conducted. Patients who maintained RECIST-defined stable disease or better for more than 3 months, and followed discontinuation all therapy due to toxicity were included. We retrospectively investigated progression-free survival (PFS) from discontinuation to progressive disease (PD), response to the following therapy, and toxicity during discontinuation, based on review of their medical records. Results: Nine patients were identified. Their median age was 69 years. One patient had prior systemic therapy history of temsirolimus; meanwhile, the remaining eight patients had no prior systemic therapy. Median follow up after cessation of sunitinib was 10.9 months. Six of nine had PD during cessation, and median PFS was 5.5 months (95% confidence interval 2.0 to 8.9). No patient had radiographic flare phenomenon (rapid and unexpected PD) after cessation. Sunitinib-induced toxicity resolved during treatment cessation. Four of the six patients who had had PD reinitiated sunitinib, and the remaining two patients switched to axitinib because of unacceptable toxicity of sunitinib. All of them had radiological response by recommencing VEGFR inhibitors. Conclusions: Temporal cessation of sunitinib might be feasible with maintaining disease control and resolving toxicity. Further prospective investigation on this treatment strategy is warranted.

In Japan, clinical trials aiming at application for approval of new drugs take a long time and a lot of money, and their quality thought to be poor. Japanese pharmaceutical companies tend to conduct more clinical studies in the United States and/or Europe than in Japan. The Ministry of Health, Labour and Welfare (MHLW) announced a three-year plan to facilitate clinical trials in Japan; the establishment of a large-scale clinical trial network, the improvement of the clinical research infrastructure, and the utilization of doctor-initiated clinical trials. The revised Pharmaceutical Affairs Law enables doctors and medical institutions to perform clinical trials using unapproved products spontaneously without any corporate sponsorship. Drugs needed by some patients but unapproved because they are unprofitable for companies are expected to be approved under this system. MHLW stipulated the ethical and scientific quality standard of doctor-initiated clinical trials, which is consistent with the principles of the Declaration of Helsinki, and Good Clinical Practice (GCP). To establish a system that allows expedited approval of safer and more effective products, the integration of the functions of the current review bodies, such as the Organization for Pharmaceutical Safety and Research (OPSR) and the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC), into an independent administrative agency is scheduled.

A high incidence of interstitial lung disease (ILD) has been reported in patients with non-small cell lung cancer (NSCLC) treated with gefitinib in Japan. We retrospectively analyzed 112 patients with advanced NSCLC who received gefitinib monotherapy. Univariate and multivariate analyses were used to identify risk factors for gefitinib-related ILD and predictive factors for tumor response to gefitinib. The incidence of ILD was 5.4%, and it was higher in the patients with pre-existing pulmonary fibrosis (33% versus 2%; P < 0.001). The results of a multivariate analysis showed that pulmonary fibrosis was a significant risk factor for ILD (odds ratio: 177, 95% confidence interval: 4.53-6927, P = 0.006). The response rate was 33% in the 98 evaluable patients and higher in women (53% versus 23%; P = 0.003), patients with adenocarcinoma (38% versus 6%; P = 0.010), never-smokers (63% versus 18%; P < 0.001), and the patients with no history of thoracic radiotherapy (39% versus 13%; P = 0.015). The results of a multivariate analysis showed that the predictors of tumor response were "no history of smoking" and "no history of thoracic radiotherapy". Never-smokers had a significantly longer survival time than smokers (P = 0.007). Although gefitinib therapy confers a clinical benefit on patients with advanced NSCLC, especially on women, patients with adenocarcinoma, never-smokers, and patients with no history of thoracic radiotherapy, it also poses a high risk of ILD, especially to patients with pulmonary fibrosis. The risk-benefit ratio must be carefully considered.

Aim: The potent RANK ligand inhibitor denosumab (Dmab) can cause hypocalcemia (hypoCa). Patients (pts) with inadequate intake of Ca and vitamin D are at increased risk for hypoCa. Additional baseline risk factors for hypoCa in pts with metastatic bone disease (MBD) were evaluated to aid clinical risk assessment for this adverse event. Methods: A post hoc analysis used data from three identically designed, randomized, blinded phase 3 trials comparing monthly dosing of 4 mg zoledronic acid (ZA) to 120 mg Dmab in pts with MBD to identify lab events of grade≥2 hypoCa (CTCAE: Results: The overall incidence of lab grade≥2 hypoCa events in those treated with Dmab was equal to or greater than in those treated with ZA and occurred in 12.4% of Dmab-treated pts. Baseline pt characteristics with the greatest incidence of hypoCa include: male gender (15.4%), prostate cancer (20.5%), small cell lung cancer (18.0%), and CrCl 30 – 2 bone mets and those with higher BSAP or uNTx levels (Table). Osseous lesion type did not significantly increase the risk of developing hypoCa (P ≥ 0.23). Baseline Factor Hazard Ratio 95% CI P-value > 2 bone mets 1.329 (1.044, 1.692) 0.021 BSAP>median (20.77 mg/L) 2.078 (1.579, 2.734) BSAP>median vs≤median > 2 bone mets 4.236 (2.117, 8.479) ≤ 2 bone mets 1.773 (1.312, 2.395) Interaction of baseline BSAP and # of bone mets 0.021 uNTX>50 nmol/mmol 1.316 (1.031, 1.680) 0.027 Interaction of baseline uNTX and # of bone mets 0.21 Conclusions: The risk of hypoCa after Dmab for MBD is associated with the # of bone mets and elevated bone turnover markers, especially high BSAP with>2 mets. BSAP may indicate the potential for deposition of Ca in undermineralized matrix. Pts with high bone turnover may be more susceptible to hypoCa when osteoclasts are rapidly inhibited, particularly when Ca and vitamin D intake is insufficient. Disclosure: J. Body: Consultant for and received research funding from Amgen; received honoraria from Amgen and Novartis; H.G. Bone: Consultant for and received honoraria from Amgen and Novartis; C. van Poznak: Received research funding from Amgen and Novartis; R.H. De Boer: Consultant for and received honoraria from Novartis; received research funding and other remuneration from Amgen and Novartis; A. Stopeck: Consultant for Amgen; honoraria from Amgen and GlaxoSmithKline; research funding from Amgen and Novartis; K. Fizazi: Consultant for Amgen and Novartis; honoraria from Amgen; D.H. Henry: Consultant for and received research funding and honoraria from Amgen, Ortho Biotech, and Watson; T. Ibrahim: Consultant for Amgen; A. Lipton: Honoraria and research funding from Amgen; F. Saad: Consultant for and received research funding and honoraria from Amgen and Novartis; N.D. Shore: Consultant for Amgen, Astellas, Bayer, Dendreon, Janssen, and Medivation; T. Takano: Consultant for and received honoraria from Daiichi-Sankyo; H. Wang: Employee of and owns stock or stock options in Amgen; O.L. Bracco: Employee of and owns stock or stock options in Amgen; A. Balakumaran: Employee of and owns stock or stock options in Amgen; P.J. Kostenuik: Employee of and owns stock or stock options in Amgen. All other authors have declared no conflicts of interest.

TPS4598 Background: Axitinib is a standard second-line treatment after sunitinib in patients (pts) with metastatic or advanced renal cell carcinoma (RCC). The previous results of pharmacokinetic (P...

1012 Background: Taxanes have been standard regimen as the first-line chemotherapy for metastatic breast cancer. However side effects such as neutropenia, peripheral neuropathy, edema or alopecia are important concerns. Phase II clinical trials of TS-1, an oral 5-fluorouracil derivatives (tegafur, 5-chloro-2,4-dihydropyrimidine, and potassium oxonate), have shown good clinical efficacy and tolerability. Therefore, we conducted a phase III open-label randomized controlled trial (SELECT BC) to verify the non-inferiority of TS-1 in overall survival (OS) to taxane as first-line chemotherapy for metastatic breast cancer. Methods: Six hundred eighteen patients receiving first-line chemotherapy for metastatic breast cancer were randomly assigned to either taxane group (n=309) or TS-1 group (n=309). In the taxane group, patients received docetaxel 60-75mg/m2 q3w, paclitaxel 80-100mg/m2 q1w or paclitaxel 175 mg/m2 q3w at the discretion of the treating physician. In the TS-1 group, patients received TS-1 40–60 mg t...

629 Background: Hepatitis C virus (HCV) infection is one of the most common blood-borne infection in the world, and with an estimated to be infected more than 880,000 people in Japan. Little is known about the changes of HCV status during chemotherapy and the influence of HCV infection on toxicity of chemotherapy. Methods: We reviewed all patients diagnosed with colorectal cancer in our institution between 2001 and 2012 who had been screened for HCV infection by testing for anti-HCV antibody and identified 77 HCV-infected patients. We retrospectively analyzed the change in HCV load and the toxicities of chemotherapy in these patients. Results: Twenty-four of the 77 HCV-infected patients with colorectal cancer had received chemotherapy.The median age was 66 years (range: 42-80 years). Four patients had liver cirrhosis at the initiation of chemotherapy. The remaining 20 patients were diagnosed with chronic hepatitis, and their liver function tests and complete blood cell counts at baseline were normal. First-line chemotherapy included 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (n = 6), S-1 and irinotecan (IRIS) (n = 1), tegafur-uracil (n = 14), capecitabine (n = 1), capecitabine and oxaliplatin (XELOX) (n = 2).Serum HCV-RNA levels both before and after chemotherapy were evaluated in 10 patients, and the median serum HCV-RNA level before and after chemotherapy was 4.0 and 3.05 logIU/ml, respectively. Transaminase levels were elevated during chemotherapy in 2 patients. There were no patients suffered from grade 3-4 neutropenia or febrile neutropenia. Conclusions: This study indicates that chemotherapy can be safely performed in HCV-infected patients with colorectal cancer without change in HCV load.

9628 Background: Patients (pts) with metastatic bone disease (MBD) are at risk of skeletal-related events (SREs). Potent antiresorptives reduce the risk of SREs, by inhibiting cancer-induced bone destruction, which also reduces release of skeletal calcium (Ca) into the bloodstream. Hypocalcemia (hypoCa) may occur if Ca and vit D intake is inadequate while taking antiresorptive agents. A combined analysis of 3 phase III trials in pts with MBD showed denosumab (DMAb) was superior to zoledronic acid (ZA) in preventing SREs. The overall safety profiles were similar; hypoCa was more common with DMAb (9.6%) than ZA (5.0%). Characteristics of hypoCa events in DMAb pts in these clinical trials and from post marketing adverse event (AE) reports are presented. Methods: Pts with solid tumors or multiple myeloma and MBD were randomized (1:1) to DMAb 120 mg SC or ZA 4 mg IV (adjusted for renal function) every 4 weeks (Q4W). Pts were advised to take daily Ca (≥ 500 mg) and vit D (≥ 400 IU); intake was collected by pt report. Albumin-corrected serum Ca was measured Q4W by central lab. HypoCa events were collected as decreases in serum Ca per central lab and investigator-reported AEs. Post marketing data from spontaneous reports of hypoCa to the sponsor's global safety department (AGS) were reviewed. Results: In the 3 trials, 2841 pts received DMAb and 2836 pts received ZA. The median Ca levels for both treatment groups were similar over time. Among DMAb pts, hypoCa was most common within 6 months of starting treatment and was more common in pts who did not report use of Ca and vit D vs those who did (15.8% vs 8.7%). Grade 3 or 4 (< 7 mg/dL; < 1.75 mmol/L) decreases in serum Ca were reported in 3.1% of DMAb pts and 1.3% of ZA pts. No fatal cases of hypoCa were reported in the trials. From May to Nov 2012, 37 cases of severe symptomatic hypoCa (seizures, tetany, prolonged QTc, altered mental state) were reported to AGS; fatal outcomes were reported for 3 other pts with advanced cancers and various comorbidities. Conclusions: HypoCa is a known risk with antiresorptive therapy, including DMAb 120 mg. HypoCa occurred less often in pts who reported taking Ca and vit D. HypoCa should be corrected prior to starting DMAb and Ca monitored during treatment. Pts should take adequate Ca and vit D while receiving DMAb. Clinical trial information: NCT00321464, NCT00321620, and NCT00330759.

LBA4024 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

613 Background: The global randomized trials with trastuzumab (H) shows increased cardiotoxicity in patients (pts) with HER2 positive early breast cancer (BC). Safety in Japanese has not been fully evaluated. We evaluated the safety, especially focused on cardiotoxicity, of H adjuvant (adj) therapy in an observational study in Japan (UMIN000002737). Methods: Pts with histopathologically confirmed HER2 positive invasive BC were registered. Women with stage I-IIIC disease who received H as neo-adj and/or adj therapy were eligible. Mean LVEF at 3, 6, 9 and 18 months (M) was evaluated. The time points represent examination on day 60-120, 150-210, 240-330 and 455-635, respectively. Results: A total of 2024 pts were registered from 56 institutes between July 2009 and June 2011. Data of 1875 pts were collected and finalized by September 2012, and 1800 of them were analyzed for safety. The median follow-up was 35 M. The mean age was 54.5 years. Elderly pts ≥60 years were 32.7%. Treatments after surgery were: concurrent chemotherapy (CT) and H in 20.1%, sequential CT and H in 43.5% and H monotherapy in 35.9%. Adverse events (AEs) associated with H were reported in 350 pts (19.4%) and grade (G) 3/4 AEs in 12 pts (0.7%). G 3/4 cardiotoxicity was reported in 7 pts (dysfunction, 4pts; angina, 1 pt; myocardial infarction, 1 pt and heart failure, 1 pt). The mean LVEF at the baseline was 69.4%. Mean LVEF at 3, 6, 9 and 18M were 66.9%, 66.3%, 65.3% and 66.3%, respectively. Compared to the baseline, LVEF decreased with significant difference at all time points (p

624 Background:Previously, five prognostic factors (ECOG PS 2, pathologically poorly differentiated adenocarcinoma, peritoneal metastasis, PFS of 1st-line therapy 400 IU/L) were identified in 124 patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy (Shitara K, et al. ASCO-GI 2009). Patients were categorized into three prognostic groups (low-risk = no factors, intermediate-risk = 1 factor, high-risk = 2 or more factors), with significant differences in median overall survival (23.5, 14.6, and 5.5 months, respectively). The purpose of this study was to validate this prognostic classification in an external validation cohort. Methods: We retrospectively analyzed 198 patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy in 3 institutions. This was our validation cohort. Results: The median overall survival of this validation cohort was not significantly different from that of the generating cohort (12.1 vs. 14.6 months; P=0.47). The distribution of the three prognostic groups in the validation cohort was as follows: low-risk (n=68; 35%), intermediate-risk (n=80; 41%), high-risk (n=45; 23%), with a higher proportion of intermediate-risk patients in comparison with the generating cohort. The median overall survival of each prognostic group in the validation cohort was 19.8, 11.0, and 7.9 months, respectively, with significant differences among groups (P Conclusions: Our results validated the previously defined prognostic classifications in patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy. This classification may be useful as a stratification factor in clinical trials or in considering treatment strategies for individual patients.

TPS659 Background: In patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab and taxanes, there are now two standard strategies: trastuzumab beyond progression or switch to lapatinib. A randomized trial comparing trastuzumab plus capecitabine (HX) and capecitabine alone (X) after first-line trastuzumab-based chemotherapy (GBG-26) showed that HX was superior to X in terms of time to progression (TTP). Another randomized trial comparing lapatinib plus capecitabine (LX) and X in patients previously treated with anthracyclines, taxanes, and trastuzumab (EGF100151) showed that LX was superior to X in terms of TTP. To evaluate which strategy is better, we are conducting an open-label, randomized phase II trial comparing HX and LX. Methods: Primary endpoint is progression-free survival, and secondary endpoints are overall response rate, overall survival, proportion of patients progressing brain metastases as site of first progression, and safety. Major eligibility criteria include: (1) HER2-positive MBC, (2) previously treated with taxanes, (3) disease progression or distant relapse while receiving trastuzumab, (4) previously untreated with capecitabine, S-1, and anti-HER2 drugs other than trastuzumab, (5) previously treated with no more than two chemotherapy regimens for MBC, (6) no symptomatic brain metastases (asymptomatic brain metastases are allowed), and (7) baseline left ventricular ejection fraction ≥50%. Patients in the HX arm receive capecitabine 2,500 mg/m2/day on days 1 to 14 plus trastuzumab (8 mg/kg loading dose and 6mg/kg thereafter) on day 1 every 3 weeks. Patients in the LX arm receive capecitabine 2,000 mg/m2/day on days 1 to 14 plus lapatinib 1250 mg/day on days 1 to 21 every 3weeks. Large-scale biomarker analyses are also performed to explore predictive factors of trastuzumab or lapatinib efficacy. We are investigating biomarkers related to HER family and other receptors, PI3K/Akt pathways, ligands, FcγR, circulating tumor cells, and so on. This study has just begun and 7 of planned 170 patients have been enrolled.

Background Denosumab was superior to zoledronic acid (ZA) in reducing the risk of a first on-study skeletal-related event (SRE; HR, 0.82; 95% confidence interval (CI) 0.71, 0.95; p = 0.01) in patients with breast cancer and bone metastases (BMs; Stopeck et al., 2010). All patients who remained on treatment after the primary analysis were offered open-label (OL) denosumab for a pre-specified 2-year extension phase. Methods Women with BMs secondary to breast cancer ( N = 2046) were randomly assigned to subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) Q4W. Patients who completed this double-blind, double-dummy treatment phase were offered OL denosumab Q4W. Patients who did not participate in the OL phase were followed up for survival every 12 weeks for up to 2 years after their last dose of investigational drug. Findings Of the 752 patients who completed the double-blind phase, 667 (89%) chose to receive OL denosumab: 325 initially randomly assigned to denosumab (DD) and 342 to ZA (ZD). Total median (Q1, Q3) cumulative denosumab exposure in DD patients was 19.3 months (9.2, 32.2) (range 0.9–59.8 months). Adverse events (AEs) were comparable between groups ( n = 283/318 [89%] for DD; n = 303/334 [91%] ZD) during the OL phase; 20 and 18 patients, respectively, reported osteonecrosis of the jaw; cumulative incidence was 4.7% in DD patients and 3.5% in ZD patients for the entire study duration of 5 years. Hypocalcaemia was comparable between groups ( n = 12 DD; n = 9 ZD). Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between the groups for the entire study: median 34.4 months (95% CI 31.5, 39.3) and 34.2 months (95% CI 31.0, 37.6), respectively. Interpretation This OL extension treatment phase confirmed the safety profile of denosumab in patients with breast cancer with BMs receiving up to 5 years of monthly denosumab therapy or switching to denosumab after up to 3 years of ZA. Funding Funding was provided by Amgen Inc. A.T. Stopeck is a consultant for Amgen and Novartis; A. Lipton is a member of the speakers’ bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; M. Martin is a consultant for Amgen; J-J. Body is a consultant for and has received lecture fees from both Amgen and Novartis; A. Paterson has received honoraria for speaking from Amgen, Roche, and Novartis; G.G. Steger has received travel grants and attended advisory boards for Amgen and Novartis; K. Tonkin has no disclosures; R.H. de Boer has no disclosures; Y. Fujiwara, Chugai Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma KK, Janssen Pharmaceutical KK, and Takeda Bio Development Center Limited; D. Yardley has no disclosures; J. Jassem has no disclosures; T. Takano is a medical consultant for Daiichi Sankyo; P. Solal-Celigny has no disclosures; and M. Fan and A. Braun are employed by Amgen and own stock.