Initiation Of Sunitinib Research Articles

Preliminary results from a phase II study comparing sunitinib alone or with stereotactic body radiotherapy (SBRT) for newly diagnosed oligometastatic renal cell carcinoma.

4533 Background: Although SBRT has become an option for oligometastatic renal cell carcinoma (oligoRCC), current trials supporting SBRT haven’t been adequately persuasive given their single-arm, non-first-line design. Our study aimed to explore if SBRT improves oncologic outcomes compared with standard first-line systemic therapy in oligoRCC. Methods: This an open-label, double-arm phase II controlled trial enrolling treatment naïve oligoRCC patients (pts), defined as ≤ 5 metastatic lesions (ChiCTR1800017136). No liver or brain metastasis was allowed. Nephrectomy was mandatory before enrollment. Pts were allocated 1:1 to receive either sunitinib alone (control arm) or sunitinib plus SBRT (SBRT arm). Sunitinib was started as 50 mg daily for 4 weeks, followed by 2 weeks off treatment. SBRT was delivered to all metastatic sites within 2 months after sunitinib initiation, with 35-50Gy in 5 fractions. Primary endpoint was objective response rate (ORR); secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Data from pts with ≥ 1 year of follow-up were reported this time. Results: Starting in 2018, the trial has currently completed its accrual, with 48 pts enrolled. Forty-two pts had ≥ 1 year of follow-up and were evaluable for the present analysis. Pt characteristics for SBRT and control arms: median age 51 vs 59 years (p=0.094); synchronous metastasis 31.8% vs 10.0% (p=0.179); clear cell carcinoma 77.3% vs 80.0% (p=1.000); IMDC low or intermediate risk 86.4% vs 80.0% (p=1.000); solitary metastasis 45.5% vs 25.0% (p=0.167). Thirty-four sites received SBRT, most frequently to bone (61.8%) and soft tissue (17.6%) metastasis. The 1-year local control rate after SBRT was 93.8%. ORR (81.8% vs. 25.0%, p=0.000) and DCR (90.9% vs. 60.0%, p=0.047) were significantly higher in SBRT arm than those in control arm. The 1y-PFS was 72.7% for SBRT arm and 35.0% for control arm (HR 0.33, 95% CI 0.16-0.69, p= 0.003). And the 1y-OS was 95.5% for SBRT arm and 80.0% for control arm (HR 1.06, 95% CI 0.31-3.67, p=0.923). Grade 3-4 treatment-related AEs occurred in 66.7% and 62.5% pts in SBRT arm and control arm (p=0.763), respectively. SBRT-related Grade 3-4 toxicity included radiation enteritis (n=1, grade 3) and radiation pneumonitis (n=1, grade 3). Conclusions: Our results showed promising efficacy and acceptable toxicity of SBRT plus sunitinib when compared with sunitinib alone for oligoRCC. Complete results are awaited in 2023 after follow-up completion of the entire cohort. Clinical trial information: ChiCTR1800017136.

Real-World Assessment of Clinical Outcomes Among First-Line Sunitinib Patients with Clear Cell Metastatic Renal Cell Carcinoma (mRCC) by the International mRCC Database Consortium Risk Group.

International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment. Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors. Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors. This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes. This analysis offers a contemporary benchmark for overall survival (median, 52.1 months; 95% confidence interval, 43.4-61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials.

Real-world assessment of clinical outcomes among first-line (1L) sunitinib (SUN) patients (pts) with metastatic renal cell carcinoma (mRCC) by the international mRCC database consortium (IMDC) risk group.

610 Background: Prognostic factors such as the IMDC criteria have included all types of targeted therapy. This study assesses clinical outcomes and provide benchmarks for mRCC pts treated specifically with 1L SUN in the real world to provide contemporary benchmarks for outcomes and survival. Methods: Clear cell mRCC pts initiating SUN as 1L therapy between 2010-2018 were included in a retrospective database study. Kaplan Meier analysis was used to estimate median time to treatment discontinuation (TTD) and overall survival (OS: time to death) by IMDC risk groups based on Karnofsky Performance Status < 80%, diagnosis to treatment interval < 1 year, anemia, neutrophilia, hypercalcemia and thrombocytosis. Results: Among 1,769 1L SUN pts with clear cell in the RW clinical database, 318 (18%) had favorable, 1,031 (58%) had intermediate and 420 (24%) had poor IMDC risk. Across the favorable, intermediate, and poor risk groups, pts had similar mean age in years, gender distribution, and year of SUN initiation (age: 63.8, 62.9 and 62.6; male: 74%, 75%, and 72%; SUN initiation year of 2010-2013: all 71%). In the favorable risk group, 99% received nephrectomy vs 88% in intermediate and 66% in poor risk group. Median TTD was 15.0, 8.5, and 4.2 months (mos) in the favorable, intermediate, and poor risk groups, respectively, and was 7.1 mos in the combined intermediate/poor risk groups. Median OS was 52.1, 31.5, and 9.8 mos in the favorable, intermediate, and poor risk groups, respectively, and was 23.2 mos in the combined intermediate/poor risk groups. Conclusions: This real world study based on a contemporary cohort of 1L SUN mRCC pts found a median OS of 52 mos which sets a new benchmark for clear cell mRCC in the favorable risk group. OS in the intermediate and poor risk groups are similar to previous reports. This affects pt counselling and clinical trial design.

Efficacy and safety of sunitinib in elderly patients with advanced renal cell carcinoma.

Elderly individuals represent a consistent proportion of all cancer patients. However, they are under-represented in clinical trials. The present study evaluated the actual tolerability of sunitinib in elderly Japanese patients with advanced renal cell carcinoma (RCC). A total of 56 consecutive patients with advanced RCC treated with sunitinib were enrolled. Patients were divided into two groups according to their age at the time of sunitinib initiation: i) elderly cohort (≥70 years); and ii) younger cohort (<70 years). Disease control rate, progression-free survival, overall survival and relative dose intensity (RDI) were compared between the two cohorts. The elderly cohort comprised of 14 patients (25.0%), and the younger cohort included 42 patients (75.0%). The elderly cohort had a significantly higher Charlson comorbidity index than the younger cohort (mean, 9.7 vs. 7.9; P<0.0001). Disease control rate, progression-free survival, and overall survival were not significantly different. The elderly cohort had a significantly lower RDI than the younger cohort (mean, 51.7 vs. 65.0%; P=0.0340). Thus, treatment with sunitinib is feasible and effective in elderly Japanese patients with advanced RCC. However, the RDI of elderly patients was significantly lower, and a relatively low dose of sunitinib provided optimal therapeutic efficacy.

Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma.

The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC). Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated. Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50ng/mL than in those with concentrations ≥ 50ng/mL. The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50-100ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC.

Open-label, randomized multicentre phase II study to assess the efficacy and tolerability of sunitinib by dose administration regimen (dose modification or dose interruptions) in patients with advanced or metastatic renal cell carcinoma: study protocol of the SURF trial

BackgroundSunitinib is a tyrosine kinase inhibitor approved in the first-line metastatic renal cell carcinoma (MRCC) setting at the dose of 50 mg daily for 4 weeks followed by a pause of 2 weeks. Due to toxicity, this standard schedule (50 mg daily 4/2) can induce up to 50% of sunitinib dose modification (reduction and/or interruption). The current recommendation in such case is to reduce the dose to 37.5 mg per day (standard schedule 4/2). Recent data highlight an alternative schedule: 2 weeks of treatment followed by 1 week of pause (experimental schedule 2/1). The SURF trial is set up to evaluate prospectively experimental schedule 2/1 when toxicity occurs. This article displays the key elements of the study protocol.Methods/designSURF [NCT02689167] is a prospective, randomized, open-label phase IIb study. Patients are included at sunitinib initiation while receiving standard schedule 4/2 (50 mg daily) according to the marketing authorization indication. When a dose adjustment of sunitinib is required, patients are randomized between standard schedule 4/2 (37.5 mg daily) and experimental schedule 2/1 (50 mg daily). Key eligibility criteria are the following: patients with locally advanced inoperable or MRCC who are starting first-line treatment with sunitinib, with histologically or cytologically confirmed renal cancer clear cell variant or with a clear cell component, and with Karnofsky performance status ≥70%. The primary objective is to assess the median duration of sunitinib treatment (DOT) in each group. The key secondary objectives are progression-free survival, overall survival, time to randomization, objective response rate, safety, sunitinib dose intensity, health-related quality of life, and the description of main drivers triggering randomization. We hypothesized that experimental schedule 2/1 would result in an improvement in median DOT from 6 to 8.5 months. It was estimated that 112 patients would be needed in each arm during 24 months. In order to take into account the possibility of treatment discontinuation before randomization, 248 patients are necessary.DiscussionThe SURF trial is asking a pragmatic question adapted to the current practice on what is the best way to adapt sunitinib when treatment-related adverse events occur. The results of the SURF trial will bring high-value data to support the use of an alternative schedule in sunitinib treatment.Trial registrationClinicalTrials.gov, NCT02689167. Registered on 26 February 2016.

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma.

Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.

Treatment modification with sunitinib in first-line (1L) metastatic renal cell carcinoma (mRCC): An analysis of the STAR-TOR registry.

602 Background: The standard dosing schedule for administration of Sunitinib is 50mg once daily for a 4-week period followed by 2 weeks off. However, in clinical practice, many patients require schedule or dose reductions to mitigate toxicity. We aimed to assess if these treatment modifications result in improved outcomes in mRCC patients. Methods: Data were drawn from STAR-TOR, a German, multi-centre, real-world, prospective registry to report outcomes of mRCC patients who received Sunitinib in 1L. Patients were categorised into 2 treatment groups: 1) Sunitinib initiated at standard schedule/dose with subsequent schedule/dose modification (SM), 2) Sunitinib as per standard schedule/dosage (SS). Kaplan-Meier survival analysis was used to determine time on treatment (TT) of Sunitinib and progression-free survival (PFS). Differences between groups were assessed using log-rank tests. Results: In total 297 patients were identified initiating 1L Sunitinib. Schedule or dose reductions occurred in 33% of patients. Significant differences between groups at baseline are noted in Table 1. Median TT was greater in SM vs. SS (15.1 vs. 3.9 months (m), p &lt; 0.0001). Median PFS was improved in SM vs. SS (15.1 vs. 6.0 m, p &lt; 0.0001). Fatigue (31/14%), hand-foot syndrome (HFS) (28/10%), diarrhea (35/19%) and stomatitis (20/6%) were more frequently reported in SM vs. SS since initiation of Sunitinib. Incidence of adverse events, (excluding diarrhea) was reduced following schedule/ dose modification of sunitinib; fatigue (before SM/ after SM) (18/7%), HFS (21/8%) and stomatitis (8/4%). Conclusions: Modifying Sunitinib schedule or individualizing the dose represent therapy management strategies that are associated with improved tolerability, prolonged treatment duration and significant improvement in PFS in a real life setting. These data suggest that effective management of toxicity of Sunitinib can optimize patient outcomes. [Table: see text]

Feasibility, Safety, and Efficacy of an Alternative Schedule of Sunitinib for the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Retrospective Study.

BackgroundStandard treatment with sunitinib for patients with metastatic renal cancer provides an ‘on-off’ schedule (daily administration of a 50-mg capsule for 4 weeks, followed by a 2-week break; consecutive 6-week cycles). We developed an alternative intermittent schedule to reduce the toxicity and symptoms of tumor regrowth during the rest period and to allow prolonged continuation of therapy, maintaining dose intensity.ObjectiveThe objective of this study was to provide a retrospective evaluation of the feasibility, safety, and efficacy of an alternative schedule of sunitinib in patients who did not tolerate classical treatment.MethodsPatients treated with the classical schedule with at least grade 2 toxicity or recurrence of symptoms during the rest period were switched to an alternative schedule (the same daily dose 5 consecutive days per week for 5 weeks and then the same daily dose on days 1, 3, and 5 in the sixth week; consecutive 6-week cycles).ResultsTwenty-five patients were enrolled. The median time from sunitinib initiation to schedule switch was 2.9 months. After the switch, the median therapy duration was 9.2 months. Rate of delay, corrected by cycle number, was 10% for both schedules. After the switch, 48.7% of patients obtained a toxicity reduction (hypertension −82%, stomatitis −71%, cutaneous toxicity −69%). A reduction in ‘on-off symptoms’ (−86%) was achieved. Overall response rate was 40% and the disease control rate was 80%. Median progression-free survival was 16.4 months and median overall survival was 41.3 months.ConclusionsDespite the small sample size and retrospective nature, we demonstrated the feasibility, safety, and efficacy of the alternative schedule, allowing prolonged treatment and better quality of life.

Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma.

Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping.Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These "on-drug" visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time.Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%-17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time.Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601-9. ©2017 AACR.

Prognostic effect of serum C-reactive protein kinetics on advanced renal cell carcinoma treated with sunitinib.

C-reactive protein (CRP) is an independent prognostic factor for renal cell carcinoma (RCC). The aim of the present study was to investigate the prognostic effect of pretreatment serum CRP level and CRP kinetics on patients with advanced RCC treated with sunitinib. A total of 56 consecutive patients with advanced RCC treated with sunitinib between December, 2008 and December, 2012 were enrolled in the present study. The patients were retrospectively divided into 3 cohorts according to pretreatment serum CRP level and CRP kinetics: i) Normal CRP cohort (pretreatment CRP ≤0.30 mg/dl); ii) normalized CRP cohort (pretreatment CRP >0.30 mg/dl that normalized within 2 cycles of treatment); and iii) non-normalized CRP cohort (pretreatment CRP >0.30 mg/dl that did not normalize after sunitinib initiation). Disease control rate, progression-free survival and overall survival times were compared for the 3 cohorts. The normal (n=17, 30.4%) and the normalized (n=8, 14.3%) CRP cohorts exhibited significantly better disease control rates compared with the non-normalized CRP cohort (n=31, 55.4%; P<0.0001 and P=0.0445, respectively). The normal CRP cohort exhibited significantly longer progression-free survival compared with the non-normalized CRP cohort (P=0.0050). The normal and normalized CRP cohorts exhibited significantly longer overall survival compared with the non-normalized CRP cohort (P=0.0005 and 0.0466, respectively). Therefore, CRP kinetics and normal pretreatment CRP level are prognostic indicators in patients with advanced RCC treated with sunitinib.

Sunitinib treatment in patients with advanced renal cell cancer: the Brazilian National Cancer Institute (INCA) experience

ABSTRACTPurpose:The aim of this study was to assess the impact of sunitinib treatment in a non-screened group of patients with metastatic renal cell cancer (mRCC) treated by the Brazilian Unified Health System (SUS) at a single reference institution.Material and Methods:Retrospective cohort study, which evaluated patients with mRCC who received sunitinib between May 2010 and December 2013.Results:Fifty-eight patients were eligible. Most patients were male 41 (71%), with a median age of 58 years. Nephrectomy was performed in 41 (71%) patients with a median interval of 16 months between the surgery and initiation of sunitinib. The most prevalent histological subtype was clear cell carcinoma, present in 52 (91.2%) patients. In 50 patients (86%), sunitinib was the first line of systemic treatment. The main adverse effects were fatigue (57%), hypothyroidism (43%), mucositis (33%) and diarrhea (29%). Grade 3 and 4 adverse effects were infrequent: fatigue (12%), hypertension (12%), thrombocytopenia (7%), neutropenia (5%) and hand-foot syndrome (5%). Forty percent of patients achieved a partial response and 35% stable disease, with a disease control rate of 75%. Median progression free survival was 7.6 months and median overall survival was 14.1 months.Conclusion:Sunitinib treatment was active in the majority of patients, especially those with low and intermediate risk by MSKCC score, with manageable toxicity. Survival rates were inferior in this non-screened population with mRCC treated in the SUS.

Abstract 2038: Sunitinib impact on kinome profiles of peripheral blood mononuclear cells from renal cell carcinoma patients: Do molecular effects correlate with clinical data

Abstract Introduction: Sunitinib, a potent multi-tyrosine kinase (TK) inhibitor, is a standard first-line treatment for metastatic renal cell carcinoma (mRCC). In addition to its antiangiogenic activity, sunitinib is known to have immune-modulating properties especially on regulatory T-cells and tumor-infiltrating lymphocytes. However, data is sparse about sunitinib impact on peripheral lymphocytes and new data is needed to gain insights into the angiogenesis and immunity bidirectional link. This study aims to fill such a gap by investigating the clinical and intracellular modifications of sunitinib on peripheral blood mononuclear cells (PBMC) from naïve mRCC patients. Methods: Initially, a retrospective study was conducted in 88 mRCC patients treated with first-line sunitinib therapy to assess the evolution of lymphocyte count (expressed as a ratio between Day 21 and Day 0 i.e. D21/D0) during the first cycle of treatment. A new prospective study was carried out to determine kinomic profiles in PBMC from 21 naïve mRCC patients and 12 healthy volunteers. TK activity profiles of PBMC lysates were generated on TK PamChip® microarrays. The ex vivo effect of sunitinib and its active metabolite SU12662 were also determined in PBMCs. All data were analyzed using BioNavigator software. Results: The retrospective preliminary study showed that an increased D21/D0 lymphocytes ratio was significantly associated with a shorter Progression Free Survival (PFS) in multivariate analysis (p = 0.0023). In the prospective study, the phosphorylation level in PBMCs from mRCC patients was significantly lower than in healthy volunteers for 74 peptides (p&amp;lt;0.05). Ex vivo exposure to sunitinib or SU12662 led to a decreased phosphorylation level for majority of peptides in PBMCs from mRCC patients. Moreover, sunitinib had a stronger inhibitory profile than SU12662 for 80 peptides (p&amp;lt;0.05). The ex vivo sunitinib effect was statistically correlated with the IMDC (“Heng”) prognostic model and D21/D0 lymphocytes ratio and 53 and 16 peptides, respectively were found to be significant. Less ex vivo inhibition was associated with both a poor prognosis according to Heng and an increased D21/D0 lymphocytes ratio. Conclusions: Our retrospective study shows a decreased lymphocyte count on D21 after sunitinib initiation is a favorable prognostic factor in mRCC patients. The kinomic analysis of TKs in PBMCs after ex vivo exposure to sunitinib correlates with both Heng prognostic score and lymphocyte D21/D0 ratio, suggesting that PBMCs could be an interesting biological matrix to seek future biomarkers regarding clinical efficacy of sunitinib. Further investigations are underway to determine the involvement of signaling pathways contributing to the inter-individual variability in kinomic profiles of PBMCs from mRCC patients treated with sunitinib. Citation Format: Audrey Bellesoeur, Gaelle Noe, Audrey Thomas-Schoemann, Olivier Huillard, Faris Naji, Savithri Rangarajan, Alicja Puszkiel, Jerome Alexandre, François Goldwasser, Benoit Blanchet, Michel Vidal. Sunitinib impact on kinome profiles of peripheral blood mononuclear cells from renal cell carcinoma patients: Do molecular effects correlate with clinical data. [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 2038.

Detecting Secondary C-KIT Mutations in the Peripheral Blood of Patients with Imatinib-Resistant Gastrointestinal Stromal Tumor

Objective: Imatinib is a standard treatment for metastatic gastrointestinal stromal tumor (GIST). Imatinib resistance is mostly caused by secondary mutations in C-KIT. The antitumor effect of second-line agents is correlated with the type of secondary mutation: indeed, sunitinib is effective against tumors with C-KIT exon 13 or 14 mutations. We investigated whether secondary C-KIT mutations can be detected in circulating tumor DNA (ctDNA) from peripheral blood. Methods: This study included 4 patients who underwent resection of imatinib-resistant GIST. Tumor-specific mutations in each tumor were determined by Sanger sequencing. ctDNA was extracted from peripheral blood obtained before and after the treatment of imatinib-resistant lesions. Each of the secondary target mutations in ctDNA was investigated, using a next-generation sequencer. Results: Imatinib-resistant lesions had single-nucleotide substitutions in C-KIT exon 13 in 3 patients and exon 18 in 1 patient. Identical secondary C-KIT mutations could be detected in ctDNA with a mutant fraction range of 0.010-9.385%. One patient had growth of an imatinib-resistant tumor containing a C-KIT exon 13 mutation, and the fraction of ctDNA decreased after initiation of sunitinib. Conclusion: Detection of secondary C-KIT mutations in ctDNA could be useful for the selection of targeted agents and prediction of antitumor effects.

Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy

BackgroundTo investigate the hypothesis that MRI derived diffusion-weighted imaging (DWI) and perfusion (MRP) parameters are sensitive image biomarkers for monitoring early antiangiogenic effects and predicting progression free survival (PFS) in advanced hepatocellular carcinoma (HCC).MethodsIn this phase II clinical trial, 23 of 34 patients were included in the imaging and circulating biomarker study. DWI and MRP were performed at the baseline and at 2-weeks after initiation of sunitinib. The imaging protocol included an axial DWI sequence using b values of 50, 400 and 800 sec/mm2, and MRP using a series of coronal 3D-VIBE following 20 ml of Gd-DTPA at 2 ml/sec. These parameters were compared with clinical outcome and PFS at 6-months. Correlation between changes in MRI parameters and plasma biomarkers was also evaluated.ResultsAfter 2-week of sunitinib, substantial Ktrans changes in HCC were observed from median baseline value 2.15 min−1 to 0.94 min−1 (P = 0.0001) with increases in median apparent diffusion coefficient (ADC) from 0.88 × 10-3 mm2/s to 0.98 × 10-3 mm2/s (P = 0.0001). Tumor size remained unchanged by RECIST and mRECIST (both P > 0.05). Patients who showed larger drop in Ktrans and Kep at 2 weeks correlated with favorable clinical outcome, and higher baseline Ktrans and larger drop in EVF correlated with longer PFS (all P < 0.05). There was a significant association between a decrease in sVEGFR2 and the drop in Ktrans and Kep (P = 0.044, P = 0.030), and a significant and borderline association between decrease in TNF-α and the drop in Ktrans and Kep, respectively (P = 0.051, P = 0.035).ConclusionIn HCC, MRP may be a more sensitive biomarker in predicting early response and PFS following sunitinib than RECIST and mRECIST.Trial registrationClinicalTrials.gov: NCT00361309

“Pseudocavitation” in Thymic Carcinoma During Treatment with Sunitinib

A 45-year-old man with stage IVA thymic carcinoma was enrolled on a phase II study of sunitinib (50 mg daily)1A Phase 2 Study of Sunitinib in Patients with Advanced Relapsed or Refractory Thymoma or Thymic Carcinoma with at Least One Prior Line of Platinum-Based Systemic Chemotherapy. NCT01621568. www.clinicaltrials.govGoogle Scholar 4 weeks after disease progression on first-line chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and belinostat.2A Phase 1/2 Study of PXD101 (Belinostat) in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Advanced or Recurrent Thymic, Malignancies. NCT01100944. www.clinicaltrials.govGoogle Scholar Molecular profiling of the tumor revealed only a p53 gene mutation (c-Kit was wild type).3Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies. NCT01306045. www.clinicaltrials.govGoogle Scholar Baseline chest computed tomography, before sunitinib, showed a mediastinal mass with compression of the proximal right main pulmonary artery (Fig. 1A) and direct invasion of pericardium. Three weeks after initiation of sunitinib, the patient reported increased left shoulder pain, cough, nausea, vomiting, and a palpable soft and fluctuating lesion measuring 2 cm in size overlying the sternum. A new computed tomography scan (Fig. 1B–D) showed an increase in the size of the mediastinal mass, which now included air (Fig. 1B–D, asterisk), air-fluid levels (Fig. 1B, D, arrow), dissection in the anterior chest wall with subcutaneous air (Fig. 1C, double arrow), and a large left pleural effusion (Fig. 1B–D). Sunitinib was discontinued, and a thoracentesis was performed to remove a liter of straw-colored fluid. Considering disease progression with tumor necrosis and superimposed infection with the possibility of bronchocutaneous fistula, antibiotic therapy was started. Subsequently, the patient's clinical condition deteriorated rapidly with development of right ventricular heart failure, and he died 2 weeks later. The autopsy revealed massive neoplastic infiltration of the heart and great vessels, including the pulmonary artery and left lung, with abundant tumor necrosis, most likely related to rapid progression of disease rather than antiangiogenesis effects of sunitinib. This represents an unusual finding in a patient with an aggressive thymic carcinoma.

1921 PROGNOSTIC IMPACT OF C-REACTIVE PROTEIN KINETICS FOR ADVANCED RENAL CELL CARCINOMA TREATED WITH SUNITINIB

You have accessJournal of UrologyKidney Cancer: Advanced (II)1 Apr 20131921 PROGNOSTIC IMPACT OF C-REACTIVE PROTEIN KINETICS FOR ADVANCED RENAL CELL CARCINOMA TREATED WITH SUNITINIB Tetsuo Fujita, Masatsugu Iwamura, Takahiro Hirayama, Daisuke Ishii, Ken-ichi Tabata, Kazumasa Matsumoto, and Kazunari Yoshida Tetsuo FujitaTetsuo Fujita Kanagawa, Japan More articles by this author , Masatsugu IwamuraMasatsugu Iwamura Kanagawa, Japan More articles by this author , Takahiro HirayamaTakahiro Hirayama Kanagawa, Japan More articles by this author , Daisuke IshiiDaisuke Ishii Kanagawa, Japan More articles by this author , Ken-ichi TabataKen-ichi Tabata Kanagawa, Japan More articles by this author , Kazumasa MatsumotoKazumasa Matsumoto Kanagawa, Japan More articles by this author , and Kazunari YoshidaKazunari Yoshida Kanagawa, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2340AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Since the introduction of sunitinib for patients with advanced renal cell carcinoma (RCC), significant objective responses have been reported. It is now widely approved for the first-line treatment of advanced RCC. A prognostic marker is required for selecting patients who will benefit most from sunitinib. We have previously revealed that pretreatment normal C-reactive protein (CRP) predicts better oncological outcomes of sunitinib. However, CRP kinetics of sunitinib have never been described. In the cytokine era, CRP kinetics have an impact on survival in patients with metastatic RCC. As such, in the present study, we evaluate CRP kinetics in advanced RCC patients treated with sunitinib. METHODS Between December 2008 and July 2012, 52 consecutive patients with advanced RCC who were treated with sunitinib, were enrolled. Patients divided into 3 groups according to the pretreatment CRP level and CRP kinetics: (i) normal CRP cohort; defined as pretreatment CRP levels ≤ 0.30 mg/dL, (ii) normalized CRP cohort; defined as pretreatment CRP > 0.30 mg/dL and normalized CRP within 2 cycles of treatment, (iii) non-normalized CRP cohort; defined as pretreatment CRP > 0.30 mg/dL and not normalized CRP after the initiation of sunitinib. Disease control rates, non-parametiric estimates of progression-free survival time and overall survival time were evaluated. RESULTS The normal CRP cohort comprised 16 patients (30.8%), the normalized CRP cohort comprised 8 patients (15.4%), and the non-normalized CRP cohort comprised 28 patients (53.8%). Disease control rates of the normal, normalized, and non-normalized CRP cohorts were 93.8%, 75.0%, and 32.1%, respectively. The normal and normalized CRP cohorts showed statistically significant better disease control rates than the non-normalized CRP cohort (P = 0.0003). The normal CRP cohort showed significantly longer progression-free survival time than the non-normalized CRP cohort (median 19.0 months vs 5.0 months, P = 0.0023). Also, the normal CRP cohort showed significantly longer overall survival time than the non-normalized CRP cohort (median 30.0 months vs 9.0 months, P = 0.0012). CONCLUSIONS CRP revealed prognostic significance in advanced RCC patients treated with sunitinib. Pretreatment CRP level could be a useful prognostic marker for sunitinib effectiveness. And a decrease of CRP level during sunitinib treatment predicts better response. CRP kinetics is a prognostic indicator as well as pretreatment CRP level for patients with advanced RCC treated with sunitinib. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e788 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tetsuo Fujita Kanagawa, Japan More articles by this author Masatsugu Iwamura Kanagawa, Japan More articles by this author Takahiro Hirayama Kanagawa, Japan More articles by this author Daisuke Ishii Kanagawa, Japan More articles by this author Ken-ichi Tabata Kanagawa, Japan More articles by this author Kazumasa Matsumoto Kanagawa, Japan More articles by this author Kazunari Yoshida Kanagawa, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Drug-induced immune-mediated thrombocytopenia secondary to sunitinib in a patient with metastatic renal cell carcinoma: a case report

IntroductionSunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for first line treatment for metastatic renal cell carcinoma and imatinib-resistant metastatic gastrointestinal stromal tumors. Sunitinib administration can cause myelosuppression resulting in neutropenia and thrombocytopenia. Here we present the case of a patient with metastatic renal cell carcinoma who developed sunitinib-induced immune-mediated thrombocytopenia and who was treated with withdrawal of sunitinib and administration of intravenous immunoglobulin and steroids.Case presentationThis case report describes a 70-year-old Aboriginal Australian with a diagnosis of metastatic renal cell carcinoma. Three weeks after the initiation of sunitinib he developed epistaxis and was admitted with thrombocytopenia (platelets 7 × 109/L) which was found to be refractory to platelet transfusion. Sunitinib was stopped and he was treated with intravenous immunoglobulin and steroids. His platelet count rapidly improved and returned to baseline in three weeks. Only two cases of sunitinib-induced immune-mediated thrombocytopenia have been described in the literature.ConclusionClinicians should have a high index of suspicion for the potential of immune-mediated thrombocytopenia after the initiation of multi-targeted tyrosine kinase inhibitors such as sunitinib. This is a diagnosis of exclusion and can be safely treated by drug withdrawal.

830P - The Predictive and Prognostic Role of O6-Methylguanine-DNA Methyltransferase (MGMT) and Tissue Transglutaminase-2 (TGASE-2) in Metastatic Renal Cell Carcinoma (MRCC) Patients Treated with Sunitinib

ABSTRACT Background Altough anti-angiogenic drugs are widely used in mRCC, the predictive markers for these agents cannot be well defined yet. MGMT is recently shown to be anti-angiogenic and responsible for the anti-proliferative effect of sunitinib in glioblastome cell lines. In preclinical studies, MGMT positive cells demonstrate high sVEGFR-1/VEGFA ratio, increased VEGFR-1 and decreased VEGFR-2. TGase-2 is known to be responsible for drug resistance, cell proliferation, migration and angiogenesis. In vitro studies showed that TGase-2 inhibits VHL and this leads to increase of HIF-1α and IGF-1R. Objective To investigate the predictive and prognostic role of MGMT and TGase-2 in mRCC patients who were treated with sunitinib. Methods We analyzed 82 RCC patients retrospectively. 43 of 82 survive without recurrence (non-metastatic group), 39 of 82 were already metastatic at the diagnosis or had metastasis during follow up (metastatic group). Expression of MGMT and TGase-2 proteins were assessed by immunohistochemical (IHC) staining in tissue samples. In the metastatic group, all patients received sunitinib as anti-angiogenic therapy and the overall survival (OS) analysis of these patients were performed according to time of sunitinib initiation. OS analysis of the entire group (metastatic and non-metastatic) were performed according to the time of diagnosis. Results In the metastatic group (n = 39), the ones with low MGMT had median OS of 30 months while ones with high MGMT had median OS of 47 months (p = 0.498). The ones with low TGase-2 had mean OS of 35.2 months while ones with high TGase-2 had mean OS of 27.9 months (p = 0.366). In the entire group, the ones with low MGMT had mean OS of 115 months while ones with high MGMT had median OS of 189 months (p = 0.498). The ones with low TGase-2 had mean OS of 212 months while ones with high TGase-2 had mean OS of 133 months (p = 0.281). Conclusions Higher MGMT and lower TGase-2 may be predictors of good response to sunitinib. Independent of the treatment, in the entire group the ones with higher MGMT and lower TGase-2 have better survival. All these results are not statistically significant. Disclosure All authors have declared no conflicts of interest.

U.K. experience of sunitinib malate in the treatment of metastatic renal cell carcinoma: Predictors of response from clinical practice.

455 Background: Sunitinib gained NICE approval in March 2009 as first line treatment for metastatic renal cell carcinoma (mRCC) and UK experience of use of Sunitinib is growing. The North of England Cancer Network (NECN) was the first cancer network in the UK to approve the use of Sunitinib in July 2007 and has the longest UK experience with this drug. The clinical outcomes of the NECN patients are presented. Methods: Data was collected and analysed regarding all patients started on Sunitinib from 01/07/2007 to 30/09/2010. Follow up extended to 28/02/2011. Previously published predictors of response were compared to the NECN data to check applicability in this population. Results: 129 patients were identified with a median age of 63 years (range 21-87), 67% were male and WHO performance status was 0, 1 or 2 (33%, 51%, 16%). 80% of patients had nephrectomy (60% radical) and 22% had prior systemic treatment. Median PFS was 10 months (range 0.25-27). Median OS (from Sunitinib initiation) was 17 months (range 0.25 - 47). Performance status was significantly associated with PFS and OS. The median number of treatment cycles was 5 (range 0.25-27). 64% of patients were dose reduced and 9% had a schedule modification to minimise toxicity. 21% of patients had a delay of 4 weeks or more which was not detrimental to median PFS. Dose reduction at treatment initiation was associated with a significant decrease in OS. 11.6% of patients required treatment for hypothyroidism which was associated with a significant improvement in PFS and OS. 15.5% of patients required treatment for hypertension, which was associated with an improvement in OS, but not PFS. Conclusions: PFS in the NECN population is similar to trial data. Strategies to deal with side effects, including dose reduction (after treatment initiation), treatment delay and schedule changes, did not adversely affect PFS. Performance status 0, the development of new hypertension or new hypothyroidism can be regarded as markers of good prognosis in this population. Initial dose reduction should be avoided as this adversely affects prognosis.