Neoadjuvant Sunitinib Research Articles

Neoadjuvant sunitinib plus exemestane in post-menopausal women with hormone receptor-positive/HER2-negative early-stage breast cancer (SUT_EXE-08): a phase I/II trial

Neoadjuvant endocrine therapy (NET) for hormone receptor-positive (HR+) breast cancer might be as effective as chemotherapy, with a better toxicity profile. Blocking a crucial process such as angiogenesis with sunitinib may have a synergistic effect with NET. We aimed to assess the efficacy and safety of neoadjuvant sunitinib plus exemestane in early-stage HR+/HER2-negative breast cancer. In this phase I/II study, postmenopausal women with HR+/HER2− stage II-III breast cancer received neoadjuvant exemestane at conventional dose of 25mg plus sunitinib in a 3 + 3 design at 25mg (3/1weeks scheme) or 37.5mg continuous dose, for 6 months. Coprimary endpoints were the recommended dose of sunitinib combined with exemestane and objective response. Secondary endpoints included safety and biomarkers of early response. For 15 months, 18 patients were enrolled, 15 at sunitinib 25mg and 3 at 37.5mg. Median age was 73, 77% of patients had T2 tumors and 67% node-positive disease. The most common grade 2 toxicity was asthenia (44%), as was hypertension (22%) for grade 3. No grade 4–5 were reported. Twelve patients (66%) achieved an objective response. VEGFR-2 levels significantly decreased after one month of treatment. Differential gene expression analysis showed downregulation of ESR1, PGR and NAT1 in post-treatment samples and upregulation of EGFR, MYC, SFRP1, and FOXC1. PAM50 analysis on 83% of patients showed a prevalence of luminal A subtype, both in pre-treatment (63.6%) and post-treatment tumors (54.5%). Sunitinib plus exemestane was associated with substantial yet reversible toxicities, providing safety, efficacy and biological impact insights of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer.Trial registration: Registered with ClinicalTrials.gov, NCT00931450. 02/07/2009

Monitoring efficacy of neoadjuvant sunitinib in metastatic renal cell carcinoma using a personalized and tumor informed ctDNA assay.

4525 Background: Approximately 30% of renal cell carcinoma (RCC) cases present as stage IV at the time of diagnosis. Metastatic RCC (mRCC) is associated with poor outcomes, with a five-year survival rate below 50%. Tools to evaluate the efficacy of novel systemic regimens are needed. Biomarkers like ctDNA can accurately and non-invasively assess molecular residual disease (MRD) in response to therapy and monitor disease status over time to predict disease progression. Here, we aimed to determine the feasibility of performing personalized and tumor-informed ctDNA testing in mRCC patients enrolled on a study integrating systemic therapy with surgical cytoreduction, as well as to measure patient response to sunitinib by assessing ctDNA dynamics. Methods: We analyzed a cohort of 21 mRCC patients with median age of 59.5 (43-76) years who were treated with sunitinib, and had planned cytoreductive nephrectomy during their second cycle of therapy. Baseline and post-first cycle ctDNA levels were measured using a personalized and tumor-informed ctDNA assay (SignateraTM bespoke mPCR NGS assay). Changes in ctDNA levels from baseline to the best response time point were correlated with disease status as assessed by radiological imaging. Results: In this cohort, baseline ctDNA was detected in 81% (17/21) of patients, with higher ctDNA concentrations observed in patients who presented with multiple distant metastases (n = 11) compared to the 10 cases with a single metastatic mass (median 5.8 vs 1.3 mean tumor molecules/mL, not statistically significant). Of those with baseline ctDNA measurement, 12% (2/17) cleared their ctDNA, 24% (4/17) had a decrease in ctDNA, and 59% (10/17) had an increase in ctDNA after 4 weeks of sunitinib. During the course of treatment, patients whose ctDNA concentration increased from baseline were more likely to experience a disease progression (HR: 3.9 95% CI 1.13-13.7; p = 0.032) compared to those whose ctDNA decreased. In addition, higher ctDNA concentration before surgery after initial treatment with sunitinib correlated with shorter time to progression (p = 0.04). Conclusions: Our results demonstrate the feasibility and prognostic value of personalized and tumor-informed ctDNA testing for determining response to systemic therapy in patients with mRCC. Early signs of unfavorable ctDNA kinetics can provide rationale for modification of systemic therapy in order to enhance response. Future work exploring the clinical utility of ctDNA testing in larger mRCC cohorts is warranted.

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. EudraCtNo: 2005-004502-82.

A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer

IntroductionNeoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. MethodsWe conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). ResultsSeventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. ConclusionsNeoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.

Vascularization, Oxygenation, and the Effect of Sunitinib Treatment in Pancreatic Ductal Adenocarcinoma Xenografts.

The purpose of the study was to investigate vascularization, oxygenation, and the effect of sunitinib treatment in pancreatic ductal adenocarcinoma (PDAC). BxPC-3 and Capan-2 xenografts grown in dorsal window chambers were used as preclinical models of human PDAC. Tumor angiogenesis and the morphology and function of tumor vascular networks were studied by intravital microscopy, and tumor hypoxia was assessed by immunohistochemistry. The PDAC models differed in vessel distribution and oxygenation, and the differences were induced by the initial tumor angiogenesis. In both models, sunitinib treatment reduced intratumor and peritumor vessel densities by selectively removing small-diameter vessels. Sunitinb treatment resulted in a general decrease in vessel density and scattered hypoxia in BxPC-3 tumors, and depleted most vessels and induced massive hypoxia in central parts of Capan-2 tumors. The study demonstrates that PDAC xenografts can differ in vascularization, and the differences can impact oxygenation and effects of treatment. Neoadjuvant sunitinib treatment is inappropriate in combination with conventional therapy for human PDACs resembling the PDAC xenografts used here, because sunitinib-induced hypoxia can impair the effect of most conventional therapies.

Neoadjuvant Sunitinib Decreases Inferior Vena Caval Thrombus Size and Is Associated With Improved Oncologic Outcomes: A Multicenter Comparative Analysis.

We analyzed outcomes of neoadjuvant sunitinib in patients with renal-cell carcinoma (RCC) and inferior vena caval (IVC) tumor and compared outcomes to patients who did not undergo neoadjuvant therapy before surgery. We performed a multicenter retrospective comparison of RCC patients with IVC tumor who underwent neoadjuvant sunitinib before surgery versus those who did not. Response to sunitinib was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Primary outcome was cancer-specific survival. Secondary outcomes included overall survival. Multivariate analysis was performed to identify risk factors associated with primary and secondary outcomes. Kaplan-Meier analysis compared survival in neoadjuvant and primary surgery groups. Data of 53 patients were analyzed (19 neoadjuvant sunitinib, 34 primary surgery; median follow-up, 58 months). Eighteen (9 in each group, P= .143) had metastatic RCC. There was no difference in IVC tumor level between the 2 groups (P= .76). After neoadjuvant sunitinib, median primary tumor decreased size from 8.1 to 6.8 cm, and IVC tumor decreased by 1.3 cm. IVC tumor level decreased in 8 (42.1%) of 19 and was stable in 10 (52.6%) of 19; 5 (26.3%) of 19 experienced partial response. Similar proportions of patients underwent robot-assisted or minimally invasive approaches (P= .351), and no differences were noted in complications (P= .194). Multivariate analysis showed neoadjuvant sunitinib was associated with improved cancer-specific survival (odds ratio= 3.28; P= .021). Kaplan-Meier analysis demonstrated significantly longer median cancer-specific survival (72 vs. 38 months, P= .023) for neoadjuvant sunitinib. Neoadjuvant sunitinib was associated with a reduction in primary tumor and thrombus size as well as improved survival. Further investigation is needed to determine the utility of neoadjuvant sunitinib in RCC with IVC tumor.

A phase II clinical study evaluating the efficacy and safety of neoadjuvant and adjuvant sunitinib in previously untreated patients with metastatic renal cell carcinoma (mRCC)(NeoSun).

e16087 Background: Sunitinib improves clinical outcomes in patients (pts) with mRCC. The single arm phase II NeoSun trial was designed to investigate its added value to nephrectomy, and to explore translational biological and imaging biomarkers. Methods: Pts with mRCC, scheduled for nephrectomy, no prior systemic therapy were recruited to receive 50mg OD sunitinib for 12 days, then post-surgery on a 4 week-on, 2 week-off, repeating 6 week cycle until disease progression. Diffusion-weighted, BOLD and dynamic contrast enhanced MR imaging (DW-MRI, DCE-MRI) and research blood sample collection were performed at baseline and end of 12 days. CT Imaging was performed at baseline, pre- and post-surgery, and then every 2 cycles. The primary endpoint was objective response rate (RECIST). Secondary endpoints included changes in diffusion DW-MRI, DCE- MRI of the tumour following 12 days suntinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Results: 14 pts received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All 14 underwent total nephrectomy, and 13 recommenced sunitinib post-operatively. The mean number of post-surgery cycles was 11 (range 2 – 22). 58.3% (7/12) of pts achieved confirmed response (95% CI: 27.7 - 84.8%).91.7% (11/12) achieved objective clinical benefit (95% CI: 61.5 - 99.8%). Median OS is 33.7m and median PFS is 15.7m. Amongst those achieving PR/CR, median response duration is 8.7m. No unexpected surgical or sunitinib-related toxicities or complications were observed and the mean number of days from surgery to hospital discharge was 5.9 (range 3.0 – 17.0).There was a trend forOS to be better in pts with high baseline plasma VEGF-A (p = 0.06) or VEGF-C (p = 0.02) expression. A larger % tumour volume reduction after 12 days treatment is correlated with a smaller baseline % necrosis (coefficient = -0.51, p = 0.03). Conclusions: Sunitinib is effective and safe when given before and after nephrectomy to previously untreated pts with mRCC. Neoadjuvant studies such as NeoSun can safely explore translational biological and imaging endpoints. Clinical trial information: 2005-004502-82.

Gene expression profile of renal cell carcinomas after neoadjuvant treatment with sunitinib: new pathways revealed.

In renal cell carcinoma (RCC) of the clear cell type, inactivity of the VHL gene induces overexpression of HIF1 α and its targets, the tyrosine kinase receptors, promoting RCC development and progression. The discovery of tyrosine kinase inhibitors (TKIs) changed the treatment of these tumors. Other molecular pathways involved in the TKI mechanisms of action have not been described in the literature. The aim of our study was to elucidate alternative mechanisms of action of sunitinib in tumor tissue after neoadjuvant treatment of RCC. The gene expression profile was accessed using microarray (Affymetrix Human Genome U133 Plus 2.0 platform) and frozen RCC tissues collected from 5 patients with locally advanced non-metastatic tumors who underwent nephrectomy after being treated with 2 cycles of neoadjuvant sunitinib. The results were compared with matched controls comprising 6 patients with no neoadjuvant intervention. There was underexpression of the majority of genes after sunitinib treatment. The lower expression levels of IGFBP1, CCL20, CXCL6 and FGB were confirmed by qRT-PCR in all cases. The downregulation of gene expression leads us to search for methylation as a mechanism of action of the TKI. IGFBP1 was shown to be methylated by methylation-sensitive high-resolution melting technique. The ultimate genetic effects of sunitinib may explain its actions as an antitumor drug that apparently suppresses the expression of important genes related to cell survival, adhesion, invasion and immunomodulation. The methylation of gene promoters was shown to be part of the mechanism of action of this class of drugs.

Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma.

The development of targeted agents has expanded the anticancer arsenal available to oncologists and revolutionized the field of cancer treatment. In patients with advanced renal cell carcinoma (RCC), small molecule targeted therapies have improved clinical outcomes compared with cytokine-based treatments. Sunitinib malate is one such drug that has demonstrated clinical efficacy in patients with metastatic renal cell carcinoma (mRCC). This oral, multi-targeted tyrosine kinase inhibitor is approved for use in multiple countries for the treatment of advanced RCC and gastrointestinal stromal tumor patients who have progressed on imatinib therapy. In patients with advanced RCC, sunitinib significantly improves clinical outcomes with a favorable safety profile compared with conventional treatment with interferon-a. The clinically proven treatment and safety outcomes have led investigators to evaluate the merits of sunitinib therapy in the adjuvant and neoadjuvant setting in patients with mRCC. In the neoadjuvant setting, preliminary data suggest that sunitinib can effectively reduce the primary tumor and facilitate surgical resection in patients with locally advanced and mRCC. Post-operative complications were observed in some patients, but the overall safety profile and efficacy suggests that mRCC patients with surgically inoperable tumors may benefit from neoadjuvant sunitinib therapy. Ongoing clinical trials should provide insight into the value of sunitinib as adjuvant therapy.

223 Predictive biomarkers in metastatic Renal Cell Carcinoma (mRCC) patients treated with neoadjuvant sunitinib (PREINSUT trial)

223 Predictive biomarkers in metastatic Renal Cell Carcinoma (mRCC) patients treated with neoadjuvant sunitinib (PREINSUT trial)

Abstract 4127: Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks

Abstract Preclinical and clinical studies have suggested that stopping antiangiogenic therapy may lead to rapid revascularization and rebound tumor growth in certain instances. However, the implications for these findings remain unclear. It is possible that treatment rebounds may impact disease progression following neoadjuvant therapy, where drugs are administered for short periods and then halted prior to surgical removal of a primary tumor. Indeed, recent retrospective clinical studies have suggested that neoadjuvant antiangiogenic treatment discontinuation increases vascular proliferation and, in turn, might increase post-surgical disease progression and metastasis. However, this hypothesis has not been studied experimentally in clinically relevant mouse models of metastatic disease. We examined the effect of treatment discontinuation in the neoadjuvant setting using approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) such as sunitinib. Our studies utilized models of spontaneous metastatic breast, melanoma, and kidney cancer following surgical removal of orthotopically grown primary tumors. Neoadjuvant sunitinib treatment periods were 14 days in duration (60 mg/kg) with treatment breaks of 0, 3, 7, and 11 days compared. Pre-surgical molecular and cellular biomarkers were investigated as potential surrogates for post-surgical metastatic disease progression. These included tumor and vascular cell Ki67 and CD31 expression, as well as circulating tumor cells (CTCs) and myeloid derived suppressor cells (MDSCs). Our results show that VEGF RTKI neoadjuvant treatment benefits observed pre-surgically (such as reduction in primary tumor growth) did not consistently correlate with post-surgical survival and reduced metastatic recurrence. The addition of treatment breaks prior to surgery had positive or negative impact on post-surgical survival depending on the tumor model used. Interestingly, high-dose bolus (3 day) neoadjuvant sunitinib (120 mg/kg) treatment consistently improved post-surgical benefits when compared to sustained treatments, despite gaps in therapy. Finally, our results show that tumoral CD31+/Ki67+ cells, CTCs, and MDSCs may serve as surrogate markers of metastatic potential and predict the impact of treatment cessation on disease recurrence. Citation Format: Michalis Mastri, Amanda Tracz, Li Shen, Roberto Pili, John M.L. Ebos. Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2015-4127

853P - Prediction of Response of Primary Tumors to Neoadjuvant Sunitinib Using Perfusion (Dce) Computed Tomography (Ct) in Metastatic Renal Cell Carcinoma (Mrcc) Patients (Preinsut Trial)

ABSTRACT Aim: Sunitinib is approved in 1st line for mRCC patients, but the prognosis remains poor with a median PFS of 11 months and an overall survival of 2-3 years. Determination of predictive biomarkers of response to sunitinib is urgently needed. The PREINSUT trial was conducted to determine biological, pathological and imaging markers for a neoadjuvant sunitinib in mRCC patients prior to nephrectomy. The perfusion imaging sub-analysis is presented here. Methods: Thirty-three patients were included to assess the efficacy of 2 cycles of neoadjuvant sunitinib (50mg, 4weeks/6) before nephrectomy. DCE scans were performed at baseline and at the end of the 4 weeks of the 1st cycle of sunitinib. The following perfusion parameters were calculated in the primary renal tumor and correlated to the response in size at the end of the neoadjuvant therapy: tissue blood flow (Ft), tissue blood volume (Vt), permeability surface coefficient (PS), area under the enhancement curve at 60s (AUC). Patients were considered responders if there was a decrease ≥ 10 % of the renal tumor size. Perfusion parameters were compared between responders and non-responders using a Mann-Whitney test and correlated to changes in size using the Spearman correlation (r). Results: Nineteen patients were eligible for the DCE imaging analysis. Mean baseline values of Ft, Vt, PS and AUC were 212 ± 136 mL/min/100mL, 29 ± 13%, 8.3 ± 4.2 mL/min/100mL, and 0.4 ± 0.2, respectively. There was a negative correlation between baseline values of Ft and the response in size (r = -0.54, p = 0.04), PS (r = -0.53, p = 0.04). Responders (N = 7) had a larger decrease in AUC between baseline and 4 weeks than non-responders (N = 12) (-39.2% vs 6.0%, p = 0.04). There was a positive correlation between size response and both PS (r = 0.62, p = 0.02), and AUC changes (r = 0.65, p = 0.02). Blood volume was negatively correlated, moderately but significantly, to plasmatic VEGF levels (r = -0.36, p = 0.01). Conclusions: Perfusion CT parameters measured on baseline and early changes (4 weeks) after neoadjuvant sunitinib therapy were predictive of the final 3-months response of the renal tumor. We demonstrate in this study that the higher the tumor perfusion and permeability, the greater the reduction in size of the primary renal tumor. Disclosure: Y. Vano: Honoraria from: Pfizer, Novartis, GSK, Sanofi, Astellas, Sandoz, Teva; S. Oudard: Consultant or Advisory Role: Sanofi, Novartis, Roche, Bayer, Keocyt, Amgen, Honoraria: Sanofi, Novartis, Roche, Bayer, Keocyt, Amgen, Pfizer. All other authors have declared no conflicts of interest.

Diffusion-weighted and multiphase contrast-enhanced MRI as surrogate markers of response to neoadjuvant sunitinib in metastatic renal cell carcinoma

Background:Current imaging criteria for categorising disease response in metastatic renal cell carcinoma (mRCC) correlate poorly with overall survival (OS) in patients on anti-angiogenic therapies. We prospectively assess diffusion-weighted and multiphase contrast-enhanced (MCE) MR imaging (MRI) as markers of outcome.Methods:Treatment-naive mRCC patients on a phase II trial using sunitinib completed an MRI substudy. Whole-tumour apparent diffusion coefficient (ADC) maps and histograms were generated, and mean ADC and AUClow (proportion of the tumour with ADC values lying below the 25th percentile of the ADC histogram) recorded. On MCE-MRI, regions of interest were drawn around the most avidly enhancing components to analyse enhancement parameters. Baseline (n=26) and treatment-related changes in surviving patients (n=20) were correlated with OS. Imaged metastases were also analysed.Results:Forty-seven per cent of the patients showed significant changes in whole-tumour mean ADC following therapy, but there was no correlation with outcome. Patients with a high baseline AUClow and greater-than-median AUClow increase had reduced OS (HR=3.67 (95% confidence interval (CI)=1.23–10.9), P=0.012 and HR=3.72 (95% CI=0.98–14.21), P=0.038, respectively). There was no correlation between MCE-MRI parameters and OS. Twenty-eight metastases were analysed and showed positive correlation with primary tumour mean ADC for individual patients (r=0.607; P<0.001).Conclusion:Primary RCC ADC histogram analysis shows dynamic changes with sunitinib. Patients in whom the tumour ADC histogram demonstrated high baseline AUClow or a greater-than-median increase in AUClow with treatment had reduced OS.

Computed Tomography Characteristics of Unresectable Primary Renal Cell Carcinoma Treated With Neoadjuvant Sunitinib

IntroductionIn patients with locally advanced and metastatic RCC, selection criteria for nephrectomy are imprecise. Neoadjuvant sunitinib might downsize unresectable tumors and enable nephrectomy. CT scans of unresectable primary RCCs before and after neoadjuvant sunitinib were retrospectively reviewed to identify radiographic features associated with patient selection for surgery. Patients and MethodsCT scans of 27 patients with RCC (31 tumors) treated with neoadjuvant sunitinib were performed as part of a prospective clinical trial. After neoadjuvant sunitinib, tumors were surgically resected in 13 patients (17 tumors) and not resected in 14 patients (14 tumors). Response to treatment with sunitinib was assessed with Response Evaluation Criteria in Solid Tumors and MASS criteria. ResultsOn the contrast-enhanced CT scan before nephrectomy compared with the baseline CT scan, 88% of resected tumors demonstrated decreased size (median decrease 26%; −2.0 cm; P < .001), 88% had decreased attenuation (median decrease 30%; −27 Hounsfield units; P = .004), and 76% had increased necrosis (P < .001). Response to sunitinib was significantly more favorable (according to MASS criteria) in resected than in nonresected tumors (P = .005). In addition, the degree of baseline necrosis was less in tumors subsequently resected than in nonresected tumors (P = .05). Multivariate analysis showed that higher tumor attenuation after 2 cycles of sunitinib therapy and a favorable response (MASS criteria) after 2 cycles of sunitinib therapy were independent predictors of subsequent tumor resection. ConclusionIn unresectable primary RCC tumors, changes in select CT parameters after 2 cycles of neoadjuvant sunitinib might be associated with the potential for surgical resection.

Multiple metastatic renal cell carcinoma treated with cytoreductive nephrectomy after neoadjuvant Sunitinib therapy: a case report and literature review

Objective To report a multiple metastatic renal cell carcinoma (RCC) case successfully treated with cytoreductive nephrectomy after neoadjuvant Sunitinib,and discuss the efficacy and treatment regime of neoadjuvant targeting therapy.Methods A 51 years man presented with painless gross hematuria for one week and admitted into our hospital in August 2010.Abdominal CT demonstrated a 6.6 cm ×6.3 cm left lower pole renal tumor associated with renal vein tumor thrombus,bulky hilar lymph nodes and extensive local invasion.The patient was also found to have lung and right tibial metastasis.The clinical stage was T3bN1 M1.Percutaneous biopsy confirmed clear cell renal carcinoma.Neoadjuvant Sunitinib 50 mg daily was administered with 4 weeks on,2 weeks off schedule for two cycles.Cytoreductive nephrectomy was preformed 2 weeks after discontinuation of neoadjuvant Sunitinib.Imaging evaluation was performed to assess the primary tumor and metastatic sites.The patient was followed up till present.Results After two cycles of neoadjuvant treatment,CT scan revealed 23％ size reduction of left renal tumor to 5.1 cm ×4.4 cm,renal vein tumor thrombus regression,local perirenal invasion improvement,lung metastasis resolution and static right tibial metastasis.According to RECIST criteria,the objective response was stabilization of disease (SD).Cytoreductive nephrectomy was successfully performed to remove the primary tumor in December 2010.Pathology revealed Fuhrman Ⅱ renal cell carcinoma with major necrosis in primary tumor and thrombus localized in renal vein.During 6 months of post-operative follow-up,there was no local recurrence,lung metastasis had vanished completely and tibial metastasis had not progressed.Local recurrence and other distant metastasis were not demonstrated in 20mon follow-up till now.Disease control of this patient was partial response (PR) by RECIST.Conclusions Neoadjuvant Sunitinib treatment could result in downstaging of primary tumor and facilitate cytoreductive nephrectomy,thus eventually increase patient overall survival. Key words: Metastatic renal cell carcinoma; Neoadjuvant therapy; Sunitinib; Cytoreductive nephrectomy

Reply

Our study affirms the role of cytoreductive nephrectomy (CRN) in the setting of multimodal treatment of metastatic renal cell carcinoma (mRCC) in the targeted-therapy era. Indeed, although complete resection of metastatic disease at presentation may still represent the best approach in selected patients, 1 Alt A.L. Boorjian S.A. Lohse C.M. et al. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011; 117: 2873-2882 Crossref PubMed Scopus (290) Google Scholar our study lends further support to a strategy that incorporates an up-front antiangiogenic challenge to patients with mRCC who are not amenable to a combination of CRN and complete metastectomy, the benefit of which is to avoid unnecessary surgery in patients with progressive metastatic disease. 2 Wood C.G. Margulis V. Neoadjuvant (presurgical) therapy for renal cell carcinoma: a new treatment paradigm for locally advanced and metastatic disease. Cancer. 2009; 115: 2355-2360 Crossref PubMed Scopus (57) Google Scholar This strategy is not without risk however, and the significant degree of toxicity associated with targeted agents, the potential for treatment-related delays and surgical morbidity, and the paucity 3 Hellenthal J. Underwood W. Penetrante R. et al. Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma. J Urol. 2010; 184: 859-864 Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar of high-level evidence supporting the approach are legitimate concerns. We look forward to the results of ongoing randomized trials being conducted by European Organisation for Research and Treatment of Cancer and the Assistance Publique-Hôpitaux de Paris, which should provide further insight regarding timing of CRN and systemic therapy, 4 Haanen JBAG, Bex A. European Organization for Research and Treatment of Cancer - EORTC. Randomized phase III trial comparing immediate versus deferred nephrectomy in patients with synchronous metastatic renal cell carcinoma. NLM Identifier: NCT01099423. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Available at: http://clinicaltrials.gov/ct2/show/NCT01099423. Accessed July 22, 2012. Google Scholar , 5 Mejean A. Assistance Publique - Hôpitaux de Paris; Pfizer. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA). NLM Identifier: NCT00930033. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Available at: http://clinicaltrials.gov/ct2/show/NCT00930033. Accessed July 22, 2012. Google Scholar and we call for further randomized prospective investigation to evaluate the role of CRN and optimal agents(s) for primary targeted therapy for mRCC. Editorial CommentUrologyVol. 81Issue 4PreviewThis retrospective outcome analysis in a relatively small cohort of patients shows that patients with metastatic clear cell renal cell carcinoma (RCC), treated with neoadjuvant sunitinib tyrosine kinase inhibitor (TKI) therapy, followed by cytoreductive nephrectomy (CRN), fared significantly better than those treated with by CRN, followed by adjuvant TKI therapy, whereas patients who received TKI without CRN had a very grim outcome. Specifically, they observed that responders to neoadjuvant TKI therapy who underwent CRN had better disease-specific survival and overall survival than patients who underwent CRN, followed by adjuvant TKI therapy. Full-Text PDF

Abstract P1-14-14: Neoadjuvant Sunitinib (S) Administered with Weekly Paclitaxel (P)/Carboplatin(C) in Patients (Pts) with Locally Advanced Triple-Negative Breast Cancer (TNBC): Preliminary Results from a Phase I/II Trial of the Sarah Cannon Research Institute.

Abstract Background: S is an oral, small molecule, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, stem cell factor receptor, and colony-stimulating factor-1 receptor with demonstrated single agent activity in multiple tumor types including breast cancer. S's anti-proliferative and anti-angiogenic activity stimulated interest in combining it with a variety of chemotherapy regimens. In the previously reported Phase I portion of this trial, S 25mg PO daily was determined feasible in combination with weekly P and C, an active regimen for TNBC. We now report the feasibility and efficacy of the phase II evaluation of this combination as neoadjuvant therapy with pathologic complete response (pCR) as the primary endpoint. Methods: Eligibility criteria included: invasive adenocarcinoma, triple negative histology defined as ER/ PR negative (&amp;lt;10% IHC staining) as well as HER2-negative (IHC 0–1+ or FISH neg), clinical T1-3, N0-1, M0 with clinical N3, T4 and T1 N0 M0 tumors excluded, ECOG PS 0–2, normal LVEF, and adequate organ function. All pts received P 70mg/m2 (Days 1, 8, 15) + C AUC=5 (Day 1) with S 25mg PO daily q 28 days for 6 cycles. Response assessments were performed after 3 cycles, and in the absence of disease progression or unacceptable toxicity, study treatment continued for 3 additional cycles. Postoperatively, pts resumed S 25 mg qd until 52 weeks from D1. Definition of pCR was an absence of invasive cancer in both breast and lymph nodes. A pCR rate of ≥ 30% would warrant additional evaluation of this regimen. Results: The phase II portion of this trial enrolled 36 pts from 2/2011 to present. This analysis is based on 22 pts evaluable for toxicity and efficacy. Median tumor size was 4 cm with 68% designated T2 and 27% as T3 and 63% with clinical N1 or N2 disease. A median of 3 preoperative cycles was delivered. Best clinical response was; cCR − 1 (5%), cPR − 9 (41%), cSD − 6 (27%), PD − 1 (5%), UE − 5 (22%). Pathologic responses are as follows: ypCR −2 pts (9%), PR2 (residual invasive cancer in breast, negative lymph nodes −1 pt, PR3 (residual invasive cancer in breast and lymph nodes) −1 pt. 3 pts of the 4 with surgical outcomes completed all 6 cycles of treatment; 2 of which had pCR. Poor tolerance/toxicity resulted in 8 pts proceeding to surgery early/or discontinuation and 2 pts experienced progression; data is pending in 8 pts. Grade 3/4 hematologic toxicity consisted of neutropenia-15 pts (68%) with fever in 2 (9%), anemia −9 pts (41%), and thrombocytopenia-8 pts (36%). No G3/4 non-hematologic toxicity was present in &amp;gt;5% of pts. Conclusions: The addition of sunitinib to paclitaxel and carboplatin was accompanied by significant hematologic toxicity resulting in the inability to deliver the planned study therapy. Treatment discontinuations were frequent as was the need for dose adjustments and modifications. The sunitinib-paclitaxel/carboplatin combination evaluated in this study is not recommended for further use in locally advanced breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-14.

The association between the treatment-induced hypertension (Htn) and response to neoadjuvant sunitinib in renal cell carcinoma (RCC).

e15095 Background: Prior studies have shown that development of htn, which is an on-target side effect of VEGF inhibition, is a potential biomarker for response to sunitinib in patients with metastatic RCC. The association of htn with response to neoadjuvant sunitinib was evaluated from a completed phase II trial. Methods: Patients with initially unresectable RCC were treated with sunitinib 50 mg daily until surgical eligibility or disease progression / toxicity. Htn was defined as SBP &gt;=140mm and/or DBP &gt;= 90mm while on sunitinib. Fisher’s exact test was used to assess associations between htn and clinical outcome. Results: Twenty-nine patients with unresectable RCC (72% male; 76% clear cell histology; median age 61 years (range 37-80)) were enrolled. One patient withdrew consent and was excluded from subsequent analysis. Overall, 78% of patients had primary tumor shrinkage, 57% became eligible for surgery based on primary tumor change in the opinion of the treating urologic surgeon, 50% underwent surgery and 57% developed htn. Patients who had primary tumor shrinkage had a non-significantly higher incidence of htn compared to patients who did not have primary tumor shrinkage (77% vs. 50%; p=0.31). Patients who became surgically resectable after sunitinib, however, had significantly more htn than patients who did not attain eligibility for surgery (88% vs. 45% p=0.03). Similar results were seen when the analysis was restricted to patients with clear cell histology tumors (n=20, p=1.0 and 0.06 respectively). Conclusions: There is a significant positive association between the incidence of htn and the ability of neoadjuvant sunitinib to affect surgical eligibility in patients with unresectable RCC.

Performing Cytoreductive Nephrectomy following Targeted Sunitinib Therapy for Metastatic Renal Cell Carcinoma: A Surgical Perspective

Objective: To describe for surgeons contemplating performing cytoreductive nephrectomy (CRN) on patients after neoadjuvant sunitinib compared to a benchmark of open radical nephrectomy, describing technical difficulties, safety and feasibility. Patients and Methods: We compared measurable surgical parameters and perioperative complications in 22 patients with metastatic renal cell carcinoma (mRCC) undergoing CRN after neoadjuvant sunitinib, with 28 patients who underwent open radical nephrectomy for non-metastatic disease (nmRCC). Results: Median blood loss (320 vs. 775 ml), median operative time (128 vs. 195 min) and median length of stay (5 vs. 7 days) were greater in the mRCC group. Surgery after sunitinib was technically challenging due to fibrosis, loss of the tissue planes that usually facilitate radical nephrectomy and abnormal blood vessel formation. Side effects of sunitinib resulted in predictable complications. Conclusion: CRN after treatment with sunitinib is safe and feasible in our hands, although the surgery is more time-consuming and technically demanding. A multidisciplinary approach is mandatory.

Proteomic analysis of pre- and post-sunitinib treated renal cancer tissue to assess tumor heterogeneity and differential protein expression.

388 Background: To investigate acquired resistance of clear cell renal cell cancer (ccRCC) patients to sunitinib and develop personalised treatment strategies, sequential tissue after a specific period of targeted therapy is required. This approach has proven successful with targeted therapy in chronic myeloid leukaemia; however, we are concerned that extensive tumour heterogeneity occurs in ccRCC. In this study we evaluated heterogeneity and differential protein expression in sunitinib treated and untreated ccRCC samples using high-throughput proteomics. Methods: Fresh frozen tissue was obtained from 27 sunitinib naïve ccRCC specimens and 27 nephrectomy samples from patients treated with neoadjuvant sunitinib (18 weeks) as part of the SuMR trial. From each tumour frozen sections were performed and up to 5 protein lysates obtained from each morphologically differing region of each tumour as well as matched normal kidney. Reverse phase protein arrays (RPPA) were performed to assess the levels of multiple proteins relevant to ccRCC pathogenesis and sunitinib activity. Appropriate statistical tests were used to examine protein heterogeneity and differential expression, including false discovery rate (FDR) correction. Kaplan-Meier method was used to correlate changes in protein expression with outcome. Results: Expression of 20 proteins has been examined to date. The range of expression in tumours normalised by matched normal renal tissue had &gt;2-fold differences in untreated (n=8 proteins) and treated samples (n=4 proteins). Four markers displayed significantly increased inter-tumoural variance in sunitinib treated tumours compared with untreated tissue (e.g. VEGFR1, FDR P&lt;0.05). Despite this heterogeneity, sunitinib was associated with significant expression changes for several key proteins (e.g. VEGFR2, CyclinD2; FDR P&lt;0.05). Conclusions: Protein expression in ccRCC is heterogenous and key proteins showed significantly increased variance of expression with sunitinib therapy. Despite heterogeneity, significant changes in protein expression can be identified with sunitinib treatment and have been correlated with outcome.