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e16525 Background: Clear cell renal cell carcinoma (ccRCC) patients classically show good response to VEGFR inhibitors; however, the biological basis by which FGFR inhibition provides tumor response was not well understood. Here, we performed an exploratory analysis of the relationship between the FGF/FGFR pathway and intra-tumor immunity to support the effectiveness of FGFR inhibitors for ccRCC. Methods: We used whole transcriptome data and immunohistochemistry with metastatic clear cell RCC specimens from patients who were treated at the Yamagata University Hospital (n = 57). FFPE samples were prepared from the primary lesions of treatment-naive metastatic ccRCC patients. FFPE was sliced by a pathologist to evaluate the immunological microenvironment. RNA extraction and immunostaining were performed at the same site. Immuno-histological quantification was performed by automatically analysis system HALO in digital whole slide imaging. Hierarchical clustering was performed, and the cohort was divided based on the profile of the FGF and immune cells. We analyzed the cancer-specific survival based on the FGF cluster classification and investigated the relationship between FGF-FGFR expression and immune cell infiltration that were evaluated histologically. Results: RNA transcriptome data showed that FGF2 and FGF7 were widely expressed in ccRCC. Hierarchical cluster analysis based on the FGF expression profile (intrinsic FGFs were excluded) revealed that metastatic ccRCC had three distinct patterns. Cluster1 showed low FGFs expression, except for FGF2 and 7, while Cluster2 and 3 expressed multiple FGFs. Survival analysis showed Cluster2and 3 had a poor cancer-specific survival rate than Cluster1 (Logrank test, p = 0.05). However, no association was detected between the FGF cluster classification and the infiltration of immune cell count in immunohistological analysis. In comparison of the expression of each FGF subfamily and the positive cells of CD4, CD8, CD68 and CD31 (Mann–Whitney U test, p < 0.05), CD4 and CD8 were higher in the cases expressing FGF20. While most FGF subfamilies have been suggested to be less associated with immune cell infiltration (excluding FGF20), further analysis among FGF receptor expression and immune signatures are ongoing. Conclusions: Our study demonstrates the possibility of intra-tumor interaction between FGF/FGFR axis and immune infiltration in ccRCC.

304 Background: We aimed to compare overall survival (OS) between patients with metastatic renal cell carcinoma (mRCC) treated by cytoreductive nephrectomy (CN) and those not treated by CN. Methods: We retrospectively evaluated 278 patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019. Patients were divided into two groups, CN group (immediate or deferred CN) and systemic TKI therapies alone without CN (Ctrl group). The OS was compared in all patients between the Ctrl and CN groups, between the Ctrl and immediate CN groups, between the Ctrl and deferred CN groups, and between the deferred CN and immediate CN groups. Analyses were weighted using the propensity score–based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances. Results: The median age of the patients was 65 (range 59–73) years. Of the 278 patients, 132 and 146 were in the Ctrl and CN (immediate: 107 and deferred: 39) groups, respectively. A significant difference was noted between the Ctrl and CN groups in age, clinical stage, IMDC risk factors, and the number of metastatic sites. An IPTW-adjusted Cox regression analysis revealed a significant difference in OS between the Ctrl and CN groups and between the Ctrl and immediate or deferred CN groups. However, there was no significant difference in OS between immediate and deferred CN groups. Conclusions: The OS in CN group was significantly longer than that in Ctrl group even after the adjustment of potential selection biases.

677 Background: Guidelines for treatment of metastatic renal cell carcinoma (mRCC) recommend nivolumab monotherapy (NIVO) for treated mRCC, and nivolumab + ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor risk mRCC patients. Though molecular targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their impact is still unclear. Methods: Japanese mRCC patients treated with TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator assessed ORR of the first TT after NIVO, and after NIVO+IPI. Secondary endpoints included treatment-free survival (TFS) after discontinuation of NIVO and NIVO+IPI, and progression-free survival (PFS) and safety of the first subsequent TT after NIVO and NIVO+IPI. Results: Twenty-six patients of CheckMate 025 and 19 patients of CheckMate 214 from 20 centers in Japan were analyzed. Median TFS after ICI discontinuation was 1.0m and 2.5m for CheckMate 025 and CheckMate 214 patients, respectively. Median follow-up period from the start of TT after ICI discontinuation to date of analysis or death was 22.1m for CheckMate 025, and 20.3m for CheckMate 214 patients. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most treated therapy for both CheckMate 025 (53.8%) and CheckMate 214 (47.4%) patients. ORR of TT after NIVO and NIVO+IPI was 26.9% and 31.6%, and median PFS was 8.9m and 16.3m, respectively. During the treatment of first TT after NIVO and NIVO+IPI, 98% percent experienced treated-related adverse events, 51% experienced grade 3-4, but no treatment related death. Conclusions: TTs have favorable antitumor activity for mRCC after NIVO and NIVO+IPI, possibly by changing the mode of action. Safety signals of TTs after ICI were similar to the previous reports. These results indicate sequential TTs after ICI may contribute for durable survival benefit.

601 Background: Myeloid derived suppressor cells (MDSCs) are found to play essential roles in various tumors and to associate with the prognosis of patients. However, the prognostic values of MDSCs in metastatic renal cell cancer (mRCC) are still undefined. Glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) is known as a regulator of Mac-1 (CD11b/CD18) and closely related with differentiation of myeloid cells. The object of our study was to interrogate the association of MDSCs in peripheral blood with clinical outcomes of mRCC patients by using GPI-80. Methods: Peripheral blood samples, collected from 23 mRCC patients before treatment and 16 healthy volunteers, were stained with several myeloid cell antigens such as CD16, CD15, CD33, and GPI-80 to mark neutrophils and monocytes. We measured the expression levels (mean of florescence intensity, MFI) and deviation (coefficient variation, CV) of myeloid antigens by flow cytometry. To investigate the immunosuppressive function of GPI-80 positive cells, reactive oxygen species (ROS) and LAP-1 (precursor of TGF-β1) were measured. The impact of the cell surface antigens on overall survival (OS) was evaluated using the univariate and multivariate Cox regression analysis. Results: The MFI or CV of GPI-80 on neutrophilic or monocytic cells were significantly difference in between patients and healthy volunteers. LAP-1 expression and ROS production in monocytic cells were increased in patients than in healthy volunteers, and correlated with expression of GPI-80 MFI (p = 0.0107 and p = 0.0381, respectively). Regarding the prognostic values, both GPI-80 CV of neutrophilic cells and GPI-80 MFI of monocytic cells were associated with poor OS of mRCC patients (p < 0.01). Multivariate analysis showed that GPI-80 MFI of monocytic cells were independent unfavorable prognosis marker (HR 2.427, p = 0.044). Conclusions: These results showed that change of GPI-80 expression on myeloid cells in peripheral blood representing appearance of MDSCs was likely to be negative predictors in patients with mRCC.

469 Background: SWITCH, a prospective, randomized sequential trial to evaluate SU/SO versus SO/SU, revealed no difference in first-line or total PFS or OS, but no direct comparison was obtained between 1st line sunitinib (SU) and sorafenib (SO) for clear cell (CC) metastatic renal cell carcinoma (mRCC). Methods: Treatment-naïve patients with CC mRCC, ECOG PS 0/1 and MSKCC favorable or intermediate risk were randomized to receive open-label SU/SO or SO/SU at the standard dosage and schedule. The primary endpoint was 1st line PFS, and secondary endpoints were total PFS and OS. The calculated sample size was 59 per group, with α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 patients enrolled in this study from February 2010 to July 2012 from 39 institutions, 120 could be evaluated (SU/SO, 57 and SO/SU, 63). Baseline patients' characteristics in the SU/SO and SO/SU groups were as follows: favorable risk, 21% and 22%; and presence ofnephrectomy, 88% and 89%, respectively. First-line mPFS was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (HR, 0.67; 95% CI, 0.42–1.08; p= 0.095). There was no statistically significant difference in total (T)-PFS, 27.8 M, and 22.6 m (HR 0.73, CI 0.428-1.246; p=0.247), or OS 38.4 m and 30.9 m (HR 0.934, CI 0.588-1.485; p=0.773). Subgroup analyses showed that T-PFS was NR and 27.8 m (p=0.021) in the favorable risk, and 38.4 m and 16.1 m (p=0.009) in with less than 5 metastatic sites, 6.5 m and 13.6 m (p=0.025) without nephrectomy in the SU/SO and SO/SU groups, respectively. The most common adverse events (AEs) in case of first-line SU or SO (all grade, all cause) were hand–foot syndrome (71% vs. 86%), hypothyroidism (70% vs. 33%), fatigue (57% vs. 40%), hypertension (55% vs. 44%), and diarrhea (23% vs. 38%). AEs were generally lower during second-line therapy. Conclusions: There was no significant difference in first-line PFS, T-PFS, and OS between the two sequential treatments. Although fewer patients received second-line treatment in the SU/SO group, OS in this group was numerically longer than that in the SO/SU group. Clinical trial information: 01481870.

e15615 Background: The present study was conducted to clarify the prognosis of Japanese patients who failed prior VEGF-TKI therapy and to investigate prognostic factors in these patients. Methods: ...

502 Background: Sorafenib (SO), an earlier introduced kinase inhibitor, and sunitinib (SU), a standard first-line treatment drug for metastatic renal cell carcinoma (mRCC), were associated with progression-free survival (PFS) of 5.7 and 11 months (M) in independent clinical trials, respectively. We compared PFS of first-line SU and SO in a multicenter, randomized, open-label, phase III trial. Methods: Patients with untreated, measurable (by RECIST v1.1) clear-cell mRCC stratified according to MSKCC risk criteria, nephrectomy, and institution were randomized in 1:1 to receive SU (50 mg qd 4 wks on-2 wks off) or SO (400 mg bid). The calculated sample size was 59/group for α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 enrolled patients, from Feb. 2010 to Jul. 2012, from 39 institutions, 120 were evaluable (SU, 57 and SO, 63). Patient baseline characteristics in the SU vs SO groups were as follows: favorable risk, 21% vs 22%; presence of stable brain metastasis, 8.8% vs 1.6% and with nephrectomy, 88% vs 89%. Median PFS (mPFS) was 8.7 and 7.0 M in the SU and SO groups, respectively (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.42–1.08; p= 0.095). mPFS was 31.2 and 6.2 M (HR 0.27, 95%CI 0.08–0.90; p = 0.023) in the favorable risk group, 11.9 and 6.5 M (HR 0.31, 95%CI 0.14–0.69; p = 0.035) in patients with T1 or T2 primary tumors, and 11.6 and 7.0 M (HR 0.41, 95%CI 0.36–0.98; p = 0.038) in those without brain metastasis, in the SU and SO groups, respectively. Objective response rates for SU group was 35.3%; SO was 27.8% (p = 0.407). Overall survival was not reached. The most common adverse events (all grade, all cause) were hand-foot syndrome (SU vs SO, 71% vs 86%), hypothyroidism (70% vs 33%), fatigue (57% vs 40%), hypertension (55% vs 44%) and diarrhea (23% vs 38%). Conclusions: The primary endpoint was not achieved, but SU tended to be associated with longer mPFS in all cases. In patients with favorable risk, T1 or T2 primary tumors or in those without brain metastasis, significantly longer mPFS were noticed. Brain metastasis was associated with poorer prognosis even if it was stable at baseline. Clinical trial number: NCT01481870. Clinical trial information: 01481870.

532 Background: We investigated the prognosis of Japanese mRCC patients with favorable or intermediate MSKCC risk factors in the era of molecular targeted therapy Methods: Data on patients who started systemic therapies including cytokine and molecular targeted therapies at 18 hospitals between 2008 and 2010 was analyzed. Of these, 269 patients classified as favorable or intermediate prognosis according to MSKCC risk classification were the subject of this analysis. The endpoints of the present study were progression-free survival (PFS) and overall survival (OS). Relationships between PFS or OS and clinical variables were assessed using the Cox-proportional hazard model. Results: The median OS of all 268 patients was 38 month, and 3-year OS rate was 51% (95%CI 45-58). Regarding the first-line therapy, IFN-alfa (IFN), sunitinib (SU), sorafenib (SO), and others were administered in 89 (33%), 104 (39%), 40 (15%), and 35 (13%). There were more patients without nephrectomy and with multiple organ metastases in patients received SU or SO compared to patients received IFN. Median PFS (mPFS) and 1-year PFS rate in patients who received IFN, SU, and SO were 5 months and 38%, 12 months and 50%, and 11 months and 48% (p=0.556), respectively. Second-line therapy was performed in 69 patients of first IFN group (mPFS: 9 months), 67 of first SU group (mPFS: 7 months), and 24 of first SO group (mPFS: 3 months). Third-line therapy was performed in 47 patients of first IFN group (mPFS: 11months), 35 of first SU group (mPFS: 5 months) and 12 of first SO group (mPFS 3 months). Median OS in patients who received IFN, SU, and SO as first-line therapy were 45, 29 and 27 months (p=0.093), respectively. Multivariate analysis demonstrated that lower value of serum C-reactive protein and first IFN therapy were associated with more favorable OS (p

e15071 Background: Metastasectomy considered to prolong survival in patients with metastatic renal cell carcinoma (mRCC). However, data on the indications for metastasectomy are limited. We aimed to examine the prognosis and the prognostic factors of mRCC patients who underwent metastasectomy. Methods: We sent questionnaires to Japanese hospitals and collected the data of patients who were diagnosed with mRCC between January 1988 and December 2009 and who had their metastatic lesions removed. We calculated the overall survival between metastasectomy and death or until the last follow-up. We also analyzed the relationship between survival and clinical features and identified adverse prognostic factors by multivariate analysis. Furthermore, we identified the group with a poor prognosis on the basis of the number of prognostic factors for which the patients were positive. These findings were internally validated using bootstrap procedures and the c-index. Results: We collected the data of 559 patients from 48 institutions. The median overall survival period was 80 months (95% CI, 69.7-90.6 months). We detected 5 adverse prognostic factors: incomplete resection by metastasectomy (hazard ratio, 1.75; p = 0.0169); brain metastasis (hazard ratio, 3.26; p = 0.0002); C-reactive protein levels of >1.0 mg/dl (hazard ratio, 2.84; p < 0.0001); Eastern Cooperative Oncology Group performance status of >1 (hazard ratio, 1.65; p = 0.0274); and the worst nuclear grade, i.e., the nuclei of tumor cells are larger than those of normal tubular cells (hazard ratio, 1.59; p = 0.0348). Patients positive for 3 or more of theseadverse prognostic factors had a worse prognosis (median overall survival, 24 months) than those positive for less than 3 factors (median overall survival, 105 months). The c-index for this model was 0.65 at 2 years. Conclusions: We identified 5 adverse prognostic factors for predicting the survival of patients who underwent metastasectomy.

TPS233 Background: Hand-foot skin reaction (HFSR) is the most clinically significant dermatologic toxicity in patients (pts) with metastatic renal cell carcinoma (mRCC) who receive sorafenib. HFSR ...

4590 Background: We previously reported that the single nucleotide polymorphisms (SNPs) in signal transducer and activator 3 (STAT3) gene were most significantly associated with better response to ...

e15051 Background: Although MSKCC risk classification is standard prognostic criteria for Caucacian patients (pts) with metastatic renal cell carcinoma (mRCC), it is questionable whether this class...

154 Background: Degarelix, a GnRH receptor antagonist inducing rapid, profound and sustained suppression of serum testosterone levels, without testosterone surge, was evaluated in a phase II dose finding study in Japan. Methods: A total of 278 patients with adenocarcinoma of the prostate were randomized and 273 patients (any stage; median age, approx. 76 years; median testosterone, 4.46 ng/mL; median prostate-specific antigen (PSA) level, 22.8 ng/mL) received study treatment. Degarelix was administered subcutaneously at an initial dose of 240 mg followed by monthly maintenance doses of either 80 mg or 160 mg. The treatment continued for 12 months in the study. Results: The primary endpoint was the proportion of patients with testosterone suppression to castrate level of ≤0.5 ng/mL during 12 months treatment. Both dose regimens of 80 mg and 160 mg kept 94.5% and 95.2% of patients on castrate level respectively throughout the treatment period. At 3 days of treatment, approximately 99% of the patients reached the castrate level without testosterone surge. The percentage change in serum PSA reduction exceeded 76% at 4 weeks. The overall tumor response rates (proportion of patients with complete and partial responses) were from 77.4% to 90.8% across the groups. Eighteen patients (6.6%) withdrew from the study due to adverse events. The most common adverse events were injection site reactions; other adverse events included pyrexia, weight increased, hypertension and hot flush. Degarelix appeared well tolerated. Conclusions: With an initial dose of 240 mg followed by monthly maintenance doses of 80 mg or 160 mg, Degarelix resulted in a rapid profound and sustained testosterone suppression to castrate level and PSA reduction without testosterone surge for 12 months. Degarelix was well tolerated. The maintenance doses of 80 mg and 160 mg had similar efficacy and safety profiles. The study shows results similar to those from the degarelix pivotal phase III study (CS21). Assessment of risk-benefit would support the recommendation of the maintenance dose of 80 mg as a safe and effective monthly dose for the treatment of prostate cancer. [Table: see text]

4617 Background: Sorafenib is a multikinase inhibitor which has been approved as the first-line treatment of advanced and/or metastaticrenal cell carcinoma (RCC). Sorafenib suppresses tumor growth ...

5100 Background: S-1 is a novel oral anticancer agent, contains tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT: CDHP: Oxo = 1:0.4:1. The purpose of this study was to evaluate the efficacy and safety of S-1 in cytokine-refractory metastatic renal cell carcinoma (mRCC), and to examine the relation between response and mRNA expression levels of 5-FU-related enzymes. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary type of RCC, measurable lesions, treatment histories with cytokines, an ECOG performance status of 0 or 1 (2 was allowed in patients with bone metastasis), an age of at least 20 years, prior nephrectomy, and adequate organ functions. Any prior treatment for mRCC was discontinued more than 4 weeks before registration. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR) as confirmed by an independent reviewer. The planned sample size was 44 patients. The threshold response rate was defined as 5%, and the expected rate was set at 17.5%. If the lower limit of the 95% CI exceeded the threshold rate (6 of the 44), S-1 was evaluated to be effective. Formalin fixed paraffin embedded specimens, which had been obtained by radical nephrectomy, were used for mRNA expression assay, performed by RT-PCR method. Results: Between April 2006 and May 2007, 45 patients were enrolled, and 31 assay samples were obtained. ORR was 24.4% (11/45, 95% CI: 12.9 - 39.5%). The median PFS was 9.2 months. The median OS could not be calculated, but the survival rate at 1 year was 87.5%. The most common grade 3–4 adverse events assessed according to the CTCAE v.3.0 included anemia (6.7%), neutropenia (8.9%), anorexia (8.9%), hyperglycemia (6.7%), stomatitis (4.4%), diarrhea (4.4%), and fatigue (4.4%). On mRNA expression analysis, the expression level of 5-FU-related enzyme correlated with ORR and PFS. Conclusions: S-1 is effective and well tolerated in patients with cytokine-refractory mRCC. Measurement of the mRNA level of 5-FU-related enzyme in tumors before treatment may facilitate prediction of the response to S-1. No significant financial relationships to disclose.

16108 Background: Sunitinib malate (SU) is an oral multitargeted receptor tyrosine kinase inhibitor that is approved multinationally for the treatment of advanced RCC. A multicenter phase II trial ...

3079 Background: A personalized selection of the right peptides for each patient could be a novel approach of cancer vaccine for boosting anti-cancer immunity in the majority of patients. Our appro...

16039 Background: Sorafenib has been approved for advanced renal cell carcinoma (RCC) worldwide, based on proven efficacy and tolerability in Phase III randomized control trial. Though sorafenib in...

5154 Background: Although the efficacy of CAB in advanced prostate cancer (PC) has been demonstrated by the PCTCG and others, more evidence is required in locally advanced (Stage C) PC. The results of a Japanese P III study of bicalutamide in Stage C/D PC suggested the efficacy of CAB was better than monotherapy. When time to progression (TTP) was evaluated in Stage C and D separately, CAB had significant benefits in both stages and results in stage D were consistent with PCTCG data. Thus, this exploratory analysis was conducted to evaluate more thoroughly the efficacy of CAB in Stage C. Methods: 205 untreated PC patients with Stage C/D were randomized to CAB (goserelin 3.6 mg/4 weeks or leuprorelin 3.75 mg/4 weeks + bicalutamide 80 mg/day) or LHRHa monotherapy (same LHRHa + placebo). Among these patients, 99 had Stage C (52/47 on CAB/monotherapy). The median of the following parameters were calculated, and log-rank tests performed: TTP in all Stage C patients; TTP in Stage C patients by age, PSA value at diagnosis, and histopathological class; time to PSA normalization when normal level was defined as =4, =1 and =0.2 ng/mL. Results: The median observation period in Stage C patients was 144 weeks. The median TTPs by each parameter in Stage C are shown below. The median times to PSA normalization on CAB and monotherapy were 7 and 16 weeks (p [Table: see text] No significant financial relationships to disclose.

14650 Background: S-1 is an oral fluoropyrimidine antitumor drug that combines three pharmacological agents: tegafur, a prodrug of 5-fluorouracil;gimeracil, an inhibitor of dihydropyrimidine dehydrogenase; and potassium oxonate, which reduces gastrointestinal toxicity. We evaluated the efficacy and safety of S-1 in patients with hormone-refractory prostate cancer. Methods: To be eligible patients (pts) had to have given informed consent, an age of 2 b.i.d. for 28 consecutive days followed by a 14-day rest period. This 42-day cycle was repeated until confirmation of disease progression. Results: 32 pts were enrolled at 15 institutions. Their median age was 73 years (55 to 79). The median number of courses administered was 2.5 (1 to 11). On the basis of the change in the PSA level, 3 pts had a complete response (CR, No significant financial relationships to disclose.

4648 Background: Combination therapy with non-steroidal antiandrogens, but not steroidal antiandrogens, is associated with a survival advantage over castration alone in advanced prostate cancer (La...

4703 Background: Bicalutamide (‘Casodex’) 80 mg (licensed dose in Japan) is being evaluated as part of combination therapy in patients (pts) with previously untreated advanced prostate cancer in an...