Metastatic Renal Cancer Patients Research Articles

A novel prognostic predictor of immune microenvironment and therapeutic response in clear cell renal cell carcinoma based on angiogenesis–immune-related gene signature

BackgroundClear cell renal cell carcinoma (ccRCC), the most common type of RCC, typically produces no symptoms initially. Patients with ccRCC are at increased risk of developing advanced metastatic disease due to the absence of dependable and effective prognostic biomarkers. Therefore, it is particularly urgent to find optimal stratification of patients with ccRCC to distinguish the clinical benefits of different malignant degrees. Angiogenesis has a profound impact on the malignant behavior of renal cancer cells, and anti-angiogenic drugs have been applied to metastatic renal cancer patients. Moreover, immune function dysregulation is also a significant factor in tumorigenesis. We aim to construct a predictive model that combines angiogenesis and immune-related genes (AIRGs) to aid clinicians in predicting ccRCC prognosis. MethodsWe gathered transcriptome and clinicopathology data from two datasets, the E-MTAB-1980 dataset and the Cancer Genome Atlas (TCGA). We utilized consensus clustering to find new molecular subgroups. A predictive model for the prognosis of angiogenesis-immune-associated genes (AIRGs) was conducted by the lasso and multivariate Cox regression analysis. The signature's predictive ability was then tested in different datasets. Meticulous scrutiny and comprehensive assessment were undertaken, both internally and externally, to establish the prognostic model. Analyses of immunogenomics were carried out to examine the relationship between risk scores and clinical/immune features, including immune cell infiltration, genomic alterations, and response to targeted and immunotherapy therapy. ResultsOur prognostic signature, comprising 4 AIRGs, stood as an independent prognostic factor for ccRCC, while risk scores emerged as a novel indicator for forecasting overall survival. Risk scores exhibited significant associations with various immunophenotypic factors, such as oncogenic pathways, antitumor response, different immune cell infiltration, antitumor immunity, and response to targeted and immunotherapy therapy. ConclusionsAIRGs-based prognostic prediction model could effectively predict immunotherapy responses and survival outcomes of ccRCC.

Treatment of Metastatic Renal Cell Carcinoma with Checkpoint Inhibitors in Clinical Practice in the Volga-Ural Region of the Eurasian Continent.

Renal cancer ranks 10th in the mortality structure of the Russian Federation. The introduction of checkpoint inhibitors has changed the paradigm of treatment of patients with malignant neoplasms. Data from clinical trials have shown good progression-free median and median overall survival. Each cancer center has been accumulating its own experience in treating patients with renal cell cancer by applying modern target drugs and immunotherapy. In routine clinical practice, oncologists do not get the results that have been demonstrated in clinical trials when evaluating the effectiveness of the therapy. In this single-center clinical study, we discuss the results of using nivolumab as mono-therapy and the combination of nivolumab with ipilimumab in metastatic renal parenchyma cancer patients.

Real-world outcomes in advanced renal cancer patients treated with stereotactic radiosurgery for intracranial metastases.

e16516 Background: The proportion of metastatic renal cancer (mRC) patients with intracranial involvement is 8%, and 2% develop brain secondaries exclusively [1]. Although renal cancer is generally regarded as relatively radioresistant, studies have shown patients treated with stereotactic radiosurgery (SRS) demonstrate a local progression free survival (PFS) rate of 79-84% at 1 year and median overall survival (OS) of 9.6 – 13.9 months [2,3]. We evaluate the outcomes of patients with mRC who have received SRS to intracranial metastases at two tertiary centres in the North West of England. Methods: Patients who received SRS from January 2017 to July 2019 at Royal Preston Hospital, and from May 2016 to March 2021 at the Christie were retrospectively identified from the database of the respective hospitals. Clinical records were used to obtain demographics, therapies received and follow up data. Results: A total of 41 patients were identified. 31 patients (76%) were male and the average age at treatment was 59.6 years. 5 patients received treatment on >1 occasion, but only the first episode was considered for analysis. 80.4% had a performance status of 0-1 and most patients had clear cell histology. 19 patients (46.3%) had lesions treated bilaterally. The median follow up time was 11 months. Prescribed doses ranged between 18Gy to 30Gy in 1-5 fractions. 11 patients (26.8%) progressed during the follow up period, with a median time to progression of 5 months. The longest time to progression was 17 months, in a patient who received Nivolumab following SRS. 28 patients (68.3%) died during the follow up period with a median time to death of 9.1 months. Median OS was 11 months, with 19 out of the 28 patients (67.9%) dying within the first year. The 1 year survival rate was 52.6% and 2 year survival rate was 16.2%. A range of systemic agents were used pre and post SRS including immunotherapy. 6 patients (23%) commenced immunotherapy following SRS (nivolumab +/- ipilimumab), with OS ranging from 6 – 49 months (average 25.5 months). Conclusions: We found that outcomes in this cohort of patients treated with SRS were comparable to previous findings. A subgroup who commenced Nivolumab following SRS demonstrated an average survival of over 2 years.[Table: see text]

76P B7-H3 immune checkpoint protein expression is associated with immune exhaustion, overall survival and metastasis in clear cell renal cell carcinoma

Immune checkpoint inhibitors in combination with targeted therapy is improving the response rates of advanced or metastatic renal cancer patients. However, many treated patients either do not respond or develop resistance to therapy, making novel immune checkpoint-based immunotherapies of potential clinical benefit for specific groups of patients.

Abstract 6675: Basal NK activity and early Tregs inhibition predicts nivolumab responsiveness in metastatic renal cancer patients (REVOLUTION) trial

Abstract Background: Regulatory T cells (Tregs) are responsible for maintaining self-tolerance, and inhibit antitumor immune responses. PD-1 blockade was reported to increase resistance of effector T cells to Tregs suppression and directly reduces in vitro Tregs suppressive function. Natural killer cells (NKs) expressed PD-1 and engagement of PD-1 reduces their cytolytic potential. To identify biomarkers informative and predictive of Nivolumab efficacy Tregs and NKs phenotype and function was determined in Nivolumab treated metastatic renal cancer (mRCC) patients (REV). Effect of CXCR4 antagonism are evaluated on ex vivo Tregs and NKs. Methods: 48 REV, 26 other than ICI treated-mRCC (CTR) and 23 Healthy Donors (HD) were enrolled. To date, the clinical evaluation is available for 42 REV [14 with objective response (OR) and 28 in progression (PD)] and 18 CTR (11 OR and 7 PD). 31 patients (pts) underwent first clinical evaluation at 3 months resulting in 25 pts with OR and 6 in PD. Tregs (CD4+CD25+CD127lowFOXP3+) and NKs (CD3-CD56+CD107a+) phenotype and function were evaluated at day 0, 14, 28, 90, and 180. CFSE-T-effector proliferation-Tregs dependent and CD107a externalization toward K562 as NKs function were evaluated. Results: Higher NKG2D was reported on CD3-CD56dim cells from OR as compared to PD pts (p=0.0054). Statistically significant low NKs basal activity was detected at T0 in 3 months PD- Nivolumab treated pts (p=0.032). CD107a+/CD53+CD56+ is higher in OR compared to PD pts over time. Percent Tregs CD4+CD25+CD127lowFOXP3+ and CD8/Tregs ratio were respectively low (p<0.001) and high (p<0.001) in 71 mRCC as compared to 23 HD. Significant lower PD-1 was observed in Tregs at 3 months of treatment in OR pts (p= 0.048). Moreover, higher % of CD4+CD25+CD127lowFoxp3+ Tregs were observed in PD compared to OR pts over time (p<0.001) with higher CTLA4 expression in PD group. Tregs function, as evaluated at 2 weeks post treatment, was inhibited in responder and potentiated in PD patients. Moreover, CXCR4 antagonism dramatically reversed Tregs function ex vivo as early as at day 14 of treatment in OR pts (p=0.0024). A statistically significant reduction in peripheral Tregs (Effector/Naïve and nonTregs) was revealed in 14 Long Responder compared to 23 PD pts (> 12 months) (p<0.05; p<0.01 and p<0.05, respectively). In 18 CTR no modification in Treg phenotype and function were detected but a common decrease in NK activity unrelated to the clinical outcome. Conclusions: Basal NK activity and 2 weeks Tregs evaluation discriminates mRCC Nivolumab responding patients. Ex vivo CXCR4 antagonism inhibits Tregs function in responding patients at early treatment time point (2 weeks). These evidence are not detected in non-immune treated mRCC patients. Citation Format: Sara Santagata, Anna Maria Trotta, Giuseppina Rea, Maria Napolitano, Anna Capiluongo, Crescenzo D'Alterio, Marilena Di Napoli, Sabrina Rossetti, Sandro Pignata, Stefania Scala. Basal NK activity and early Tregs inhibition predicts nivolumab responsiveness in metastatic renal cancer patients (REVOLUTION) trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6675.

1906P - Basal NK activity and early Treg function inhibition predicts Nivolumab responsiveness in metastatic renal cancer patients (REVOLUTION) trial

BackgroundPD-1 blockade on Regulatory T cells (Tregs) increases resistance of effector T cells to Tregs suppression and directly reduces in vitro Tregs suppressive function. NKs expressed PD-1 and engagement of PD-1 reduces their cytolysis potential. and the effect of CXCR4 antagonism are evaluated on ex vivo Tregs and NKs. Methods43 Nivolumab treated-mRCC patients, 20 other than ICI treated –mRCC (CTR) and 15 Healthy donors (HD) were enrolled. 29 patients underwent first clinical evaluation at 3 months resulting in 23 patients with Objective Response (OR) and 6 in progression (PD). Tregs (CD4+CD25+CD127lowFOXP3+) and NKs (CD3-CD56+CD107a+) phenotype and function were evaluated at day 0, 14, 28, 90, and 180. CFSE-T-effector proliferation-Treg dependent and CD107a externalization toward K562 as NK function were evaluated. Results29 patients underwent first clinical evaluation at 3 months resulting in 23 patients with Objective Response (OR) and 6 in progression (PD). Higher NKG2D was reported on CD3-CD56dim cells from OR patients as compared to PD patients (p=0.0054). A clear reduction in NK basal activity was detected at T0 in 3 months progressed Nivolumab treated patients (p=0.029). Percent of basal Tregs CD4+CD25+CD127lowFOXP3+ was robustly high (p<0.001) and CD8/Tregs ratio low (p<0.001) in 63 mRCC patients as compared to 15HD. Significant lower PD-1 in Treg cells was observed at 3 months treatment in OR patients ( p=0.048) and a decrease of HELIOS was showed in PD vs OR patients at time 0 (p=0.017). Ex vivo Tregs were significantly inhibited by CXCR4 antagonism at day 14 in OR patients (p=0.0024). Characterization of primary RCCs tumor microenvironment and proteomic/ cyto-chemokines profile are ongoing. ConclusionsBasal NK activity and early detection (2 weeks) of CXCR4 dependent reversal of Treg suppressive activity significantly discriminates mRCC Nivolumab responding patients. Clinical trial identificationNCT03891485. Legal entity responsible for the studyThe authors. FundingTranscan 2016. DisclosureAll authors have declared no conflicts of interest.

Influence of access on survival of renal cancer in a Brazilian center.

644 Background: The introduction of tyrosine kinase inhibitors (TKI) and recently immunotherapy has brought major survival benefits for metastatic renal cancer (mRCC) patients (pts). In Brazil, there is no approved 2nd line treatment for mRCC in the Public Health System (PHS). Our center is unique, because it provides care for both PHS and Private System (PrS) population, enabling us to make the comparison of overall survival (OS) of these pts. Methods: We retrospectively reviewed medical records of all mRCC pts treated with 1st line TKI at our service from 2007 to 2018. Categorial variables were compared by Fisher’s exact test and continuous by Mann–Whitney. Survival was estimated by Kaplan-Maier method, prognostic factors adjusted by Cox regression model. Results: 171 pts were eligible, 37 (21.6%) PHS and 134 (78.4%) PrS pts. Between the two groups, there was no differences in age, gender, number and sites of metastasis (mets). PHS pts had worst ECOG (≥2, in 35.1 vs 13.5%, p .007), a trend towards more poor IMDC risk (IMDC favorable 16.2 vs 26.6%, intermediate 51.4 vs 57%, poor 32.4 vs 16.4%, p.09), had less nephrectomies (73 vs 92.5%, p.008) and more non clear cell histology (32.4 vs 12.7%, p.01). Median lines of therapy were 1 for PHS vs 2 for PrS pts (p.03). Sunitinib was the 1st line agent for 91.9 vs 67.2%, and pazopanib 8.1 vs 29.9%, of the PHS and PrS pts, respectively. Median time from diagnosis of mets to treatment start was 2.29 vs 1.79 m (p.59). Median OS was 16.5 vs 26.5 m (p.0002) and progression free survival, 8.4 vs 11 m (p.01), for the PHS vs PrS. On multivariate analysis, after adjusting for factors that were present before the beginning of treatment and were statistically significant for OS in the univariate model, PHS pts still had higher risk of death (HR 1.85, IC 95 1.2-2.9, p.01), probably due to having received fewer lines of therapy (≥2 lines of therapy vs 1, HR 0.51, IC95 0.4-0.7, p .001). Conclusions: Brazilian PHS pts had significant worse OS compared to PrS pts, in part due to less access to drugs. Access to cancer drugs is a challenge worldwide, and in Brazil effort has to be done to change this reality.

Traitement des métastases osseuses du cancer du rein

Bone metastases (BMs) are common and cause morbidity in cancer patients. One third of metastatic renal cancer (mRCC) patients present metastatic disease to the bone. BMs cause severe complications such as fracture, spinal cord compression and pain requiring surgery or radiotherapy. Hypercalcaemia is a common feature in mRCC as well as an established poor prognosis factor. BMs impact negatively on prognosis and affect quality of life. Correct management of BMs from RCC requires a multimodal evaluation to optimize care and quality of life. In this review, we discuss current evidences on the role of systemic treatments in BMs management, bone-targeting agents benefits in skeletal-related events prevention and local therapeutic approaches to BM in mRCC. Define prognosis of systemic disease and identify the main goal of treatment are crucial for the selection of the best strategy.

Roles and molecular mechanisms of hypoxia-inducible factors in renal cell carcinoma

Renal cancer is a common urologic malignancy. However, the therapeutic options for metastatic renal cancer patients are limited. Hypoxia (low oxygen) is a fundamental microenvironmental determinant of solid tumor pathophysiology. Recent data from molecular and clinical studies indicate that hypoxia-inducible factors (HIFs) play critical roles in the development and progress of renal cell carcinoma (RCC). The HIF transcription factor family is a type of heterodimeric transcription factor consisting of HIF-α and HIF-β subunits and can transcriptionally activate genes that mediate the hypoxic response. In RCC, HIF-1α and HIF-2α have opposing effects: HIF-1α is a tumor suppressor while HIF-2α acts as an oncogene. In this review, we summarize the current advances in understanding the roles and molecular mechanisms of HIF signaling in RCC. We also discuss recent HIF-targeted strategies proposed to improve RCC treatment, which may provide a foundation for further research, including the development of precision medicine for the treatment of RCC.

Abstract 580: Nivolumab treatment of metastatic renal cancer patients impairs Tregs and potentiates NK function: The role of CXCR4 inhibition (“REVOLUTION Trial”)

Abstract Despite encouraging results, Nivolumab response is not as wide as expected in renal cancer ( RCC). Among mechanisms of immunoresistance T-regulatory cells(Tregs) activity plays a central role. We previously showed that tumoral Tregs in RCC patients are more suppressive than healthy donors Tregs. Since tumoral Tregs express high level of CXCR4, the receptor antagonism was evaluated on patients Tregs revealing that CXCR4 antagonism reverted Treg suppressive activity( Santagata et al, submitted manuscript). To identify biomarkers informative and predictive of nivolumab efficacy Treg function, tumoral access and NK interactions was determined in nivolumab treated mRCC patients (“ Revolution” trial). At today eleven patients were analyzed for Tregs and NKs function at time 0-2-4 weeks-3-6 months of treatment. 2 patients died for unrelated causes, 5 Patients showed PR, 4 SD and 1 PD at six months. At time 0 Tregs function, evaluated as inhibition of T-effector (Teff) proliferation, varied among patients; two patients showed anergy reversed by Nivolumab treatment. Overall, increase in Teff proliferation, compatible with a decreased Tregs activity, was revealed during nivolumab treatment and, while the total peripheral Tregs was unaffected, a decrease in CD4+CD25+127lowFOXp3 highCD45RA - (suppressive Tregs) was detected. NK activity, evaluated as CD107a exposure, increased with nivolumab treatment with a concomitant reduction in the inhibitory receptors CD158a, PD-1 and CXCR4. Moreover patients Tregs and NKs were evaluated in vitro for the efficacy of CXCR4 inhibition in affecting cell function. CXCR4 antagonists suppressed the Treg mediated inhibition of Teff proliferation. In conclusion the evaluation of 11 patients enrolled in the REVOLUTION study revealed detectable variations on Tregs and NKs function relatively to Nivolumab treatment to be correlated with clinical outcome. Tregs suppressive function was impaired by inhibition of CXCR4 receptor. Citation Format: Sara Santagata, Anna Maria Trotta, Maria Napolitano, Luigi Portella, Sabrina Rossetti, Sisto Perdona, Sandro Pignata, Stefania Scala. Nivolumab treatment of metastatic renal cancer patients impairs Tregs and potentiates NK function: The role of CXCR4 inhibition (“REVOLUTION Trial”) [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 580. doi:10.1158/1538-7445.AM2017-580

Retrospective Analysis on Safety and Efficacy of Everolimus in Treatment of Metastatic Renal Cancer Patients Receiving Dialysis

This retrospective study aimed to investigate safety and efficacy of everolimus in patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease requiring dialysis. From November 2009 to December 2012, 11 mRCC patients undergoing dialysis were treated with everolimus after failure of anti-VEGF therapy at six Italian institutions. Patient characteristics, safety and outcomes were collected. Progression-free survival and overall survival were determined using the Kaplan-Meier method. Median progression-free survival and overall survival were 9.01 and 15.7 months, respectively. No unexpected adverse events were reported. Everolimus appears to be safe in mRCC patients with renal impairment or end-stage renal disease requiring dialysis. Larger prospective studies are required to confirm these findings.

A Randomised Phase Ii Study of Cediranib with or Without Src Inhibition (Saracatinib) in Metastatic Clear Cell Renal Cancer (Rcc) Patients Resistant to Vegf Targeted Therapy

ABSTRACT Aim: Metastatic clear cell renal cancer (RCC) patients who are resistant to VEGF targeted therapy have a poor outcome. Further VEGF targeted therapy is a standard treatment option for these patients. It is speculated that SRC may play a role in this VEGF resistance. In the study cediranib (a VEGF tyrosine kinase inhibitor), was given with saracatinib (a SRC TKI) or placebo in VEGF resistant disease to test this hypothesis. Methods: This investigator led double bind randomised (1:1) phase II study recruited patients between 2010 and 2012 (n = 138). The primary endpoint was progression free survival (PFS) by RECIST v1.1. Toxicity was assessed using CTC V4. Patients received cediranib and saracatinib (CS) (n = 69) or cediranib and placebo (C) (n= 69). All patients had metastatic measurable RCC and had progression of disease on VEGF targeted therapy. Stratification factors included MSKCC prognostic score. Results: 15%,70%, 15% had MSKCC good, intermediate or poor risk disease respectively. Overall the characteristics of the 2 groups were well balanced. Partial responses were seen in 13% for C and 14.5% for CS respectively (p = NS). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS [HR 1.18 (0.94-1.48)], or overall survival [HR 1.28 (1.00-1.63)] for the 2 groups. The median overall survival for the whole cohort was 12.0 months (8.5-15.6 months. There was no significant difference in the frequency key adverse events. Discontinuation and dose reductions due to adverse events with C and CS occurred in 13%/8% and 19%/18% respectively. Biomarker analysis will be presented at the meeting. Conclusions: The addition of saracatinib to VEGF targeted therapy did not result in clinical benefit in VEGF resistant metastatic RCC. Cediranib appears to have modest activity in VEGF resistant disease. Disclosure: T. Powles: Research Funding from: AZ GSK Novartis. Honoraria from Pfizer GSK Novartis; R.J. Jones: Research funding from AZ; S. Chowdhury: GSK and Pfizer for speaking. All other authors have declared no conflicts of interest.

Drug safety evaluation of sorafenib for treatment of solid tumors: consequences for the risk assessment and management of cancer patients

Introduction: Sorafenib is a multi-tyrosine kinase inhibitor (TKI). Considerable clinical experience has been accumulated since its first Phase III clinical trial in metastatic renal cancer patients in 2007. The management of its early acute toxicity in fit patients is well known. The management of prolonged treatment becomes the new challenge.Areas covered: Using sorafenib as a key word for PubMed search, we review preclinical and clinical data and discuss the pharmacokinetics and pharmacodynamics of sorafenib, its acute and cumulative toxicities and their consequences for patient management.Expert opinion: The systematic multi-disciplinary risk assessment of cancer patients prior to TKI initiation reduces the risks of acute and late toxicity, especially drug–drug interactions and arterial risks. Sarcopenia is now identified as a major risk of severe toxicity. The very diverse clinical pictures of cumulative toxicity must be known. The monitoring of sorafenib systemic exposure is helpful especially in elderly patients. Moreover, at disease progression, it allows distinguishing between underexposure to sorafenib and truly acquired resistance to the drug. The optimal use of sorafenib should allow improving the reported results of flat-dose. Finally, most of this knowledge could be used for the development and optimal use of the other TKIs.

Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy

Background:We examine how changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy.Methods:In metastatic renal cancer patients treated with anti-angiogenic tyrosine kinase inhibitors, arterial phase contrast-enhanced computed tomography was used to simultaneously measure changes in: (a) tumour size, and (b) tumour enhancement (a surrogate marker of tumour vessel density) within individual lesions.Results:No correlation between baseline tumour enhancement and lesion shrinkage was observed, but a reduction in tumour enhancement on treatment was strongly correlated with reduction in lesion size (r=0.654, P<0.0001). However, close examination of individual metastases revealed different types of response: (1) good vascular response with significant tumour shrinkage, (2) good vascular response with stabilisation of disease, (3) poor vascular response with stabilisation of disease and (4) poor vascular response with progression. Moreover, contrasting responses between different lesions within the same patient were observed. We also assessed rebound vascularisation in tumours that acquired resistance to treatment. The amplitude of rebound vascularisation was greater in lesions that had a better initial response to therapy (P=0.008).Interpretation:Changes in a surrogate marker of tumour vessel density correlate with response and resistance to anti-angiogenic therapy. The data provide insight into the mechanisms that underlie response and resistance to this class of agent.

Plasma MN (carbonic anhydrase IX) and outcome in sunitinib-treated metastatic renal cell cancer.

405 Background: The transmembrane protein MN (carbonic anhydrase IX)(CAIX) catalyzes the hydration of carbon dioxide to carbonic acid and decreases pH. In cancer, up-regulation of CAIX gene expression occurs under hypoxic conditions within tumors. Significant levels of CAIX protein have been detected in a variety of cancers including kidney, cervix, lung, bladder, colon, breast, liver, gall bladder, and pancreas. Methods: Pretreatment plasma CAIX and VEGF-A levels were determined from 52 metastatic renal cell cancer patients enrolled in a phase III first-line trial of sunitinib vs. interferon alpha (IF). The CAIX and VEGF-A ELISAs (WILEX/Oncogene Science, Cambridge MA) were used for determination of plasma biomarker levels. 51 of 52 patients had an MSKCC score of 0 or 1. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with both continuous and dichotomous (median) plasma CAIX and VEGF levels. Results: Pretreatment plasma CAIX levels averaged 371 pg/ml, with a median of 194 pg/ml and 25th and 75th percentile values of 125 and 298 pg/ml, respectively. In the whole population, higher plasma CAIX was significant on a continuous basis for predicting reduced PFS (p &lt; 0.007) and shorter OS (p &lt;0.0001). When analyzed using the median as cutpoint, the elevated plasma CAIX cohort trended for reduced PFS (p = 0. 13) and had a significantly reduced OS (HR 2.77, p = 0.026) (median 94 vs. 115 weeks). In univariate analysis plasma VEGF-A did not predict for PFS or OS when analyzed as a continuous or dichotomous variable. In multivariate analysis for PFS (including treatment arm, CAIX, and MSKCC score), treatment with sunitinib (vs. IF) (p = 0.006) and lower plasma CAIX (p = 0.04) resulted in a significantly longer PFS. In multivariate analysis for OS, again treatment with sunitinib (vs. IF) (p=0.037), and lower plasma CAIX (p &lt; 0.0001) resulted in a significantly longer OS. Conclusions: Elevated pretreatment plasma CAIX predicted for reduced PFS and overall survival in metastatic renal cancer patients. In addition, sunitinib was superior to interferon, regardless of plasma CAIX status.

174O - VEGF-a-induced Treg Proliferation, A Novel Mechanism of Tumor Immune Escape in Colorectal Cancer: Effects of Anti-VEGF/VEGFR Therapies

ABSTRACT Background Regulatory T cells (Treg) are suspected of hindering an effective antitumor immune response in cancer. Multi-target anti-angiogenic tyrosine kinase inhibitors (TKI) that are routinely used as first or second line treatment of cancer patients, have been shown to decrease Treg proportion in tumor-bearing mice and metastatic renal cancer patients. However, the role of VEGF/VEGFR blockade in this effect is still debatable, and the direct impact of VEGF-A on Treg has not been studied. Methods Treg proportion, number were analyzed by flow cytometry in peripheral blood of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, and in CT26 tumor-bearing mice treated with drugs targeting the VEGF axis. The direct impact of VEGF on Treg increase in cancer was also studied. Results Sunitinib (a TKI targeting VEGFR, PDGFR, c-kit), and anti-VEGF-A antibody both decreased Treg in CT26 tumor-bearing mice. Masitinib, a TKI that does not target VEGFR, did not reduce Treg proportion in CT26 bearing mice. Bevacizumab, an anti-VEGF-A monoclonal antibody, reduced Treg proportion in peripheral blood of mCRC patients. Proliferation of Treg was enhanced in CT26 tumor-bearing mice compared to tumor-free mice and was decreased after anti-VEGF-A treatment. Furthermore, in vitro experiments have shown that VEGF-A could directly induce Treg proliferation. VEGFR1 and 2 were expressed on Treg in the presence of a tumor. Anti-VEGFR2 antibody administration reduces Treg proportion and also proliferation in CT26 bearing mice, but anti-VEGFR1 antibody did not, suggesting that VEGF-A-induced Treg proliferation was dependent on VEGFR2 expression. In metastatic CRC patients, Treg proliferation was also enhanced compared to healthy volunteers and was blocked by bevacizumab treatment. Conclusions We identified a new mechanism by which VEGF-A induced by the tumor could stimulate Treg proliferation. VEGF-A/VEGFR2 blockade reduced Treg proportion and proliferation in tumor-bearing mice and metastatic CRC patients suggesting that combination of anti-VEGF-A/VEGFR2 therapies with immunotherapeutic approaches in the future might be particularly relevant in CRC patients. Disclosure J. Taieb: advisory role, Roche; research grant, Roche. All other authors have declared no conflicts of interest.

822P - A Phase I Dose Escalation Study Investigating Dovitinib and Everolmus in Combination in Metastatic Clear Cell Renal Cancer Patients who have Previously Failed VEGF Targeted Therapy

ABSTRACT Introduction Both dovitinib and everolimus are agents used, or under investigation in patients with renal cancer refractory to VEGF targeted therapy. It is potentially attractive to use these agents in combination in patients with VEGF TKI refractory disease. Together they target mTOR, VEGF and FGF-2. The purpose of this study is to establish a dose for this combination to take forward in randomised trials. Method This phase I study (EUDRACT 2010-021250-19) followed a classic dose escalation 3 + 3 designed. Sequential patients with metastatic clear cell renal cancer, who had previously failed VEGF tyrosine kinase inhibitors were included. Patients received fixed doses of drug in each escalating cohort (maximum n = 6) until dose limiting toxicity (DLT) was reached. DLT included grade 3 toxicity during the first 6 weeks of therapy. If 2 episodes of grade 3 or more toxicity occurred in a specific cohort the DLT cohort had been reached. The study has appropriate ethical approval. Assement of response and progression free survival was by RECIST v1.1 Results Patients were entered into 2 cohorts before DLT occurred (cohort 0: dovitinib 200 mg/everolimus 5mg [n = 6]; cohort 1: dovitinib 300 mg/everolimus 5mg [n = 3]) . DLT in cohort 1 included grade 3 fatigue (2/3) after 2 and 3 week of therapy. In cohort 0 the following toxicity was identified: Lethargy grade 2 3/6 and 3 1/6; Diarrhoea Grade 2 2/6 and 3 0/6 mucositis; grade 2 0/6 and 3 0/6; nausea/vomiting grade 2 0/6 and 3 1/6, pulmonary fibrosis grade 2 1/6 3 0/6 . Grade 3 toxicity after the first 6 weeks of therapy included pulmonary fibrosis 1/6, lipid abnormalities 2/6. Overall 1 patient (11%) had a partial response to therapy. Of the 5 patients who did not stop therapy during the first 6 weeks due to toxicity, 3 continued for 6 months or more without progression. Conclusion The maximum tolerable dose for this combination was dovitinib 200mg and everolimus 5mg. This dose is being taken forward in an expansion cohort which will explore efficacy. Disclosure T.B. Powles: Novarits Has supplied an educational grant for this project. Advisroy role for Novratis. S. Chowdhury: Advisory role. All other authors have declared no conflicts of interest.

Sequential FDG-PET/CT as a surrogate marker of response to sunitinib in metastatic clear cell renal cancer.

301 Background: The purpose of this study was to investigate sequential FDG PET-CT as a correlative marker in metastatic clear cell renal cancer (mRCC) patients treated with first line sunitinib. Three sequential scans were performed to determine the importance of the timing of scans. Methods: Forty-four untreated mRCC patients with MSKCC intermediate risk and poor risk disease were enrolled into a prospective study. FDG PET-CT scans were performed before (n=44), after 4 weeks (n=43) and 16 weeks (n=40) of sunitinib given at standard doses as the translational aspect of this trial ( NCT01024205 ). The primary endpoint was to determine whether 18F-FDG PET-CT response (defined as a 20% reduction in SUVmax) correlated with survival. Results: Forty-three (98%) patients had FDG PET-CT avid lesions at diagnosis (median SUVmax 6.8 range: &lt;2.5–18.4). In multivariate analysis a high SUVmax and increased number of PET positive lesions correlated with worse overall survival (OS) (HR: 3.30 (95%CI: 1.36–8.45) and 3.67 (95%CI: 1.43–9.39) respectively[p&lt;0.05]). After 4 weeks of sunitinib, metabolic responses occurred in 24 (57%) patients at 4 weeks, but this did not correlate with progression-free survival [PFS] (HR for responders= 0.87 [95%CI: 0.40–1.99]) or OS (HR for responders= 0.80 [95%CI: 0.34–1.85]) (p&gt;0.05 for both). After 16 weeks of treatment, FDG PET-CT demonstrated disease progression in 28% (n=12) patients. At this time point, the FDG PET-CT correlated with both OS and PFS (HR 5.96 [95%CI: 2.43–19.02] and HR 12.13 [95%CI: 3.72–46.45] respectively). Conclusions: Baseline FDG PET prior to sunitinib yields prognostically significant data. FDG PET response at 16 weeks predicts outcome, which is not the case at 4 weeks. This subsets of patients with a poor prognosis at 16 weeks could be investigated within the context of a randomized clinical trial. [Table: see text]

Correlation of hypothyroidism with survival in metastatic renal cancer patients treated with sorafenib or sunitinib.

379 Background: To investigate prognostic markers in patients with metastatic renal cell carcinoma (mRCC) undergoing treatment with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su). Methods: Eighty-three patients with mRCC, who were treated at our institution between 2006 and 2009, were evaluated prospectively. Clinical and laboratory parameters were investigated, as well as, treatment-related adverse events. Subclinical hypothyroidism was characterized by serum TSH above the upper limit of normal and both total triiodtyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. Results: Thirty-one (37.3%) patients received So, and 52 (62.7%) were treated with Su. In univariate analyses, a poor ECOG status was associated with an unfavorable progression-free survival (PFS) (p&lt;0.0001); similarly high risk MSKCC criteria correlated with a worse PFS (p=0.003). Furthermore, response to therapy was a surrogate parameter (p&lt;0.0001). Twenty-one of 66 (31.8%) patients developed hypothyroidism during treatment, which was associated with a positive prognosis (p=0.032). In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, p=0.018) and hypothyroidism (p=0.01) were independent prognostic parameters. Conclusions: The development of hypothyroidism during treatment might be useful as a clinical predictor of PFS for mRCC patients undergoing treatment with targeted agents. No significant financial relationships to disclose.

Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib

To investigate prognostic markers in patients with metastatic renal cell carcinoma (mRCC) undergoing treatment with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su). Eighty-three patients with mRCC, who were treated at our institution between 2006 and 2009, were evaluated prospectively. Clinical and laboratory parameters were investigated, as well as, treatment-related adverse events. Subclinical hypothyroidism was characterized by serum TSH above the upper limit of normal and both total triiodothyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. Thirty-one (37.3%) patients received So, and 52 (62.7%) were treated with Su. In univariate analysis, the ECOG status (P < 0.0001) as well as MSKCC criteria (P = 0.003) and response to therapy (P < 0.0001) were associated with progression-free survival (PFS). Twenty-one of 66 (31.8%) evaluable patients developed hypothyroidism during treatment. Of those patients, 8/21 (38.1%) were treated with So and 13/21 (61.9%) with Su. Response rate in this subgroup was 49.2%. Hypothyroidism was associated with a longer PFS (16.0 ± 0.8 months vs. 6.0 ± 0.8 months, P = 0.032). Most patients [16/21 (76.2%)] developed abnormal TSH values during the first 4 weeks of treatment. Hormone replacement with l-thyroxine did not have an influence on survival. In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, P = 0.018) and hypothyroidism (P = 0.01) were independent prognostic parameters. The development of hypothyroidism during treatment might be useful as a predictor of PFS for mRCC patients undergoing treatment with targeted agents.