Treatment Of mRCC Patients Research Articles

Safety and toxicity of cabozantinib monotherapy in patients with advanced renal cell carcinoma: a Russian multicenter observational study

Aim. To assess the safety and to analyze an influence of cabozantinib monotherapy toxicity on treatment efficacy in unselected Russian patients with metastatic renal cell carcinoma (mRCC).
 Materials and methods. Medical data of 92 patients with verified mRCC were included in the study. The median age of the patients was 56 (1979) years, most of them - 60 (65.2%) were of male gender. Twenty five (27.2%) persons had Eastern Cooperative Oncology Group performance status (ECOG PS). At the time of cabozantinib monotherapy start 5 (5.4%) patients had favorable, 54 (58.7%) intermediate, and 33 (35.9%) unfavorable prognosis by International Metastatic Renal Cancer Database Consortium (IMDC) model. Eighty-three (90.2%) patients were pretreated, including 76 (82.6%) patients who previously received anti-angiogenic agents. All patients were administered with cabozantinib monotherapy (60 mg/day); dose adjustment was performed according to the instruction.
 Results. Adverse events (AEs) were reported in 81 (88.0%) of 92 patients; 30 (32.6%) AEs were grade 34. Toxicity-related dose reduction of cabozantinib was required in 28 (30.4%), treatment interruption in 15 (16.3%), and discontinuation in 2 (2.2%) patients. The most common AEs were hypertension (69 patients, 75.0%), asthenia (47 patients, 51.1%), diarrhea (43 patients, 46.7%), and palmar-plantar erythrodysesthesia (43 patients, 46.7%). The most common severe AEs were: arterial hypertension (17 patients, 18.5%), diarrhea (6 patients, 6.5%), and palmar-plantar erythrodysesthesia (2 patients, 2.2%). The most frequent laboratory abnormalities during therapy were elevated serum transaminases (33 patients, 35.9%), anemia (13 patients, 14.1%), and thrombocytopenia (10 patients, 10.9%). No previously unreported AEs or laboratory abnormalities were observed. There was a significant increase in progression-free survival (hazard ratio 2.5; 95% confidence interval 1.05.9; p=0.046) and overall survival (hazard ratio 3.0; 95% confidence interval 1.28.3; p0.025) in patients with treatment-related arterial hypertension.
 Conclusion. The observational study confirmed the acceptable safety profile of cabozantinib in the first and subsequent lines of treatment in mRCC patients. No new safety signals were identified. Treatment-related arterial hypertension may be a favorable predictor of survival.

Global circulating free DNA methylation and fragmentome deconvolution in patients with metastatic renal cell carcinoma treated with immunotherapy (GOLDEN).

4544 Background: Metastatic renal cell carcinoma (mRCC) lacks molecular biomarkers. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) is a new, non-invasive approach to the detection of RCC-derived DNA in the circulation. In the GOLDEN study (NCT03702309), we explored the role of cfMeDIP-seq and fragmentomic dynamics as a biomarker, during immune checkpoint inhibition (ICI)-based treatment in mRCC patients (pts). Methods: Blood samples from mRCC pts were collected before and during treatment. Response to treatment was defined by the treating oncologist as: response, any degree of radiological tumor regression; stable disease (SD), no radiological change; or progressive disease (PD), radiological/clinical progression. More than 10ng of plasma cfDNA was subject to cfMeDIP-seq. A prognostic pan-cancer methylation signature previously generated using TCGA tissue methylation arrays was applied to cfMeDIP-seq output and cancer-signal methylation (CSM) score was calculated. An RCC-specific methylation signature, previously generated by identifying differentially methylated regions between RCC pts and controls, was applied ( Nuzzo et al, Nat Med 2020). Genome-wide fragmentation profiles were generated using DELFI. Using medians as cut off, log-rank test was performed to assess overall survival (OS) and progression-free survival (PFS). Results: Thirty-five patients were enrolled and n=33 received systemic treatment. 31/35 pts (89%) had clear cell and 4/35 (11%) non-clear cell histology. Median age was 61 (30-81) years and the M:F ratio was 6:1. Patients’ IMDC prognostic risk score was favorable n=6/35 (17%), intermediate n=23/35 (65%) and poor n=6/35 (17%). 20/33 (61%) patients received ipilimumab/nivolumab, 10/33 (30%) nivolumab and n=3/33 (9%) pembrolizumab/axitinib. There were n=14/33 (42%) responders, n=4/33 (12%) pts with SD and 15/33 (45%) pts with PD. Patients with high pan-cancer CSM score at baseline trended towards worse OS (HR 3.86, p = 0.079). Fragmentomics signature, consisting of increased proportion of short cfDNA fragments, showed a trend for worse PFS (HR = 3.04, p = 0.075) in on-treatment samples. Using the RCC-specific methylation signature, we found that those with an increase in signature score from baseline to on-treatment had better PFS (HR=2.4x10-10, p=0.002, n=10) and a trend towards better OS (HR=0.17, p=0.074, n=10). We hypothesize that RCC tissue-specific cell death early during ICI treatment could underpin this increase in the methylation score. Conclusions: This small study is the first report on the role of cfMeDIPseq-derived methylation and fragmentomic signatures in patients with mRCC undergoing ICI-based treatment. We found several trends and one significant association between these signatures and pt outcomes, which support further validation in larger cohorts. Clinical trial information: NCT03702309 .

MP39-01 SYSTEM ASC TRANSPORTER 2, A KEY ENZYME FOR GLUTAMINE PATHWAY, IS A POSSIBLE BIOMARKER FOR METASTATIC PROGRESSION AND SURVIVAL IN RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP39)1 Sep 2021MP39-01 SYSTEM ASC TRANSPORTER 2, A KEY ENZYME FOR GLUTAMINE PATHWAY, IS A POSSIBLE BIOMARKER FOR METASTATIC PROGRESSION AND SURVIVAL IN RENAL CELL CARCINOMA Yoshinari Muto, Makoto Sumitomo, Kenji Zennami, Masashi Takenaka, Takuhisa Nukaya, Kosuke Fukaya, Manabu Ichino, Kiyoshi Takahara, Hitomi Sasaki, and Ryoichi Shiroki Yoshinari MutoYoshinari Muto More articles by this author , Makoto SumitomoMakoto Sumitomo More articles by this author , Kenji ZennamiKenji Zennami More articles by this author , Masashi TakenakaMasashi Takenaka More articles by this author , Takuhisa NukayaTakuhisa Nukaya More articles by this author , Kosuke FukayaKosuke Fukaya More articles by this author , Manabu IchinoManabu Ichino More articles by this author , Kiyoshi TakaharaKiyoshi Takahara More articles by this author , Hitomi SasakiHitomi Sasaki More articles by this author , and Ryoichi ShirokiRyoichi Shiroki More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002054.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The glutamine (Gln) pathway has been implicated in tumor progression in various malignancies including renal cell carcinoma (RCC). However, the detail underlying this pathway remains to be elucidated. Since both glutaminase 1 (GLS1) and system ASC transporter 2 (ASCT2) were reported to play a crucial role in this pathway, we investigated whether these enzymes could be associated with cancer development and survival in RCC. METHODS: Tumor (T) and non-tumor (N) tissues were sampled from 66 RCC patients. Metabolome analyses were performed by liquid chromatography mass spectrometry (LC/MS) and important metabolites including Gln and glutamate (Glu) were analyzed. The protein expression of GLS1 and ASCT2 was evaluated by immunohistochemistry (IHC) using formalin-fixed, paraffin-embedded sections of surgical specimen from 80 metastatic RCC (mRCC) patients who received standard treatment using tyrosine-kinase inhibitors (TKIs) with or without immune checkpoint inhibitors (ICIs). The mRCC patients who received treatment with ICIs in the first- or second-line treatment were categorized into the “ICI group”, whereas others were categorized into the “TKI-only group”. In this study, the endpoint was progression-free survival 2 (PFS2) defined as the interval between first-line treatment and the second relapse. RESULTS: LC/MS analyses showed that both Gln T/N ratio and Glu T/N ratio in mRCC patients were significantly increased compared with those in non-mRCC patients (p=0.002 and p=0.048, respectively). On the other hand, the median value of Gln T/N ratios was shown to be over 100-fold higher than that of Glu T/N ratios. IHC analyses using mRCC tumor tissues revealed that ASCT2 was expressed more strongly in tumor cells than in normal cells, while GLS1 was expressed both in normal and tumor cells at the equal level. Kaplan–Meier analysis showed that ICI group had better PFS2 than TKI-only group in patients with ASCT2 high expression levels (p=0.009), while there was no significant difference on PFS2 between two groups in patients with ASCT2 low expression levels. CONCLUSIONS: Our results suggest that ASCT2 rather than GLS1 may be a key enzyme for Gln pathway in RCC. Our results also suggest that ASCT2 is associated with metastatic progression and survival, confirming its role as a possible biomarker to determine the appropriate treatment for mRCC patients. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e704-e704 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshinari Muto More articles by this author Makoto Sumitomo More articles by this author Kenji Zennami More articles by this author Masashi Takenaka More articles by this author Takuhisa Nukaya More articles by this author Kosuke Fukaya More articles by this author Manabu Ichino More articles by this author Kiyoshi Takahara More articles by this author Hitomi Sasaki More articles by this author Ryoichi Shiroki More articles by this author Expand All Advertisement Loading ...

Determinants of treatment for first-line immune-based combinations in metastatic renal cell carcinoma: a critical overview of recent evidence.

The last three decades have witnessed a revolution in the therapeutic scenario of metastatic renal cell carcinoma (mRCC), due to the advent of novel agents including tyrosine kinase inhibitors, immune checkpoint inhibitorsand the combination of both treatments. These strategies have reported unprecedented response rates, thus improving the clinical outcomes of mRCC patients, and current international guidelines support the use of immune-based combinations as first-line treatment in patients with metastatic disease. However, more data are awaited to help clinicians in the decision-making process. Herein, we provide an overview of recently published results regarding immune-based combinations as first-line treatment in mRCC patients, critically discussing available data that could help in suggesting determinants of treatment in this setting.

The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma.

Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC. This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method. We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups. In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC. Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.

18F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing tyrosine kinase or checkpoint inhibitor therapy: preliminary results

IntroductionTyrosine kinase (TKI) and checkpoint inhibitors (CI) prolonged overall survival in metastatic renal cell carcinoma (mRCC). Early prediction of treatment response is highly desirable for the individualization of patient management and improvement of therapeutic outcome; however, serum biochemistry is unable to predict therapeutic efficacy. Therefore, we compared 18F-PSMA-1007 PET imaging for response assessment in mRCC patients undergoing TKI or CI therapy compared to CT-based response assessment as the current imaging reference standard.Methods18F-PSMA-1007 PET/CT was performed in mRCC patients prior to initiation of systemic treatment and 8 weeks after therapy initiation. Treatment response was evaluated separately on 18F-PSMA-PET and CT. Changes on PSMA-PET (SUVmean) were assessed on a per patient basis using a modified PERCIST scoring system. Complete response (CRPET) was defined as absence of any uptake in all target lesions on posttreatment PET. Partial response (PRPET) was defined as decrease in summed SUVmean of > 30%. The appearance of new, PET-positive lesions or an increase in summed SUVmean of > 30% was defined as progressive disease (PDPET). A change in summed SUVmean of ± 30% defined stable disease (SDPET). RECIST 1.1 criteria were used for response assessment on CT. Results of radiographic response assessment on PSMA-PET and CT were compared.ResultsOverall, 11 mRCC patients undergoing systemic treatment were included. At baseline PSMA-PET1, all mRCC patients showed at least one PSMA-avid lesion. On follow-up PET2, 3 patients showed CRPET, 3 PRPET, 4 SDPET, and 1 PDPET. According to RECIST 1.1, 1 patient showed PRCT, 9 SDCT, and 1 PDCT. Overall, concordant classifications were found in only 2 cases (2 SDCT + PET). Patients with CRPET on PET were classified as 3 SDCT on CT using RECIST 1.1. By contrast, the patient classified as PRCT on CT showed PSMA uptake without major changes during therapy (SDPET). However, among 9 patients with SDCT on CT, 3 were classified as CRPET, 3 as PRPET, 1 as PDPET, and only 2 as SDPET on PSMA-PET.ConclusionOn PSMA-PET, heterogeneous courses were observed during systemic treatment in mRCC patients with highly diverging results compared to RECIST 1.1. In the light of missing biomarkers for early response assessment, PSMA-PET might allow more precise response assessment to systemic treatment, especially in patients classified as SD on CT.

Tyrosine kinase inhibitors in the treatment of metastatic renal cell cancer patients with early cytokine intolerance: TURCOS, a Turkish national, prospective observational study

Cytokines have been the mainstay of treatment in metastatic renal cell cancer (mRCC) for decades before the introduction of tyrosine kinase inhibitors (TKIs), which dramatically changed the therapeutic landscape in these patients. This observational study was designed to evaluate use of TKIs in the treatment of cytokine-intolerant mRCC patients. A total of 151 cytokine-intolerant mRCC patients who were treated with TKIs (sunitinib, pazopanib and sorafenib) were enrolled in this prospective, non-interventional, multi-center observational study at 16 oncology centers across Turkey. Mean (SD) age was 61.3 (11.1) years and 74.8% were males. Data on duration of TKI treatment was the primary outcome measure. Additionally, overall response rate (ORR), progression free survival (PFS), overall survival (OS) and safety data were recorded. Median duration of treatment was 8.2 months at a median follow up of 17.9 months. ORR and disease control rate were 12.5% and 70.8%, respectively. Median PFS and OS were 7.5 months (95%CI: 6.4-10.4) and 27.3 months (95%CI: 17.6-27.3) with no significant difference among three TKI agents in terms of treatment duration, ORR, PFS and OS. The most common adverse events excluding progression-which was the protocol requirement were diarrhea (13.6%), asthenia (13.6%) and hand-foot syndrome (12.6%). Dose modifications were required in 30.5% of the patients and 15% discontinued TKIs because of toxicity. Our findings confirm the efficacy and safety profile of TKIs in the first-line treatment of mRCC patients intolerant to cytokine treatment. There was no significant difference among three TKI agents in terms of treatment duration, ORR, PFS and OS.Trial registration: TURCOS ClinicalTrials.gov Identifier: NCT01585974. Registered April 25, 2012.

Predictors of first line systemic therapy for metastatic renal cell carcinoma in IMDC favorable risk patients.

e17086 Background: With the induction of molecular targeted agents, which interfere with proteins that play critical roles in tumor growth and progression, and immune checkpoint inhibitors (ICI), the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) have dramatically been changed with improved survival. Prognostic risk assessment is essential for choosing the most appropriate first line treatment option, with selection based on International Metastatic RCC Database Consortium (IMDC) Risk Category. This study was designed to evaluate the actual efficacy of systemic therapy in the IMDC favorable risk group patients with mRCC. Methods: A total of 218 patients with mRCC who received systemic therapy were retrospectively reviewed (Institutional review board approval No 2013-0425). Among them, 55 (25%) patients were classified as favorable risk group based on the IMDC Risk Category. These mRCC patients in the favorable risk were divided into 2 groups by following factors; gender (male or female), age (≥70, or not), baseline serum CRP levels (≥0.6, and < 0.6 mg/dl), metastatic sites (exclusive lung, or lung and others), BMI (≥22, or < 22), respectively. The overall survival (OS) of patients in the favorable risk group were compared between the two cohorts. Results: The median PFS for first line treatment and OS of patients in favorable risk group were 31.6 (95% CI 19.9–33.7)) and 85.8 (56.8-NE) months, respectively. The median OS in patients with BMI≥22 and < 22 was 65.6 (95% CI 56.8–NE) and 56.8 (95% CI 30.8–NE) months, respectively (p = 0.0497). The median OS in patients with exclusive lung metastasis, and lung and other metastases were 115.1 (95% CI NE) and 65.6 (95% CI 43.9–NE) months, respectively (p = 0.0073). No significant difference was found in OS between male and female, age≥70 and < 70, and baseline serum CRP levels ≥0.6 mg/dl and < 0.6, respectively. Conclusions: The first line systemic treatment for mRCC patients in IMDC favorable risk group was feasible and effective in patients with BMI≥22 or exclusive lung metastasis.

Occurrence of tyrosine kinase inhibitors-induced renal impairment and its predictive value for the prognosis of patients with metastatic renal cell carcinoma.

693 Background: To investigate the tyrosine kinase inhibitors (TKIs) related renal impairment (RI) on the therapy efficacy and survival of patients with metastatic renal cell carcinoma (mRCC). Methods: Clinical and pathological parameters of patients with mRCC treated with TKIs were retrospectively reviewed. Blood urea nitrogen (BUN), proteinuria(PU) and estimated glomerular filtration rate (eGFR) were defined as main renal function related parameters, and their levels at the time of pre- and post- TKIs treatment were recorded and analyzed. Abnormal BUN, PU and/or eGFR were defined as RI. Primary and secondary treatment outcomes were progression-free survival (PFS) and overall survival (OS), and tumor response was defined as secondary treatment outcome. SPSS 24.0 and GraphPad Prism 7.0a were used for statistical analyses. Results: A total of 110 patients were included in this study. At baseline, patients with abnormal BUN, abnormal eGFR and PU were 25 (22.7%), 27 (25.5%) and 30 (27.3%), respectively, which increased to 46 (41.8%), 55 (50.0%) and 64(58.2%) after TKI treatment. Survival analysis showed that baseline RI had no impact either on prognosis, or the effectiveness of TKIs. On the contrary, for post-treatment RI, PU level, elevated PU, and eGFR level were independently related to PFS and OS. Besides, eGFR decrease >10% was indicated for longer OS time (19.0 vs 41.0 months, p=0.034). Sub-analysis suggested that, among 51 patients without RI pre-TKI therapy, eGFR level (P=0.004), eGFR decrease > 10% (P=0.012), PU level (P=0.014) as well as elevated PU level (P=0.006) were statistically correlated with OS time. However, the similar trend was not identified in those with baseline RI. Furthermore, baseline eGFR level (P=0.020) and eGFR decrease > 10% (P=0.016) within 1y after TKI therapy were identified to be effective biomarkers predicting OS. Conclusions: The occurrence of TKI-induced RI was indicated for better tumor response and survival outcomes, and provide valuable information for the individual treatment of mRCC patients. Thus, routinely monitoring of renal function, especially eGFR and PU, was highly recommended in TKIs-treated mRCC patients.

Efficacy of incomplete metastasectomy in combination with targeted therapy in metastatic kidney cancer patients

Objective. To increase the effectiveness of drug treatment via systemic therapy (ST) in combination with incomplete cytoreductive interventions – incomplete metastasectomy (iME).Materials and methods. Three centers took part in the study. All 147 patients with mRCC received anticancer drug therapy. Part of them (n = 47) underwent surgery (iME) before or together with anticancer treatment, where iME meant complete metastasis excision within one organ with residual tissue in other organs (research group). Control group (n = 100) included patients who received only systemic antitumor treatment. Primary control point was overall survival (OS), secondary – time to progression.Results. Median OS in combined treatment group was 32 months, while in control group – 29 months (p = 0.21). When analyzing surgical stage in combined treatment, OS was statistically more significant in patients with iME before ST (n = 20) than in patients with two parallel treatment schemes: 46 and 31 months, respectively (p = 0.007). When analyzing metastases localization, it was found that iME is effective for metastases to distant lymph nodes and adrenal gland. Adrenalectomy (p = 0.03) and lymphadenectomy (p = 0.04) showed higher results than ST: 17 and 15 months versus 6 month, respectively. IME in patients with poor prognosis did not reveal any advantages: median OS reached 7 months, which was significantly inferior to the favorable prognosis group, where median OS was 25 months (p = 0.03).Conclusion. IME can be used as a part of combined treatment in mRCC patients. It should be considered as the first treatment stage with subsequent ST.

Pazopanib as Second-line Antiangiogenic Treatment in Metastatic Renal Cell Carcinoma After Tyrosine Kinase Inhibitor (TKI) Failure: A Phase 2 Trial Exploring Immune-related Biomarkers for Testing in the Post-immunotherapy/TKI Era

Pazopanib is an oral angiogenesis tyrosine kinase inhibitor (TKI) recommended in metastatic renal cell carcinoma (mRCC) for treatment-naïve patients or those experiencing cytokine failure. We conducted a phase 2, open-label, single-arm study in ten Spanish centres among mRCC patients whose disease progressed on first-line TKI. Patients received pazopanib until disease progression, death, or unacceptable toxicity. Twenty-seven patients were included (median age 62yr, 51.9% male). The objective overall response rate was 14.8% (95% confidence interval [CI] 1.4–28.2%). Median progression-free survival was 6.7mo (95% CI 3.7–11.2) and median overall survival was 20.6mo (95% CI 12.6–27.4). Lower circulating levels of IL-10 (p=0.002) were observed in responding patients at 8 wk after treatment. The median pazopanib treatment duration was 6.0mo (range 1.0–47.0). Most patients (48.1%) had mild or moderate adverse events (AEs), while 44.4% had severe AEs. Pazopanib was clinically active and well tolerated as a second-line treatment in mRCC patients after TKI failure, and circulating IL-10 levels could predict response. Patient summaryPazopanib could be used as a second-line therapy for the treatment of metastatic renal cell carcinoma after failure of tyrosine kinase inhibitor (TKI) therapy when drugs such as nivolumab and cabozantinib are not available. Now that immunotherapy plus antiangiogenic therapy is a first-line option, IL-10 levels deserve further exploration as a potential predictor of response to sequential TKI-TKI therapy.

The correlation between the incidence of adverse events and progression-free survival in patients treated with cabozantinib for metastatic renal cell carcinoma (mRCC)

Clinical practice shows significant differences in treatment outcomes across patients treated with cabozantinib for metastatic renal cell carcinoma (mRCC). It is not known whether cabozantinib-induced adverse events are predictive factors of survival as in case of drugs such as sunitinib or axitinib. The study participants were 30 adult patients with mRCC treated with cabozantinib as a second- or further line setting. All adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Progression-free survival (PFS) values were calculated by taking the beginning of cabozantinib treatment as the start date and either disease progression or death as the end date. PFS were estimated using the Kaplan-Meier method, and compared using the log-rank test. We identified independent PFS predictors using multiple Cox proportional hazards models and reported hazard ratios (HR) with 95% confidence intervals. The median observation time cabozantinib treatment was 7.5months, with a range of 2-15months. During that time, 11 (37%) of the patients had mRCC progression. Median PFS on cabozantinib was not reached, and lower quartile was 6months. All patients developed at least one adverse event in the course of cabozantinib therapy. Hypertension, hypothyroidism and HFS were observed most frequently, in about two-thirds of the patients. The co-incidence of multiple adverse events was common. Hypertension, hypothyroidism, diarrhea and liver toxicity were significantly associated with longer PFS values. Patients with three or more side effects had significantly longer PFS than those with two or fewer. Even though this study was conducted in a small patient sample and the observation time was relatively short our results confirm the predictive value of the incidence of adverse events during cabozantinib treatment in mRCC patients. To the best of our knowledge, this is the first study of this kind conducted in this group of patients.

Development of Response Classifier for Vascular Endothelial Growth Factor Receptor (VEGFR)-Tyrosine Kinase Inhibitor (TKI) in Metastatic Renal Cell Carcinoma

Vascular endothelial growth factor receptor (VEGFR)-targeted therapy improved the outcome of metastatic renal cell carcinoma (mRCC) patients. However, a prediction of the response to VEGFR-tyrosine kinase inhibitor (TKI) remains to be elucidated. We aimed to develop a classifier for VEGFR-TKI responsiveness in mRCC patients. Among 101 mRCC patients, ones with complete response, partial response, or ≥24weeks stable disease in response to VEGFR-TKI treatment were defined as clinical benefit group, whereas patients with <24weeks stable disease or progressive disease were classified as clinical non-benefit group. Clinicolaboratory-histopathological data, 41 gene mutations, 20 protein expression levels and 1733 miRNA expression levels were compared between clinical benefit and non-benefit groups. The classifier was built using support vector machine (SVM). Seventy-three patients were clinical benefit group, and 28 patients were clinical non-benefit group. Significantly different features between the groups were as follows: age, time from diagnosis to TKI initiation, thrombocytosis, tumor size, pT stage, ISUP grade, sarcomatoid change, necrosis, lymph node metastasis and expression of pAKT, PD-L1, PD-L2, FGFR2, pS6, PDGFRβ, HIF-1α, IL-8, CA9 and miR-421 (all, P<0.05). A classifier including necrosis, sarcomatoid component and HIF-1α was built with 0.87 accuracy using SVM. When the classifier was checked against all patients, the apparent accuracy was 0.875 (95% CI, 0.782-0.938). The classifier can be presented as a simple decision tree for clinical use. We developed a VEGFR-TKI response classifier based on comprehensive inclusion of clinicolaboratory-histopathological, immunohistochemical, mutation and miRNA features that may help to guide appropriate treatment in mRCC patients.

Abstract 429: Establishment of the classifier for a response to vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI) in metastatic renal cell carcinoma

Abstract Vascular endothelial growth factor (VEGF)-targeted therapy has been demonstrated to improve the outcome of metastatic renal cell carcinoma (mRCC) patients. However, validated predictors that predict response and prognosis to VEGF-tyrosine kinase inhibitors (VEGF-TKIs) remain to be elucidated. We aimed to define a classifier for VEGF-TKI response in mRCC patients. Among 101 mRCC patients treated with VEGF-TKIs, 73 patients were responder defined as patients showing complete or partial response, or ≥24 weeks stable disease to VEGF-TKI; and 28 patients were nonresponder defined as &amp;lt;24 weeks stable or progressive disease. Clinical and laboratory data were obtained from the medical records. Histologic features of all tumors were reviewed. Twenty-one protein expressions such as VEGF, pAKT, PD-L1, PD-L2, HIF-1α and HIF-2α were evaluated on immunohistochemical staining. Mutation of various cancer-related genes was investigated on OncoMap ver. 4.4 core. Microarray and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) were also performed to compare the expression patterns of miRNAs between responders and nonresponders in tissues samples. Patient's age, time from diagnosis to TKI initiation and thrombodytosis were different between responder and nonresponder (all, p &amp;lt;0.05). Histologically, tumor size, T stage, ISUP grade, sarcomatous change, necrosis and lymph node metastasis of responder were significantly lower or smaller than nonresponder (all, p &amp;lt;0.05). pAKT, PD-L1, PD-L2, FGFR2, pS6 and PDGFRβ showed more expression in nonresponder than in responder; on the other hands, HIF-1α, IL-8 and CA9 showed more expression in responder than in nonresponder (all, p &amp;lt;0.05). Expression of miR-421 was higher in responder than nonresponder (p = 0.008). A classifier to VEGF-TKI response was developed with various clinicopathological features, protein expression and miRNA expression. Tumor size, T stage, ISUP grade, necrosis, sarcomatoid change, pAKT, PD-L1, CA9, pS6, HIF-1α and miR-421 were selected by chi-square test with p &amp;lt;0.01. Using 10-fold cross validation (CV) by support vector machine, 3 features, i.e., necrosis, sarcomatoid change and HIF-1α, were finally selected as features for classifier and accuracy of 10-fold CV was 0.87. When the classifier was checked with all patients, apparent accuracy was 0.875 (95% CI, 0.782-0.938). In addition, the classifier could be presented by a simple decision tree for clinical use. In conclusion, we built a VEGF-TKI response classifier by comprehensive inclusion of clinical, laboratorical, histological and immunihistochemical features, mutation of cancer-related genes and miRNA expression using machine learning method and it may be helpful to receive a proper treatment in mRCC patients. Citation Format: Heounjeong Go, Mun Jung Kang, Pil-Jong Kim, Ja-Min Park, Jae-Lyun Lee, Ji Young Park, Yong Mee Cho. Establishment of the classifier for a response to vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI) in metastatic renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 429.

Association between diabetes mellitus and the survival of sunitinib-treated patients with metastatic renal cell carcinoma.

546 Background: Diabetes mellitus is one of the major risk factor for renal cell carcinoma (RCC) development. Although, in various cancers, the relationship between diabetes mellitus and worse prognosis is pointed out, the association between RCC prognosis and diabetes mellitus is under discussion. We sought to determine the association between diabetes mellitus with outcome of sunitinib treatment in metastatic RCC (mRCC) patients. Methods: A retrospective study of sunitinib-treated mRCC patients was performed. 69 patients who had been treated with sunitinib in Japanese two institutions (Teikyo University Chiba Medical Center and Chiba University) were entered. Kaplan-Meier and the log-rank test were performed to investigate the association between the pretreatment status of diabetes mellitus and the outcome of the patients who received the treatment with sunitinib. Results: Between 2008 and 2015, 69 mRCC patients were treated with sunitinib. 53 (76.8%) patients received sunitinib treatment as the first line molecular target drug. 15 (21.7%) patients were diagnosed as diabetes mellitus at the time of sunitinib treatment. Median time to treatment failure (TTF) was 7.1 months, cancer specific survival (CSS) was 33.9 months for all patients. With regard to TTF, there was no difference between diabetic and non-diabetic patients, 9 months for diabetic patients and 7.1 months for non-diabetic patients respectively (P = 0.3271). CCS was significantly shorter for diabetic patients, 11 months for diabetic patients and 39.4 months for non-diabetic patients respectively (P = 0.0469). When focusing on HbA1c, CSS was significant longer for the patients with HbA1c under 6.5% than the patients with HbA1c was 6.5 or more, median CSS was 44.5 months and 11.3 months, respectively (P = 0.0055). Conclusions: Diabetes mellitus did not influence the TTF of sunitinib treatment for mRCC patients. Diabetes mellitus may negatively affect the CSS of sunitinib-treated mRCC. Clinicians should consider controlling patient’s HbA1c status at the initiation of sunitinib treatment for mRCC.

Molecular Concepts of Immunomodulation for the Treatment of Metastatic Renal Cell Carcinomas: Where are We Now?

The introduction of molecular targeted agents has started to transform the treatment of metastatic renal cell carcinoma (mRCC), leading to a significant improvement of the prognosis of patients affected by that disease. However, treatment of metastatic disease still remains challenging as almost all patients will experience tumour progression and long-term survivors are very rare. This clearly warrants a continued search for improved treatment options. In recent years, the development of new substances and treatment approaches involving the targeted activation and modulation of the immune system have moved immunotherapy back into the focus of interest. A major development is the use of checkpoint inhibitors, which enable a targeted (re)activation of T cells. The following article describes the current methods used to improve standard treatment with the established targeted substances and discusses them along with the new immunooncological approaches of checkpoint modulation in the context of the treatment of mRCC patients.

Abstract 919: BIM as a predictive biomarker for VEGFR inhibitor in metastatic renal cell carcinoma

Abstract Angiogenesis is an important target for metastatic renal cell carcinoma(mRCC), resulting in several VEGFR tyrosine-kinase inhibitors(TKIs)in clinical practice. Approximately 35% of mRCC patients do not get the benefit from TKIs treatment, including sunitinib, sorafenib or the other VEGF pathway blockers, due to resistance and/or drug induced toxicities. Despite these initial insights, no validated biomarkers that identify which mRCC patients benefit most from antiangiogenic therapy have been discovered. Pro-apoptotic Bcl-2 family member (BIM) is a particularly critical mediator of targeted therapy-induced apoptosis in solid tumors. BIM upregulation is required for TKI to induce apoptosis in tyrosine kinase driven cancer. According to recent several studies, BIM deletion polymorphism was identified as one of the primary resistant mechanisms of various TKIs in EGFR mutated NSCLC or CML. However, there has been no study that confirms germline BIM deletion could confer the resistance to several VEGFR TKIs in treatment with mRCC. Here, we evaluated the possibility of germline and tumor tissue BIM deletion as a potential biomarker for VEGFR TKI resistance in mRCC. BIM deletion polymorphism status of gDNA from 55 formalin fixed paraffin embedded(FFPE) tumor tissues and 98 peripheral blood mononucleated cells (PBMC) of mRCC patients was determined by separated PCR. BIM protein expression level was evaluated by immunohistochemistry. Among these samples, 19 samples overlapped FFPE and PBMC and these sample results were exactly the same comparing either wild type or deletion. BIM deletion(heterozygous) accounted for 18.2% of the 121 total mRCC patients.We observed these patients with BIM deletion showed poor prognosis with TKIs treatments (response rate of treatment with sunitinib in BIM wild group and BIM deletion group : 24.6% versus 16.7%). Our study identified BIM a possible genetic biomarker that can predict the efficacy to VEGFR TKIs treatment in mRCC patients. Especially, as germline BIM deletion in the PBMC showed the concurrdence with tissue polymorphysim, it might be feasible to predict the response to antiangiogenic agent therapy simply through simple blood sampling. In conclusion, BIM deletion polymorphism might be a useful candidate marker for selecting mRCC patients for TKIs treatment. Citation Format: Jee Hung Kim, Hoi Young Lee, Woo Sun Kwon, Kyu Hyun Park, Ho-yeong Lim, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. BIM as a predictive biomarker for VEGFR inhibitor in metastatic renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 919. doi:10.1158/1538-7445.AM2014-919

U.S. regional practice patterns in metastatic renal cell carcinoma (mRCC) patients: A real-world retrospective analysis.

505 Background: The treatment landscape for metastatic renal cell carcinoma (mRCC) has changed in recent years, with several targeted therapies becoming available for 1st and 2nd line use. The rapidly evolving treatment landscape has left physicians with an abundance of choices for the treatment of mRCC patients. This study aimed to understand whether this has resulted in varying treatment patterns across US regions in 1st and 2nd line targeted therapy for mRCC. Methods: RCC patients who initiated 1st line targeted therapy with a vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFr) or mammalian target of rapamycin (mTOR) inhibitor between January 1, 2004 and June 30, 2011 were identified in the MarketScan database. First-line therapy was defined as the first claim in the database for a targeted therapy. One drug claim was sufficient to establish a line of therapy and a new line was defined as switching to another agent. Treatment patterns in the 1st and 2nd line settings were assessed in patients who initiated 2ndtherapy line after FDA approval of everolimus (Ev) (March 30, 2009) and stratified by geographic region. Results: Of the 6,524 patients included in the study, 1,298 (36%) received a 2nd line targeted therapy after March 30, 2009. Although all possible permutations of treatment sequences were observed, overall, sunitinib (Su) and temsirolimus (Te) combined made up 80% to 83% of the 1st line regimens across regions. The most common sequence was Su-&gt;Ev, observed in 18% of patients in the North Central US to 31% in the Northeast; Su-&gt;Te was the next most common sequence in all regions. Among patients who received 1st line temsirolimus, the majority initiated 2ndline on either bevacizumab (Be) (7%-12%) or Su (6%-10%) across regions. Conclusions: The most common treatment sequences across all regions were Su-&gt;Ev and Su-&gt;Te. Although a consistent pattern of sequential therapy emerged across regions, a wide range of on- and off-label strategies was observed outside of the predominant pattern of care. Furthermore, very few patients in this study received additional targeted therapy after 1st line. Further research is needed to identify factors influencing these treatment strategies.

Comparative Efficacy of Sunitinib versus Sorafenib as First-Line Treatment for Patients with Metastatic Renal Cell Carcinoma

Background: This study investigated the efficacy and toxicity of sorafenib and sunitinib as primary treatment for patients with metastatic renal cell carcinoma (mRCC). Methods: We identified 49 and 220 patients treated with sorafenib and sunitinib, respectively, as first-line therapy in the Asan Medical Centre from April 2005 to March 2011. Results: Disease control rates of 71 and 74% were achieved with sorafenib and sunitinib, respectively (p = 0.687). After a median follow-up of 27.6 months, progression-free survival (PFS) and overall survival (OS) were not significantly different between the sorafenib and the sunitinib group (PFS 8.6 vs. 9.9 months, respectively, p = 0.948, and OS 25.7 vs. 22.6 months, p = 0.774). Patients treated with sorafenib required dose reduction due to toxicities less frequently than those treated with sunitinib (37 vs. 54%, p = 0.034). Haematological toxicity of grade 3 or 4 was more common in the sunitinib group than in the sorafenib group (45 vs. 4%, p < 0.001). Multivariate analysis showed old age, Heng's risk group, and bone and liver metastases, but not the type of vascular endothelial growth factor tyrosine kinase inhibitor, were independent prognostic factors affecting OS. Conclusion: The results of this study indicate that sorafenib has comparable efficacy to sunitinib in the treatment of mRCC patients and fewer and less severe toxicities, but the number of patients included in the study was small.

Effect of VEGF and VEGFR polymorphisms on clinical outcome and response in patients with advanced renal cell carcinoma receiving first-line treatment.

388 Background: For the last few years, sunitinib has been considered the standard treatment for first-line metastatic renal cell carcinoma, but in 2010 a new drug pazopanib had been approved for treatment in this setting. Recent data from the COMPARZ and PISCES study seem to suggest a non-inferiority of pazopanib confronted with sunitinib in PFS and OS and a patients’ preference for pazopanib if we consider quality of life parameters. The aim of our study is to investigate whether polymorphisms of VEGF and VEGFR can influence PFS and OS when patients are treated either with sunitinib or pazopanib as first-line treatment. Methods: 97 histologic samples of mRCC patients were tested for VEGF-A, VEGF-C, and VEGFR-1, 2, 3 single nucleotide polymorphisms (SNPs). Patients’ progression free survival (PFS) and overall survival (OS) were analyzed for first-line treatment. Results: In patients treated with sunitinib VEGF-A rs833061 resulted significant in PFS (CC+CT vs TT, p &lt; 0.0001) and OS (p &lt; 0.0001). VEGF-A rs699947 was significant for PFS (AA+AC vs. CC) p = 0.0001) and OS (p &lt; 0.0001). VEGF-A rs2010963 was significant in PFS (CC vs. CG vs. GG, p = 0.0001) and in OS (p = 0.0045). VEGR3 rs6877011 was significant in PFS (CC vs. CG, p = 0.0075) and OS (p = 0.0001). At multivariate analysis rs833061, rs2010963, and rs68877011 were significant in PFS. rs833061 and rs68877011 were independent factors in OS. In the pazopanib treated groups of patients VEGF-A rs833061 resulted significant in PFS (TT+CT vs. CC p = 0.027) Conclusions: In our analysis patients with CC or CT polymorphism of rc833061 had a favourable PFS and OS if treated with sunitinib instead patients treated with pazopanib seems to have benefit if CT+TT polymorphism, A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line with sunitinib. Patients with C polymorphism of rs6877011 and G polymorphism of rs307822 seem equally to have a favourable impact in first-line therapy with sunitinib. Our data seem to suggest that biology could have a role in the choice of first-line treatment for mRCC patients. Further data will be presented at the Symposium.