Sunitinib Treatment In Patients Research Articles

Sequential Capecitabine/Temozolomide and Sunitinib Treatment in Patients With Metastatic Well-Differentiated Grade 1/Grade 2 Pancreatic Neuroendocrine Tumors

ObjectiveThe role of alternate sequential administration of sunitinib and capecitabine/temozolomide (CAPTEM) in metastatic pancreatic neuroendocrine tumors (PanNETs) remains unexplored. We thus aimed to analyze the efficacy and tolerability of this strategy in advanced grade 1/grade 2 PanNETs. MethodsIn total, data of 43 patients with metastatic PanNET were collected from a real-world database of a cancer center. Twenty-four patients were treated with sunitinib followed by CAPTEM (group 1), and 19 patients were treated with CAPTEM followed by sunitinib (group 2). ResultsTwenty-three patients were treated with first-line sunitinib or CAPTEM, and 20 patients were pretreated with somatostatin analog (SSA) or SSA in combination with transcatheter arterial chemoembolization. The objective response rate with first-line treatment was similar in both groups, whereas that with second-line treatment was higher in group 1 than in group 2, albeit with no significant differences (21.1% vs 5.3%, respectively; P = .205). Median progression-free survival (mPFS) for first-line and second-line treatments did not differ between the 2 groups (11 and 12 months vs 12 and 8 months, respectively). Following subgroup analyses, treatment with first-line sunitinib and sunitinib after pretreated SSA had a longer mPFS than that with second-line sunitinib after CAPTEM (11 months vs 8 months, respectively; P = .046), whereas treatment with first-line CAPTEM and CAPTEM after pretreated SSA had an mPFS similar to that of second-line CAPTEM after sunitinib treatment. CAPTEM and sunitinib had similar tolerability. ConclusionAlternating sunitinib and CAPTEM were well tolerated and associated with similar mPFS in grade 1/grade 2 PanNETs. However, larger prospective studies are required to investigate the efficacy of alternate sequential therapies for metastatic PanNET.

Prediction of response to sunitinib in patients with advanced renal cell carcinoma (RCC) using mass spectrometry-based (phospho) proteomics.

e16556 Background: Sunitinib, a multi-targeted antiangiogenic tyrosine kinase inhibitor has improved the outcome of patients with advanced RCC considerably. Unfortunately, ± 30% of patients are intrinsically resistant, which underscores the urgent need to develop a clinically applicable method to select sunitinib treatment for patients. Since RCC is not single oncogene driven, but rather by multiple aberrantly activated kinase signaling pathways, we hypothesized that a functional read-out by large scale (phospho)proteomics can identify predictive biomarkers for sunitinib. Methods: Frozen tumor tissue of 26 patients (pts) with RCC, treated with sunitinib upon recurrence or progression, was obtained. Pts were classified as primary resistant (progression-free survival (PFS) < 3 months, n = 8) or sensitive (PFS ≥ 3 months, n = 18). Mass spectrometry-based tyrosine (pTyr) phosphoproteomics was performed by pTyr-immunoprecipitation followed by LC-MS/MS. Discriminatory phosphosites (p-sites) were identified (p < 0.05, fold-change (FC) > 2). Expression proteomics was performed by LC-MS/MS and differentially expressed proteins identified (p < 0.05, FC > 2, ≥ 50% data presence in group with highest abundance). Tumor biology was further analyzed by INferred Kinase Activity analysis, posttranslational modifications signature enrichment analysis (PTM-SEA, Krug et al 2019) and gene ontology mining. Results: pTyr-phosphoproteomics was successfully performed in 23 of 26 samples. Seventy-eight differential p-sites were identified, of which 22 (4 unique; BCAR3, NOP58, EIF4A2, GDI1) were upregulated in resistant and 56 in sensitive pts (35 unique). Supervised cluster analysis of these p-sites resulted in near-complete separation of the groups. EIF4A1 and its homolog EIF4A2 were differentially expressed in resistant pts both at the (phospho-)proteome and, in an independent cohort, at transcriptome level. Significantly higher inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) was found in sensitive pts. PTM-SEA showed 3 p-site-centric signatures that were significantly enriched (p < 0.05) in resistant pts, including FGF1 and prolactin pathways. Fifteen signatures were significantly enriched (p < 0.05) in sensitive pts, including insulin, VEGF and FGF2 treatment and KIT receptor pathway. Expression proteomics revealed significantly higher expression (p < 0.05) of proteins related to vesicle mediated transport in resistant pts, while this was not the case in sensitive pts. Conclusions: This MS-based (phospho)proteomics analysis of RCC tissues revealed discriminatory phosphosite and protein signatures and differential kinase and pathway activities that are associated with sensitive and resistant tumors. These findings warrant validation in an independent cohort and the clinical utility for treatment selection remains to be demonstrated.

Exploratory analysis of the platelet-to-lymphocyte ratio prognostic value in the adjuvant renal cell cancer setting.

Aim:To examine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in the adjuvant renal cell carcinoma setting.Materials & methods:Patients received adjuvant sunitinib (50 mg/day; 4 weeks on/2 weeks off) or placebo. The primary end point was disease-free survival (DFS).Results:In 609 patients, DFS was similar for baseline PLR <140 versus ≥140 overall (median: 6.4 vs 5.9 years; hazard ratio: 0.9; 95% CI: 0.7–1.2). A ≥25% decrease in PLR at week 4 overall was associated with longer DFS versus no change (hazard ratio: 0.8; 95% CI: 0.6–1.0).Conclusion:Baseline PLR was not prognostic for DFS with adjuvant sunitinib treatment in patients with renal cell carcinoma.Clinical Trials Registration: NCT00375674 (ClinicalTrials.gov)

Splice variants of lysosome‑associated membrane proteins 2A and 2B are involved in sunitinib resistance in human renal cell carcinoma cells.

Sunitinib, a tyrosine kinase inhibitor, is among the first-line treatments for metastatic or advanced stage renal cell carcinoma (RCC). However, patients with RCC develop resistance to sunitinib. We have previously demonstrated that lysosome-associated membrane protein 2 (LAMP-2), which has three splice variants with different functions (LAMP-2A, LAMP-2B, and LAMP-2C), is involved in RCC. In the present study, we examined which splice variants of LAMP-2 contributed to sunitinib resistance in RCC cells. In vitro analysis using ACHN, human RCC cell line, revealed that the IC50 of sunitinib was significantly increased by overexpression of LAMP-2A and LAMP-2B, but not LAMP-2C (P<0.01). Kaplan-Meier survival analysis using clinical samples revealed an association between shorter survival and high expression of LAMP-2A and LAMP-2B, but not LAMP-2C, in patients with RCC treated with sunitinib (P=0.01). Furthermore, high expression of LAMP-2A and LAMP-2B in RCC revealed a weak to moderate inverse correlation with the tumor shrinkage rate and progression-free survival, respectively. Thus, high expression of LAMP-2A and LAMP-2B contributed to the acquisition of sunitinib resistance, indicating that the expression of these two variants can predict the efficacy of sunitinib treatment in patients with RCC.

Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib

BackgroundPatients with metastatic renal cell cancer (mRCC) are commonly treated with the tyrosine kinase inhibitor sunitinib, which blocks signalling from vascular endothelial growth factor (VEGF) - and platelet-derived growth factor-receptors, inhibiting development of new blood vessels. There are currently no predictive markers available to select patients who will gain from this treatment. Epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is up-regulated in tumor endothelial cells in many types of cancer and may be a putative predictive biomarker due to its association with ongoing angiogenesis.MethodsELTD1, CD34 and VEGF receptor 2 (VEGFR2) expressions were analysed in tumor vessels of renal cancer tissues from 139 patients with mRCC using immunohistochemistry. Ninety-nine patients were treated with sunitinib as the first or second-line therapy. Early toxicity, leading to the termination of the treatment, eliminated 22 patients from the analyses. The remaining (n = 77) patients were included in the current study. In an additional analysis, 53 sorafenib treated patients were evaluated.ResultsPatients with high ELTD1 expression in the tumor vasculature experienced a significantly better progression free survival (PFS) with sunitinib treatment as compared to patients with low ELTD1 expression (8 versus 5.5 months, respectively). The expression level of CD34 and VEGFR2 showed no correlation to sunitinib response. In sorafenib treated patients, no association with ELTD1 expression and PFS/OS was found.ConclusionsOur results identify tumor vessel ELTD1 expression as a positive predictive marker for sunitinib-treatment in patients suffering from mRCC. The negative results in the sorafenib treated group supports ELTD1 being a pure predictive and not a prognostic marker for sunitinib therapy.

Real-world Experience With Sunitinib Treatment in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to Risk Score.

ADONIS is an ongoing observational study in 9 European countries, designed to evaluate treatment patterns/outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line sunitinib and/or second-line axitinib post sunitinib. We present an evaluation of sunitinib efficacy by risk group, in the real-world setting examined in ADONIS. Patients were enrolled at the start of first-line sunitinib treatment or second-line axitinib post sunitinib treatment. Evaluation of sunitinib efficacy was assessed by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center risk criteria. For all patients in this analysis (N= 467), the median progression-free survival was 23.8 months (95% confidence interval [CI], 16.5-28.5 months), 11.8 months (95% CI, 8.1-17.4 months), and 4.6 months (95% CI, 2.5-7.7 months) for IMDC favorable-, intermediate-, and poor-risk groups, respectively. The median overall survival was 97.1 months (95% CI, 46.3 months-not evaluable [NE]), 33.5 months (95% CI, 20.5-46.6 months), and 10.0 months (95% CI, 4.5-19.8 months) for the respective risk groups. Data on individual risk factors were available for a subgroup of patients, allowing analysis by intermediate risk by 1 versus 2 risk factors. When including this subgroup (n= 120), the median overall survival for IMDC favorable-, intermediate-1, and intermediate-2 risk factors was 21.6 months (95% CI, 16.3months-NE), 20.5 months (15.5 months-NE), and 15.1 months (4.1 months-NE), respectively. For patients overall and by risk-group stratification, survival estimates were aligned with previously published data. In patients with intermediate-1 risk, overall survival was very similar to patients with favorable risk. However, further exploration of outcome data from different sources is needed to confirm these observations.

Real-world experience with sunitinib treatment in patients with metastatic renal cell carcinoma: Clinical outcome according to risk score.

606 Background: ADONIS, an ongoing, observational study in 9 EU countries, evaluates treatment patterns/outcomes in patients (pts) with metastatic renal cell carcinoma treated with 1st-line (1L) sunitinib (SU) and/or 2nd-line (2L) axitinib (AX) post SU. Analysis of the data is planned in 4 parts, to occur stepwise as data matures; evaluation of SU efficacy in intermediate (INT) risk pts is presented here. Future analyses include sequencing data, SU followed by AX and other treatments (cabozantinib, nivolumab and others); SU and AX therapy management strategies, and quality of life. Methods: Pts enroll at start of 1L SU or 2L AX post SU. Data cutoff: May 31, 2018. Analysis focused on 1L SU. Results: 467 pts, median age 64 y (range 31–90), 77.7% were male, with ECOG PS &lt; 2 = 90.2% and ECOG PS ≥ 2 = 9.8% at SU initiation. Overall median progression-free survival (mPFS) was 10.4 mo (95% CI 9.3–12.5), and median overall survival (mOS) 34.0 mo (95% CI 28.3–46.6). Data on individual risk factors (RF) were available for 120 pts, allowing analysis by INT 1RF and INT 2RF groups for this subset. Clinical trial information: NCT02184416. Conclusions: For pts overall and by risk group stratification, survival estimates were aligned with improvements in clinical practice over the past decade. In pts with INT risk with 1RF, OS was very similar to pts with good risk. However further exploration is needed to confirm these observations.[Table: see text]

Outcome of Restarted Sunitinib Treatment in Patients with Metastatic Renal Cell Carcinoma: a Retrospective Trial and Combined Case Reports from Literature

In practice it is still not clear whether a drug holiday in sunitinib (Su) treatment can be safety, without impairing the overall outcome of patients with metastatic renal cell carcinoma (mRCC). The aim was to retrospectively evaluate the outcome in patients who restarted Su after an interruption of ≥3months and a combined analysis of case studies from literature. From 556 patients treated between January 2006 and March 2016 a group of 38 patients were selected whose treatment was interrupted for other reasons than disease progression. During interruption Su was restarted in case of RECIST-defined progression. The primary objective was the objective response (OR) and progression free survival (PFS) of baseline and restarted therapy. The secondary objective was the overall survival (OS) calculated from the start of baseline treatment. Multivariate survival analysis was also applied. The major causes of interruption were toxicity (39%) and patient' choice (24%). Median duration of interruption was 7 (range 3-41) months. The OR of baseline and restarted treatment was 63% and 39%, respectively. After a median follow-up of 76 (95% CI 65-79) months the median PFS of baseline and restarted treatment was 21 (18-27) and 14 (10-18) months, respectively. The median OS was 61 (56-80) months. In multivariate analysis the lack of OR of restated treatment was an independent predictor of shorter PFS of restarted Su. According to our findings and also on combined case studies from literature restarted Su can be effective in selected cases of patients who progressed during treatment holiday.

PP.27.18] EFFECTS OF SUNITINIB TREATMENT ON PITUITARY-ADRENAL AXIS IN NEOPLASTIC PATIENTS

Objective: Hypertension is a frequent side effect of antiangiogenic treatment with tyrosine kinase inhibitors (TKIs) in neoplastic patients; the pathogenetic mechanism of hypertension, in particular the role of pituitary-adrenal axis, is still controversial. In a clinical study, indeed, increased circulating levels of ACTH and cortisol have been observed during Vandetanib treatment; conversely, adrenal toxicity and necrosis has been documented in experimental animals treated with Sunitinib. In this clinical study we measured blood pressure (BP) and circulating levels of ACTH and cortisol during Sunitinib treatment in patients with metastatic renal cell carcinoma (mRCC). Design and method: In 8 patients with mRCC (M/F 5/3) we performed 24 h Blood Pressure (BP) Monitoring and measured plasma ACTH and cortisol (by radioimmunoassay and electrochemiluminescence immunoassay, respectively) in peripheral venous blood sampled in the morning in supine patients. Hemodynamic and humoral parameters were measured at baseline, after Sunitinib (50 mg/day for 4 weeks, first cycle) and after 2 weeks of recovery. Results: Data are shown as means±SD*p < 0.01 vs baseline Baseline body weight (83.5 ± 12.6 kg) and serum glucose (89.1 ± 10.8 mg/dL) were unchanged after Sunitinib. Conclusions: In front of marked increments of systolic/diastolic BP, plasma ACTH and cortisol levels were not significantly affected by Sunitinib treatment in neoplastic patients. These data do not support an increased glucocorticoid activity as pathogenetic mechanism of Sunitinib-induced hypertension.

Abstract 5219: Characterization of the breast cancer resistance protein BCRP in clear cell renal cell carcinoma

Abstract Introduction: The breast cancer resistance protein BCRP, encoded by ABCG2, is a member of the ABC transporter family and is well-known for its contribution to multi-drug resistance in cancer. Although BCRP expression is altered in various cancer types, its role and function in cancer, independent from drug efflux, remains largely elusive. In this study, we aimed to elucidate regulatory mechanisms of ABCG2 expression and its biological relevance in clear cell renal cell carcinoma (ccRCC) as well as associations with response to sunitinib treatment in patients with metastatic ccRCC. Experimental Procedures: Data from the ccRCC cohort of The Cancer Genome Atlas (TCGA) was used to assess ABCG2 mRNA expression (n=463), DNA methylation (n=288) and genetic variants present in tumor tissue (n=326) within the ABCG2 gene region. An independent ccRCC cohort of 64 patients was used for the analysis of ABCG2 mRNA and protein expression by TaqMan quantitative real time PCR or immunohistochemical staining of TMAs, respectively, and for genotyping of 34 variants in the ABCG2 gene by MALDI-TOF mass spectrometry. The influence of miRNAs on ABCG2 expression was investigated in the second cohort and validated in in vitro cell culture experiments performed in the renal cancer cell line A498 to confirm the interaction of selected miRNAs with the ABCG2 3’UTR. ABCG2 mRNA data and treatment information of a third ccRCC cohort was used to elucidate potential links of ABCG2 with sunitinib response. Results: In the TCGA cohort low ABCG2 mRNA expression was significantly associated with clinicopathological features (T: P=4.79e-11, N: P=9.76e-04, M: P=1.28e-06, G: P=6.61e-15 and tumor necrosis: P=9.76e-04) and with inferior patient survival (HR=0.22; 95%CI: 0.15-0.32; P[logrank]&amp;lt;10e-14). DNA methylation levels within the ABCG2 gene were low and hardly variable in ccRCC patients. Somatic variants were only found in a minority of patients and together with genetic variants had only a moderate influence on ABCG2 expression and patient survival. The link between ABCG2 expression with survival could be confirmed in the second ccRCC cohort. The investigated variants did not significantly affect ABCG2 expression on mRNA or protein level. miR-212-3p and miR-132-3p were identified to be linked to ABCG2 protein expression in ccRCC patients of the second cohort. The interaction of these miRNAs with the ABCG2 3’UTR was confirmed in in vitro cell culture experiments by reporter gene assays. Analysis of a potential association of ABCG2 expression with sunitinib response revealed a better outcome for patients with high ABCG2 levels. Conclusion: In this study, we found that higher ABCG2 expression contributes to longer survival in ccRCC patients and better response to sunitinib treatment. Whereas genetic variants had only a minor impact on ABCG2 variability in ccRCC, epigenetic regulation by miRNAs, in particular miR-212-3p and miR-132-3p, contributed to aberrant ABCG2 expression. Citation Format: Pascale Fisel, Anna Reustle, Olga Renner, Florian Büttner, Stefan Winter, Stephan Kruck, Steffen Rausch, Anne T. Nies, Jörg Hennenlotter, Marcus Scharpf, Falko Fend, Arnulf Stenzl, Jens Bedke, Matthias Schwab, Elke Schaeffeler. Characterization of the breast cancer resistance protein BCRP in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5219. doi:10.1158/1538-7445.AM2017-5219

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 LB-257: The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma

Abstract Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer1-4. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2−ve tumors correlating with poor prognosis5. However, there is no evidence so far of a functional contribution of AT1R to breast tumorigenesis. We explored the potential benefit of ARB use in breast cancer patients and clarified the mechanisms associated with its success. Compared to normal breast, high AT1R expression occurs in 73% of tumors, with &amp;gt;10-fold higher AT1R levels observed in 30% of tumors. We show that therapeutic inhibition of AT1R, with Losartan, results in a significant reduction in tumor burden and no mammary tumor incidence in 20% of animals. We observe a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This is associated with reduced tumor IL-6, pSTAT3 and TNF levels, reduced tumor cell proliferation and de-differentiation. Our data demonstrate that the AT1R is a potential therapeutic target, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.

Metformin Use and Outcome of Sunitinib Treatment in Patients With Diabetes and Metastatic Renal Cell Carcinoma

BackgroundAlthough studies in several cancer types suggest that metformin has antitumor activity, its effect on the outcome of targeted therapies in metastatic renal cell carcinoma (mRCC) is poorly defined. We aimed to analyze the effect of metformin use on the outcome of sunitinib treatment in diabetic patients with mRCC. Patients and MethodsWe performed a retrospective study of diabetic patients with mRCC, who were treated with sunitinib in 8 centers across 2 countries. Patients were divided into metformin users and nonusers. The effect of metformin use on response rate, progression-free survival (PFS), and overall survival (OS), was tested. Furthermore, univariate and multivariate analyses of the association between clinicopathologic factors and metformin use, and outcome were performed using the entire patient cohort. ResultsBetween 2004 and 2014, 108 diabetic patients with mRCC were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The groups were balanced regarding clinicopathologic factors. Clinical benefit (partial response + stable disease) in group 1 versus 2 was 96% versus 84% (P = .054). Median PFS was 15 versus 11.5 months (P = .1). Median OS was 32 versus 21 months (P = .001). In multivariate analyses of the entire patient cohort (n = 108), factors associated with PFS were active smoking and pretreatment neutrophil to lymphocyte ratio > 3. Factors associated with OS were metformin use (hazard ratio, 0.21; P < .0001), Heng risk, active smoking, liver metastases, and pretreatment neutrophil to lymphocyte ratio > 3. ConclusionMetformin might improve the OS of diabetic patients with mRCC who are treated with sunitinib.

The best objective response of target lesions and the incidence of treatment-related hypertension are associated with the survival of patients with metastatic renal cell carcinoma treated with sunitinib: a Japanese retrospective study

BackgroundThe aim of this study is to investigate the prognostic relevance of the best objective response of metastatic target lesions during sunitinib treatment in patients with metastatic renal cell carcinoma.MethodsRadiographic analysis of the best objective response according to the Response Evaluation Criteria in Solid Tumors was assessed in 50 patients. Clinicopathological characteristics including the Heng risk classification and sunitinib-related adverse reactions were compared among four patient subgroups [complete response or partial response (CR/PR), stable disease (SD), progressive disease (PD), and those without treatment evaluation (NE)]. Kaplan–Meier and Cox proportional regression analyses of progression-free survival and overall survival were performed to identify prognostic variables.ResultsThe best objective response was CR/PR in 12 (24 %) patients, SD in 22 (44 %), PD in 6 (12 %), and NE in 10 (20 %). The incidence of hypertension and hypothyroidism was associated with a better objective response. Progression-free survival was 15.0, 9.2, 6.8, and 2.2 months in the CR/PR, SD, PD, and NE groups, respectively (P = 0.0004, log-rank test), while the corresponding median overall survival was 59.7, 24.2, 17.1, and 18.1 months, respectively (P = 0.007). Multivariate analysis revealed that hazard ratios for risk of death of the SD, PD, and NE groups were 4.51 (P = 0.06), 7.93 (P = 0.02), and 4.88 (P = 0.04), respectively, as compared to the CR/PR group.ConclusionsOur findings suggested that the best objective response of target lesions was a prognostic marker for both progression-free survival and overall survival in sunitinib treatment. Furthermore, the incidence of sunitinib-induced hypertension was associated with a longer progression-free survival.

Thyroid Complications of Cancer Therapy: An Increasing Challenge

Thyroid Complications of Cancer Therapy: An Increasing Challenge

Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma

BackgroundThe aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib. Patients and Methods274 patients were treated with sunitinib (50 mg/d, 4-weeks-on and 2-weeks-off schedule). Physical and laboratory evaluations were done every sixth week. AEs were diagnosed at every visit. Clinical response was assessed every 3 months. The objective response rate (ORR), median progression-free (mPFS) and median overall survival (mOS) and AEs were evaluated. Besides χ2 and log rank tests, multivariate Cox regression analysis and for synergism 1-sided t tests were used. ResultsThe ORR was 25%. After a median follow-up of 32 months, the mPFS and mOS were 9 and 19 months, respectively. Hypertension, diarrhea, hypothyroidism, mucositis, hand-foot syndrome (HFS), skin toxicity, and leukopenia were the most frequent treatment-associated AEs. Significantly longer (P < .01) mPFS and mOS were observed when hypertension, diarrhea, HFS, hypothyroidism, skin toxicity, or leukopenia occurred. A statistically significant synergistic effect of the listed AEs was observed for progression-free survival (P < .001) and overall survival (P < .001). Multivariate analysis revealed that besides the prognostic category, the higher number of AEs (3-6 vs. 0-2) was an independent marker of longer mPFS (24 vs. 5 months, respectively; P < .001) and mOS (51 vs. 9 months, respectively; P < .001). ConclusionResults of this study provide evidence for the synergistically enhanced efficacy of sunitinib treatment in patients who present multiple AEs. These AEs are diagnosed routinely and their coexistence can help physicians to predict which group of patients would benefit the most from first-line sunitinib treatment.

O1-5-2 - Temporal Cessation of Sunitinib Treatment in Patients with Metastatic Renal Cell Carcinoma: a Retrospective Study

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

Temporal cessation of sunitinib treatment in patients with metastatic renal cell carcinoma: A retrospective study.

e15552 Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor against vascular endothelial growth factor receptors (VEGFR), platelet derived growth factor receptors and other ...

Impact of rechallenge with imatinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib and sunitinib.

Purpose. This retrospective, nonrandomized study investigated the effect of imatinib rechallenge plus best supportive care (BSC) on overall survival after imatinib and sunitinib treatment for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST). Methods. Twenty-six patients who had previously been exposed to both imatinib and sunitinib were enrolled in this study. The treatment regimen was BSC with or without imatinib, based on the patient's choice after discussion with his or her physician. The primary endpoint was overall survival, and secondary endpoints were time to treatment failure, clinical response rate assessed by Choi criteria, and safety. Results. Fourteen patients were treated with imatinib plus BSC and 12 received BSC alone. Median overall survival was greatly improved for the imatinib group, although differences were not significant (22 months for imatinib plus BSC versus 4 months for BSC; P = 0.058). Three patients (21%) had a clinical response in the imatinib group, and one had a clinical response in the BSC alone group. Imatinib was well tolerated. Conclusions. Rechallenge with imatinib may be associated with improvement in overall survival without deteriorating performance status in patients who failed imatinib and sunitinib. A prospective study should be considered to confirm the efficacy of rechallenge with imatinib.

870 - Compliance with Sunitinib Treatment in Patients with Renal Cell Cancer

ABSTRACT Introduction Sunitinib (SUN) is one of the standard treatment options for metastatic renal cell cancer (mRCC). There are several possible reasons for non-compliance to the prescribed doses: oral intake of the drug, side effects and the existence of multiple dosage forms. Prescribers are not always aware of this non-compliance. Methods In Belgium SUN can only be delivered by the hospital pharmacy. This allows calculation of the used versus the prescribed dose. Based on these data, the minimum number of non-compliant weeks per patient were calculated. Results 34 incident patients were considered, treated in the Ghent University Hospital between 2007–2012. The total number of treatment weeks for this patient group was 1079 (ranging between 1 and 108 weeks). A total of 850 weeks were suitable for analysis. 14 out of these 34 patients (41.2%) had at least one week in their treatment period of non-compliance (insufficient number of pills), with the percentage of time of treatment non-compliance in these individual patients ranging from 2–40 % of the total treatment time, the average being 19 % of the weeks. The group with one or more weeks of non-compliance were the patients with the longest SUN intake: 47.2 versus 20.8 months of intake. On the other hand 5/34 patients (14.7%) received considerably more pills from the pharmacy than their treatment regimen warranted. Conclusions In our single-center database of patients treated by SUN for mRCC, we demonstrated that over 40% of the patients were possibly non-compliant with their prescribed SUN dose. This occurred more frequently in long-term treatment. Given the average non-compliance time in this subgroup (19% of the weeks) we can conclude that this might significantly influence overall survival and response to treatment. We thus advocate a tighter patient follow-up and a control of drug prescription and delivery, which could result in detection of non-compliance more rapidly. Disclosure S. Rottey: Advisory board Pfizer, Novartis, Bayer, GSK Research grant Pfizer, Bayer. All other authors have declared no conflicts of interest.