Highlights in the management of renal cell carcinoma

1. Highlights in the management of renal cell carcinoma novel insights and treatment perspectives

2. Time IL IFN CHT 2005 Vasudev et al. BMC Medicine 2012, 10:112 Before the era of targeted therapies, cytokine therapy with interferon and interleukin-2 were the main treatment, with little benefit in terms of progression-free survival (PFS) and OS. Multiple pathways angiogenesis - metabolism - chromatin remodelling Since 2005, progress in systemic therapy has led to the approval of many new agents by the (FDA) and EMA With newer therapies, the median overall survival (OS) duration in mRCC is about 26 months or even more

3. classification remains largely morphology based there are still no biomarkers in routine clinical use in RCC biologically driven strategies of treatment have not yet been developed in the clinical setting

4. STAGE IV Tools used routinely to determine prognosis have not changed over the past decade • The choice offirst-line agent currently depends on the prognostic criteria • Motzer et al. [J Clin Oncol 1999;17:2530–2540] • Heng et al. [J Clin Oncol 2009; 27: 5794–5799] Between 20% and 30% of patients with ccRCC derive no benefit from first-line TKI treatment patients developed resistanceand the rate of complete response was low patients continue to be exposed to potentially toxic therapy with no indication of the likelihood of response treatment cost STAGE I - III ADJUVANT NEOADJUVANT

5. ADVANCES GENETICS Loss-of-function mutations in the VHL allele are thought to represent an early event in ccRCC development not sufficient alone to drive tumour growth. SW1/SNF chromatin remodelling complex gene polybromo1 (PBRM1) SET domain containing protein 2 and Jumonji AT-rich interactive domain 1C BRCA related protein-1 (BAP1) have been reported, with inactivation of BAP1 protein in 15% of ccRCCs PBRM1 and BAP1 were largely observed to occur exclusively In comparison with the PBRM1 mutation, BAP1-deficient tumours were of higher grade and had distinct gene expression profiles

6. ADVANCES Toward a molecular genetic classification of clear cell renal cell carcinoma Methods: Tumors from 145 patients with primary ccRCC were sequenced for PBRM1 and BAP1. second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) was used for validation. Results: When compared to PBRM1-mutant tumors, BAP1-mutant tumors were associated with aggressive pathological features including high Fuhrman grade and tumor necrosis. BAP1-mutant and PBRM1-mutant tumors exhibited distinct gene expression signatures. The median overall survival (OS) was shorter for patients with BAP1-mutant tumors (4.6 years; 95% CI, 2.1-7.2), than for patients with PBRM1-mutant tumors (10.6 years; 95% CI, 9.8-11.5), corresponding to a hazard ratio (HR) of 2.7 (95% CI, 0.99-7.6, p = 0.044). A similar HR was observed in the independent dataset from the TCGA (2.8; 95% CI, 1.4-5.9; p = 0.004). The BAP1-mutant group could be further subdivided into tumors with mutations exclusively in BAP1 and those with mutations in both BAP1 and PBRM1. Double mutant tumors constituted a minority (n = 4; in TCGA), and were associated with the shortest OS (HR, 10; 95% CI, 3.2-33.6). Conclusions: Our findings reveal novel biological subgroups of ccRCC with distinct clinical outcomes, a high-risk BAP1-mutant group and a favorable PBRM1-mutant group. These data establish the basis for a molecular subclassification of ccRCC that could influence treatment decisions in the future. James Brugarolas J Clin Oncol 31, 2013 GENETICS

7. ADVANCES GENETICS Gene expression microarrays • studies have typically been small, with limited numbers of genes analysed, and not independently validated • a recently published meta-analysis of gene-expression studies in ccRCC, just 6 studies were included The meta-array assembled gene expression data from480 tumours, encompassing 6,386 genes.ccA tumours relatively overexpressed genes associated with hypoxia, angiogenesis and fatty acid metabolism and carried a favourable prognosis in comparison withccB tumours, which overexpressed a more aggressive panel of genes associated with epithelial-mesenchymal transition, cell cycle and wound healing. unclassifiable tumours, or in cases that are otherwise difficult to distinguish (for example, eosinophilic tumours). In addition, the increasing interest in neoadjuvant therapy means that pathologists are required to make initial diagnoses on much more limited amounts of tissue, derived from core biopsies alone, where expression profiling may also prove useful

8. ADVANCES GENETICS Single nucleotide polymorphisms • In the largest study of 397 patients treated with pazopanib, 27 polymorphisms amongst 13 genes, including those related to angiogenesis (VEGFA/IL-8/fibroblast growth factor 2), metabolism (cytochrome P450 (CYP) 3A4/5)}) and transport (ATP-binding cassette (ABC) B1) were evaluated. Two IL-8 polymorphisms, linked to increased gene expression, were associated with a significantly shorter median PFS (27 weeks) than those carrying the wild-type genotype (48 weeks) • examined both response (n = 89) and toxicity (n = 95) to sunitinib in patients with ccRCC. A total of 16 polymorphisms were examined in nine genes. Two VEGFR3 missense polymorphisms were associated with reduced PFS and a high metabolising variant of CYP3A5*1 was associated with increased toxicity Effect of VEGF and VEGFR polymorphisms on clinical outcome and response in patients with advanced renal cell carcinoma receiving first-line treatment. Conclusions: In our analysis patients with CC or CT polymorphism of rc833061 had a favourable PFS and OS if treated with sunitinib instead patients treated with pazopanib seems to have benefit if CT+TT polymorphism, A polymorphism rs699947 and G polymorphism of rs2010963 seem to have a better PFS and OS in first line with sunitinib. Patients with C polymorphism of rs6877011 and G polymorphism of rs307822 seem equally to have a favourable impact in first-line therapy with sunitinib. Our data seem to suggest that biology could have a role in the choice of first-line treatment for mRCC patients. Bianconi MJ Clin Oncol 31, 2013 LIMITS studies to date in this area show little concordance

9. ADVANCES EPIGENETICS DNA methylation In sporadic ccRCC, the VHL TSG is inactivated via methylation in approximately 10% to 30% of cases The Ras association domain family 1 gene, for example, codes for a protein that functions as a negative regulator of the cell cycle and is methylated in approximately 45% of cases Secreted frizzled related protein 1, which antagonises Wnt signalling, is methylated in 34% to 68% of ccRCC tumour Methylation of gremlin1, a protein that antagonises growth factor signalling, has been correlated with a poorer overall survival in patients with ccRC CUB EGF-like domain-containing protein 3, risk of cancer death or relapse was significantly increased

10. ADVANCES EPIGENETICS DNA methylation

11. ADVANCES GENETICS microRNA miR210 upregulated in ccRCC in response to hypoxia - promotes anaerobic respiration and cell cycle progression and inhibits pro-apoptotic signalling expression of miR210 has been correlated with a significantly poorer overall survival miRNA-based signatures may also allow for improved classification of tumour subtypes. In a recent study of 94fresh frozen samples, composed of normal renal epithelium and clear cell, papillary and chromophobe RCC subtypes as well as oncocytomas, 91 miRNAs were found to be significantly differentially expressed. the system had a sensitivity of 97% in distinguishing normal from RCC, 100% for clear cell RCC, 97% for papillary subtype and 100% accuracy in distinguishing oncocytoma from chromophobe tumours. recent studies have shown, miRNAs can also be measured in serum and serve as potential diagnostic markers of disease

12. ADVANCES EPIGENETICS DNA methylation Therapeutic implications In preclinical studies, treatment with the histone deacetylase inhibitor vorinostat augmented the activity of the mTOR inhibitor temsirolimus to induce apoptosis in xenografted RCC cell Lines phase II trial of panobinostat, in patients with refractory metastatic RCC failed to demonstrate an objective response A more precise understanding of the role of epigenetic alterations could indicate other targetable strategies.

13. ADVANCES EPIGENETICS DNA methylation Phase I study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase inhibitor, entinostat, in patients with metastatic renal cell carcinoma: Safety and tolerability results. Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor activity in different malignancies and to induce immuno-modulatory effects. We have previously reported that a class I selective HDAC inhibitor, entinostat, has synergistic anti-tumor effects in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model (Kato Y, et al. Clinical Cancer Res 2007). The results from the phase I portion suggest that entinostat can be given safely in combination with high dose IL-2. Preliminary results also show encouraging biological and efficacy data Roberto Pili J Clin Oncol 31, 2013 (suppl 6; abstr 369)

14. ADVANCES A number of large-scale biomarker initiatives are underwayin RCC CAGEKID The Cancer Genomics of the Kidney (CAGEKID) EuroTARGET (TArgeted therapy in Renal cell cancer: GEnetic and Tumour related biomarkers for response and toxicity SCOTRRCC The Scottish Collaboration on Translational Research into RCC (SCOTRRCC) PREDICT Consortium TCGA The Tumour Cancer Genome Atlas (TCGA)

15. Time IL IFN CHT 2005 Vasudev et al. BMC Medicine 2012, 10:112 New Agents in Renal Cancer

16. PAZOPANIB Guidelines recommend the use of VEGF inhibitors as first-line therapy in patients with good and intermediate risk PISCES trial showed that 70% of patient preferred pazopanib over sunitinib in the first-line setting due to fatigue decrease and improved quality of life The COMPARZ phase 3 trial comparing first-line pazopanib with sunitinib has completed patient enrolment and it is hoped that the results of this study will provide an answer as to whether pazopanib is as effective as sunitinib with less toxicity Quality of life (QoL) among patients with renal cell carcinoma (RCC) treated with pazopanib versus sunitinib in the COMPARZ study Background: Pazopanib and sunitinib are targeted therapies associated with particular treatment-related side effects that may affect patients’ QoL. COMPARZ was a randomized, open-label, parallel group, phase III study of pazopanib vs. sunitinib in 1,110 subjects with advanced RCC who had not received prior systemic therapy.The study demonstrated pazopanib is non-inferior to sunitinib with respect to progression-free survival. The study also confirmed the differentiated safety profiles of the two drugs Conclusions: In this study, better patient-reported QoL scores for pazopanib indicate subjects experienced less worsening of fatigue, as well as mouth/throat, hands, and feet soreness, and fewer limitations due to soreness, while on pazopanib compared with sunitinib. The differences observed are likely to be clinically meaningful. The FACIT-F and SQLQ results are also highly consistent with the previously-reported PISCES study. David Cella J Clin Oncol 31, 2013 (suppl 6; abstr 346)

17. AXITINIB Overcoming Resistance to Angiogenesis Inhibitors second-generation VEGF inhibitors axitinib, has shown in vitro a VEGFR-2 inhibition potency 40 times greater than sunitinib AXIS trial, axitinib was shown to be effective as second-line therapy compared with sorafenib a preplanned subgroup analysis was conducted in this population and showed a benefit of axitinib in sunitinib- refractory patients. In January 2012, the FDA has approved axitinib in this indication Axitinib versus sorafenib as first‑line therapyin patients with metastatic renal cell carcinoma Background: In the phase III AXIS trial, second-line therapy with axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib for mRCC. We conducted a multicenter, randomized, open-label, phase III trial to compare PFS of axitinib vs sorafenib as first-line therapy. Methods:. Primary endpoint was PFS per independent radiology committee. Conclusions: The study did not achieve its primary endpoint statistically, but axitinib demonstrated numerically longer mPFS and significantly higher ORR vs sorafenib, with an acceptable safety profile, as first-line therapy for mRCC. Thomas E. Hutson J Clin Oncol 31, 2013 (suppl 6; abstr LBA348)

18. Tivozanib Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor targeting all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib has shown tolerability and superior progression-free survival and overall response rate versus sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma Overall survival results from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma Background: . Final overall survival (OS) data (August 27, 2012) from TIVO-1 and its open-label, multicenter extension study are reported. Methods: A total of 517 patients were randomized 1:1 to tivozanib 1.5 mg/d (3 weeks on, 1 week off) or sorafenib 400 mg/d (twice a day, continuously) (J Clin Oncol2012;30[suppl]:Abstract 4501). In the extension study, patients who progressed (PD) on sorafenib based on investigator assessment were eligible to receive tivozanib, and patients with PD on tivozanib received subsequent treatment according to regional standards of care. Results: At the time of final OS analysis (2 years after last patient was enrolled) Median OS (95% CI) was 28.8 months (22.5–NA) for tivozanib and 29.3 months (29.3–NA) for sorafenib. Of the 257 patients on sorafenib, 155 (60.3%) had started next-line tivozanib at the time of the analysis. Conclusions:There was no significant difference in OS between the two treatment arms. The high rate of utilization of second-line tivozanib in patients following PD on sorafenib may have affected the OS outcome. Robert John Motzer J Clin Oncol 31, 2013 (suppl 6; abstr 350

19. Tivozanib Subgroup analyses of a phase III trial comparing tivozanib hydrochloride versus sorafenib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC) Background: Tivozanib hydrochloride (T) is a potent, selective, tyrosine kinase inhibitor of all 3 VEGF receptors with a long half-life. T has shown tolerability and has extended progression-free survival (PFS) compared with sorafenib (S; median 11.9 months vs. 9.1 months; p =0.042) in a phase III trial (TIVO-1) as initial targeted therapy for pts with mRCC. We report results of PFS subgroup analyses from TIVO-1. Methods: Pts with clear-cell mRCC, prior nephrectomy, and ≤1 prior treatment for mRCC were randomized to T (n=260) or S (n=257). Cox proportional hazards model was used to evaluate PFS. Results: Significant improvement in PFS by T vs. S was observed for the following prespecified subgroups: white, Eastern Cooperative Oncology Group (ECOG) performance status 0, ≥1 year since diagnosis, no prior treatment, ≥2 metastatic sites, North America/Western Europe, baseline systolic blood pressure (SBP) ≤140 mm Hg, and baseline diastolic BP (DBP) ≤90 mm Hg. Exploratory subgroup analysis showed a similar significant improvement by T vs. S in Memorial Sloan-Kettering Cancer Center (MSKCC) favorable prognostic group, and pts who developed hypertension on study had significantly longer PFS than pts with normal BP. The improvement in PFS by T vs S was more marked for the subgroups that developed hypertension (selected subgroups shown in the table). Conclusions: PFS subgroup analyses showed a consistent advantage with T vs. S for Mrcc Thomas E. Hutson J Clin Oncol 31, 2013 (suppl 6; abstr 354)

20. Overcome the resistance to VEGFi Preclinical studies demonstrated that simultaneous blockade of FGF and VEGF pathways restored antitumor efficacy Dual inhibitors of VEGFR-1, -2, and -3, and FGFR-1, -2 and -3 (together with PDGFR) are being developed in clinical trials. In a phase 1/2 trial involving 31 mRCC patients previously treated with VEGF or mTOR inhibitors, Dovitinib, an oral TKI anti-FGFR and -VEGFR: Dovitinib is currently being evaluated in a phase 3 study (the GOLD trial) compared with sorafenib, in third-line mRCC after one anti-VEGF and one anti-mTOR treatment. Signalling through the hepatocyte growth factor (HGF)and its receptor c-Met is the subject of active research in kidney cancer. This pathway mediates motility, proliferation and differentiation of the cells, and cooperates with VEGF to induce tumor invasion and vascularization RCC tumors resistant to sunitinib have a greater amount of HGF than sunitinib- sensitive tumors, especially in endothelial cells associated with the tumors.. Moreover, the combination of a c-Met inhibitor with sunitinib restored the antitumor efficacy in sunitinib-resistant cell line

21. Overcome the resistance to VEGFi Cabozantinib is a dual TKI of c-Met and VEGFR2 that showed improved efficacy relative to VEGFR2-only inhibitors in preclinical models AMG102, a monoclonal antibody directed against HGF, has demonstrated modest activity in mRCC. Furthermore, the combination of AMG102 with bevacizumab or motesanib appears to be safe and feasible and should be evaluated in metastatic renal tumors. Beside its role in angiogenesis, c-Met is directly implicated in the carcinogenesis of papillary renal tumors

22. FORETINIB Foretinib (XL880), a c-Met and VEGFR2 inhibitor, showed antitumor activity in papillary tumors Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutation Results Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached.The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli In conclusion, although the primary end point of the study was not met in the overall PRCC population, other clinical end points such as PFS and a decrease in tumor SLD make the activity of foretinib noteworthy, especially in the subgroup of patients with germline MET mutations Toni K. Choueiri VOLUME 31 NUMBER 2 JANUARY 10 2013

23. Overcome the resistance to VEGFi mTor Second-generation mTOR inhibitors are small-molecule mimetics of adenosine triphosphate that target the mTOR kinase domain; they have also entered clinical trials. These second-generation kinase inhibitors could inhibit mTOR, PI3K and other PI3K-related protein kinases. NVP-BEZ235 and GDC-0980 are PI3K/mTORC1/mTORC2 inhibitors that recently entered into phase 2 development in patients with mRCC previously treated with antiangiogenic therapy.

24. Overcome the resistance to VEGFi The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC). Background: Single-agent VEGF and MTOR directed targeted therapy have improved outcomes for pts with RCC. Phase I trials suggested that CTT might delay resistance. This randomized phase II trial was designed to find the best CTT regimen in comparison to bev alone for potential comparison to the best available single-agent therapy in a phase III trial. Methods: 361 treatment naïve RCC pts were randomized to receive Bev (10mg/kg Q2wks), Tem (25mg Qwk) + Bev (10mg/kg), Bev (5mg/kg Q2wks) + Sor (200mg po 5d on/2d off), or Sor (200mg QD) + Tem (25mg Qwk) until disease progression or unacceptable toxicity. The study was designed to detect a 67% improvement in median PFS on the combination arms, compared to single-agent bev (median 9 vs. 15 mo). Results: The median PFS was 8.7 mo for Bev versus 7.3 mo for Bev/Tem (HR = 0.91; 95% CI, 0.68-1.23), 11.3 mo for Bev/Sor (HR = 0.84; 95% CI, 0.62-1.13), 7.7 mo for Sor/Tem (HR = 1.11; 95% CI, 0.83-1.49). The response rates (CR+PR) were 12% for Bev versus 28% for Bev/Tem, 30% for Bev/Sor and 27% for Sor/Tem. No difference in OS was observed. Common toxicities included hypertension, fatigue, hand-foot syndrome, and diarrhea. Grade 3/4 adverse events and dose reductions were more common on CTT. Conclusions: CTT was not superior to single-agent Bev for the PFS primary endpoint. Common severe toxicities were expected, but more prevalent with CTT than with Bev alone. The VEGF/VEGFR co-inhibition strategy may warrant further investigation possibly with more selective VEGFR inhibitors. J Clin Oncol 31, 2013 (suppl 6; abstr 345)

25. ADVANCES it was observed that targeted agents do not only inhibit angiogenesis and tumor cell proliferation, but also show immunomodulatory effects directing the immune system to a stronger anti-tumor response sunitinib-treated mRCC patients show decreased frequencies of Tregs and myeloid-derived suppressor cells (MDSCs) in the peripheral blood. At the same time, sunitinib may shift T-helper cells toward a Th1-type response sorafenib has immunosuppressive effects with a reduced induction of antigen-specific T cells in vitro and in immunized mice. Additionally, mTOR antagonists inhibit the calcineurin-dependent activation of the IL-2 gene transcription in response to T-cell receptor activation. Therefore, combining the compatible targeted agents with immune therapy appears like a promising therapeutic option, especially if the non-specific immune stimulation can be redirected toward a more specific, efficient and durable adaptive immunity against tumor cells

26. ADVANCES Anti-CTLA-4 has been evaluated in patients with metastatic RCC. In a Phase II trial, two cohorts of patients with advanced RCC received two different dosing schedules of ipilimumab: a 3mg/kg loading dose followed by either 1mg/kg or 3mg/kg maintenance doses every 3 weeks agents such as ipilimumab and MDX-1106 will likely be assessed, possibly with cytokines and other therapies, in various sequences and combinations with the goal of achieving higher rates of durable responses than is possible with currently available therapies.

27. Clinical activity and safety of antiprogrammed death-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) in patients (pts) with previously treated, metastatic renal cell carcinoma (mRCC): An updated analysis. J Clin Oncol 31, 2013 (suppl 6; abstr 351) Author(s): David F. McDermott, Abstract: Background: BMS-936558 is a fully human monoclonal antibody that blocks the PD-1 coinhibitory receptor expressed by activated T cells. In the initial portion of a phase I study (CA209-003), BMS-936558 showed promising activity in pts with various solid tumors, including mRCC. Accrual was expanded to better characterize antitumor, safety, and dose effects. Methods: Pts with RCC were treated with BMS-936558 IV q2wk at 10 mg/kg initially, followed by additional pts at 1 mg/kg. Pts received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or complete response (CR). Clinical activity was assessed by RECIST v1.0. Results: As of July 3, 2012, 34 mRCC pts had been treated at 1 mg/kg (n=18) or 10 mg/kg (n=16). ECOG performance status was 0 in 13 pts and 1 in 21 pts. More than 40% of study patients received ≥3 prior therapies, >70% received prior antiangiogenic therapy, and >50% received prior immunotherapy. Sites of metastatic disease included lung (n=30), lymph node (n=28), bone (n=10), and liver (n=9). The incidence of grade 3-4 related adverse events was 21% and included hypophosphatemia (6%) and respiratory disorders (6%); there were no drug-related deaths among mRCC pts. Ongoing durable clinical responses were observed at both 1 and 10 mg/kg doses (Table) with some continuing off treatment. Three pts demonstrated nonconventional response patterns and were not categorized as responders by conventional RECIST. Current median duration of response was 12.9 months for both 1 and 10 mg/kg doses. Conclusions: BMS-936558 is tolerable and exhibits ongoing durable clinical activity in pts with previously treated mRCC.

28. Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavorable risk metastatic RCC (mRCC). J Clin Oncol 31, 2013 (suppl 6; abstr 357) Author(s): Asim Amin, Arkadiusz et al Background: During the past decade, VEGF targeted therapies have become standard treatment for advanced RCC. While targeted therapies have yielded improved efficacy, durable remissions are rare, particularly in unfavorable risk subjects. In a pivotal trial, treatment with sunitinib yielded a median OS of 5.3 months for poor risk and 20.7 months for intermediate risk subjects. Similarly, the validation dataset for the Heng risk model (ASCO 2011) revealed a median OS of 8 months for poor risk and 21 months for intermediate risk patients treated with VEGF targeted therapies. Durable responses have been elicited by immunotherapy in RCC. We report an update on patients with mRCC treated with combined VEGF TKI (sunitinib) plus autologous immunotherapy (AGS-003). Methods: In this phase II study, subjects with unfavorable prognosis mRCC (poor and intermediate risk) were treated with sunitinib plus autologous dendritic cell immunotherapy (AGS-003). Treatment consisted of standard 6-week cycles of sunitinib plus AGS-003 (once every 3 weeks x5 doses, then every 12 weeks until PD). Tumor response was assessed per RECIST and subjects were followed for PFS and OS. Immune monitoring samples were taken at screening, baseline and after the third and fifth doses of AGS-003 and analyzed by multiparametric flow cytometry. Results: 21 subjects were treated. As previously reported, the median overall PFS was 11.2 months and the final median OS was 30.2 months. When analyzed by baseline Heng risk status, the median PFS was 19.4 months for intermediate (n=11) and 5.8 months for subjects with poor risk features (n=10) at baseline. The median OS is 39.5+ months for intermediate and 9.1 months for subjects with poor risk. Conclusions: The results from this single-arm phase II study represent a near doubling of expected PFS and OS for unfavorable risk subjects treated with AGS-003 plus sunitinib.

29. Overall survival (OS) of sorafenib (So) plus interleukin-2 (IL-2) versus So alone in patients with treatment-naive metastatic renal cell carcinoma (mRCC): Final update of the ROSORC trial. J Clin Oncol 31, 2013 (suppl 6; abstr 356) Author(s): Giuseppe Procopio et al Background: A randomized phase II trial evaluating So plus IL-2 versus So alone as first-line treatment of mRCC, did not show any difference in progression-free survival (PFS) (primary endpoint) between the two groups. The final overall survival analysis is here reported. Methods: In this open-label phase II study, 128 patients with mRCC were randomized to receive either oral So 400 mg bid continuous dosing plus IL-2 4.5 MIU subcutaneously administered 5 times weekly for 6 weeks every 8 weeks (Arm A), or So alone (Arm B). At relapse, most patients of the two arms underwent treatment with other targeted therapies (TTs) including sunitinib, everolimus, and axitinib. Overall survival was estimated by Kaplan-Meier method and compared by two-sided log-rank test. Results: According to Motzer criteria 55 % of the patients were low risk in both arms, and 41% and 39% were intermediate risk in Arm A and B respectively. After a median follow-up time of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in Arm A and B, respectively (p = 0.667). Five-year OS was 26.3% (95% CI: 15.9-43.5) for the combination arm and 23.1% (95% CI: 13.2-40.5) for single agent arm. The overall number of death was 85, 42 of whom in the So monotherapy group. Median PFS survival was 7.3 and 6.9 months for Arm A and B, respectively (p = 0.109). Overall, 49 (77%) and 48 (75%) patients in Arm A and B, respectively, received at least one subsequent targeted therapy (TTs). The most common adverse events (AEs) in both arms were asthenia, hand-foot syndrome, hypertension and diarrhoea. Grade 3-4 AEs were documented in 38% of patients treated with the combination regimen and in 25% of those undergoing single agent treatment. Conclusions: The OS results suggest an improved outcome in patients with mRCC treated with TTs which appears independent of the treatment initially administered. This prospective study, regarding use of sorafenib in first line of treatment, was associated with a surprising median OS.