1st Line Sunitinib Research Articles

957P - Overall and progression-free survival according to MSKCC scores in 1st line sunitinib treatment of metastatic renal cell carcinoma (mRCC)

BackgroundData on the efficacy and safety of all targeted therapies for metastatic renal cell carcinoma (mRCC) including sunitinib are collected in the Czech RENIS patient registry. RENIS thus provides a uniquely large sample of long-term effectiveness and prognostic data of sunitinib according to adverse/risk factors measured by the Memorial Sloan Kettering Cancer Center (MSKCC) score. The aim of this study was to analyze the long-term overall (OS) and progression-free survival (PFS) of sunitinib, when used as 1st line treatment, based on MSKCC risk group scores including MSKCC scores for two intermediate subgroups. MethodsData from mRCC patients treated using sunitinib in the 1st line were collected in RENIS between 06/2007 and 02/2018. OS/PFS were then stratified based on MSKCC scores: a) favorable risk (0 adverse factors (AF)), b) intermediate risk (pooled 1–2 AFs), and c) poor risk (3+ AFs). The OS/PFS of the intermediate risk group was further stratified into two subgroups: i) 1AF and ii) 2 AFs. All OS/PFS data were analyzed using Kaplan-Meier estimates. Differences in OS/PFS between risk groups were assessed using median survival, 95% confidence intervals (CI), and the log-rank test. Then we assessed the OS/PFS for 1-, 3-, and 5-year survival. ResultsOver the 11-year follow-up, 2390 patients were treated using sunitinib with 806, 1450, and 134 patients in the favorable, intermediate, and poor MSKCC risk groups. The more favorable MSKCC risk group was accompanied by an improved OS and PFS (p<0.001). Regarding the MSKCC for the two intermediate sub-groups, 1AF was associated with improved survival compared to 2 AFs (p<0.001) (Table).Table957P OS and PFS results for sunitinib treatment based on MSKCC risk groupsTableMSKCC favorableMSKCC intermediateMSKCC poorMSKCC intermediateAll patients1AF2 AFsOverall survivalMedian survival (95% CI)44.7months (40.9-50.5)24.1months (21.9-26.0)9.5months (7.2-14.1)28.2months (25.9-30.7)16.2months (14.5-20.2)28.5months (26.3-30.5)1-year survival (95% CI)85.0% (82.4-87.6)69.1% (66.6-71.7)44.3% (35.0-53.7)74.3% (71.4-77.2)58.0% (53.1-62.9)73.3% (71.4-75.2)3-year survival (95 %CI)57.3% (53.4-61.3)37.1% (34.1-40.1)9.6% (3.1-16.2)42.0% (38.3-45.7)26.3% (21.4-31.2)42.9% (40.5-45.2)5-year survival (95% CI)35.6% (31.2-40.1)23.4% (20.4-26.4)3.2% (0.0-8.8)26.5% (22.7-30.3)16.5% (11.8-21.2)26.8% (24.3-29.2)n80614501349694812390Log-rank p-value< 0.001< 0.001-Progression-free survivalMedian survival (95% CI)17.0months (15.4-18.8)9.0months (8.3-9.5)4.5months (3.9-6.1)10.1months (9.4-11.4)6.2months (5.5-7.5)10.6months (9.9-11.5)1-year survival (95% CI)61.8% (58.3-65.3)40.7% (38.0-43.4)20.8% (13.1-28.5)45.1% (41.8-48.4)31.6% (27.1-36.1)46.9% (44.7-49.0)3-year survival (95 %CI)25.1% (21.7-28.5)13.0% (11.0-15.1)1.8% (0.0-5.1)15.9% (13.2-18.6)7.0% (4.2-9.7)16.6% (14.9-18.4)5-year survival (95% CI)10.4% (7.7-13.2)8.0% (6.2-9.8)1.8% (0.0-5.1)9.7 (7.3-12.0)4.5% (2.1-6.9)8.4% (7.0-9.9)n80614501349694812390Log-rank p-value< 0.001< 0.001- ConclusionsBetter MSKCC risk scores were associated with significantly longer OS and PFS. To our knowledge, this is the largest published sunitinib mRCC cohort described relative to MSKCC risk groups. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureJ. Finek: Honoraria (self): Amgen; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Bayer; Honoraria (self): Teva; Honoraria (self): MSD; Honoraria (self): Merck; Honoraria (self): Sanofi; Honoraria (self): Pierre Fabre. A. Poprach: Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): BMS; Honoraria (self): Bayer. B. Melichar: Honoraria (self): BMS; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Astellas Pharma; Honoraria (self): Pfizer; Honoraria (self): Bayer. J. Kopecky: Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): Pfizer. M. Zemanova: Advisory / Consultancy: Novartis; Honoraria (self): Eli Lilly; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. Buchler: Honoraria (self): Amgen; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Janssen. K. Kopeckova: Honoraria (self): Novartis; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Pfizer. T. Mlcoch: Full / Part-time employment: Value Outcomes. T. Dolezal: Full / Part-time employment: Value Outcomes. All other authors have declared no conflicts of interest.

Immunotherapy with nivolumab in metastatic renal cell carcinoma in resource constraint settings: Impact of increasing intervals between standard doses, and stopping treatment early in responding patients.

e16078 Background: Nivolumab is now a standard 2nd line treatment for patients of metastatic Renal cell cancer (mRCC) who progress on 1st line Sunitinib or Pazopanib. Most western centers use Nivolumab for either 2 years duration, or indefinitely, or till severe side effects. Due to high drug cost and lack of insurance, it is difficult for most of our Indian patients to afford this duration of treatment. So, we decided to study the impact of increasing intervals between standard doses of Nivolumab, and stopping treatment early in responding patients of mRCC. Methods: This is a single centre, retrospective study of mRCC patients. Nivolumab was given at either 3 mg/kg or 240mg at 2 weekly intervals for the initial 6 cycles. If the patient were found to have either Complete Response (CR), Partial Response (PR) or stable disease, the interval between cycles was extended to 3 weeks (at same dose). After 9 months, the doses were extended to 4 weekly intervals (at same dose). The treatment was stopped at 18 doses in patients with CR or PR. The endpoints were objective response rate (ORR), overall survival (OS) and adverse events (AE). Results: Between May 2016 and Dec 2018, 28 patients received Nivolumab. 24 patients had received oral TKIs initially- 13 Sunitinib, 10 Pazopanib, and 1 Sorafinib. 4 patients received Nivolumab as 1st line therapy (2 as single agent, 2 with oral TKI). Response was assessed by RECIST criteria. 3 patients (11%) achieved CR, 7(25%) achieved PR, 7 (25%) had stable disease and 11(39%)had progressive disease. Treatment was stopped after 18 doses in the 3 patients who had CR. The duration of followup after stopping treatment ranges from 8 months to 18 months, and all 3 patients continue to be in CR. 3 patients with stable disease have received more that 18 cycles (1 at 22 cycles, 2 at 19 cycles). OS at 1 year is 60% and median OS has not been reached. Conclusions: In our experience, Nivolumab is an effective agent in mRCC, even when the dosage intervals are increased, and when the treatment is stopped early in responding patients. An ORR of 36% and a OS at 1 year of 60% is the best we have seen. Long-lasting responses, even after discontinuing therapy, have been seen. This enables us to reduce the cost of treatment without possibly losing efficacy, and this could be an important step forward for treating more patients with Nivolumab in our resource constraint setting.

Prospective phase II study of sunitinib rechallenge in metastatic renal cell carcinoma (mRCC): A G.I.O.N. trial.

e16081 Background: Sunitinib is a 1st-line standard of care in mRCC. Lack of cross-resistance to sequential VEGF-targeting drugs and the possibility of a successful rechallenge with Sunitinib have been postulated. Whether mRCC patients (pts) could benefit from rechallenge with Sunitinib after progressing on 1st-line Sunitinib and 2nd-line Everolimus was the aim of this phase II study Methods: 39 mRCCpts were prospectively treated with Sunitinib (50 mg/daily, 4:2); main inclusion criteria were: histologically proven RCC with clear cell component, previous 1st-line Sunitinib with a Disease Control Rate lasting at least 10 months, 2nd-line Everolimus, and written informed consent. The primary end-point of this study was 6-months progression-free survival (PFS). A Simon’s 2-stage design was used; after testing Sunitinib on 12 pts in the first stage, the trial would have been terminated if 5 or fewer had a PFS of less than 6 months. Otherwise, the trial would have proceeded to the second stage, enrolling a total of 38 pts. If the total number of pts free of progression at 6 months would have been less than or equal to 18, Sunitinib would have been rejected Results: As a whole, 39 pts (30 males, 9 females) were enrolled. The study quickly moved from the first stage to its completion and ultimately succeeded; indeed, 6-months PFS was 60%, median PFS being 8.6 months (average: 9.59, range: 0.7-24.6 months). In terms of safety no unexpected toxicities were observed. Tx-related grade 3-4 AEs observed in ≥5% of the pts were: hand-foot skin reaction, fatigue, nausea, hypertriglyceridemia, hypophosphatemia, hypocalcemia, hyperglycemia, and neutropenia. One case each of myocardial infarction, atrial flutter and spontaneous pneumothorax were also reported, but resolved Conclusions: Despite an ineluctable time-lead-bias, median PFS on Sunitinib rechallenge was high (8.6 months), clearly showing that many pts may become sensitive again to VEGFRs-inhibition. Although many agents are presently available from 2nd-line on, in countries where treatment options are still limited, Sunitinib rechallenge could still represent a reasonable treatment option. EudraCT number: 2012-000473-23. Clinical trial information: 2012-000473-23.

Sunitinib versus sorafenib as first-line therapy followed by sorefenib and sunitinib for patients with metastatic renal cell carcinoma (RCC) with clear cell histology: A multicenter randomized trial, CROSS-J-RCC.

469 Background: SWITCH, a prospective, randomized sequential trial to evaluate SU/SO versus SO/SU, revealed no difference in first-line or total PFS or OS, but no direct comparison was obtained between 1st line sunitinib (SU) and sorafenib (SO) for clear cell (CC) metastatic renal cell carcinoma (mRCC). Methods: Treatment-naïve patients with CC mRCC, ECOG PS 0/1 and MSKCC favorable or intermediate risk were randomized to receive open-label SU/SO or SO/SU at the standard dosage and schedule. The primary endpoint was 1st line PFS, and secondary endpoints were total PFS and OS. The calculated sample size was 59 per group, with α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 patients enrolled in this study from February 2010 to July 2012 from 39 institutions, 120 could be evaluated (SU/SO, 57 and SO/SU, 63). Baseline patients' characteristics in the SU/SO and SO/SU groups were as follows: favorable risk, 21% and 22%; and presence ofnephrectomy, 88% and 89%, respectively. First-line mPFS was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (HR, 0.67; 95% CI, 0.42–1.08; p= 0.095). There was no statistically significant difference in total (T)-PFS, 27.8 M, and 22.6 m (HR 0.73, CI 0.428-1.246; p=0.247), or OS 38.4 m and 30.9 m (HR 0.934, CI 0.588-1.485; p=0.773). Subgroup analyses showed that T-PFS was NR and 27.8 m (p=0.021) in the favorable risk, and 38.4 m and 16.1 m (p=0.009) in with less than 5 metastatic sites, 6.5 m and 13.6 m (p=0.025) without nephrectomy in the SU/SO and SO/SU groups, respectively. The most common adverse events (AEs) in case of first-line SU or SO (all grade, all cause) were hand–foot syndrome (71% vs. 86%), hypothyroidism (70% vs. 33%), fatigue (57% vs. 40%), hypertension (55% vs. 44%), and diarrhea (23% vs. 38%). AEs were generally lower during second-line therapy. Conclusions: There was no significant difference in first-line PFS, T-PFS, and OS between the two sequential treatments. Although fewer patients received second-line treatment in the SU/SO group, OS in this group was numerically longer than that in the SO/SU group. Clinical trial information: 01481870.

Abstract 430: Novel biomarkers for VEGFR inhibitors in metastatic renal cell carcinoma: BIM expression, and germline polymorphisms of BIM and PIK3R1

Abstract Molecular targeted therapy, especially VEGFR tyrosine-kinase inhibitors (TKIs) including sunitinib, pazopanib and sorafenib has been the most efficacious therapy for metastatic renal cell carcinoma (mRCC). However, approximately 35% of mRCC patients do not get the benefit from TKIs treatment, due to resistance and/or drug induced toxicities. Pro-apoptotic Bcl-2 family member (BIM) is a particularly critical mediator of targeted therapy-induced apoptosis in solid tumors. In previous, it had known that TKIs induced to BIM upregulation and then accelerated to apoptosis of tumor. However, according to recent several studies, BIM germline deletion polymorphism was identified as one of the primary resistant mechanisms of various TKIs in EGFR mutated NSCLC or CML. In addition, the alteration of phosphoinositide 3 kinase(PIK3)/protein kinase B(AKT) pathway has also been found as important mechanism in various cancer cell growth, proliferation and survival. PI3KR1 encodes the p85α subunit, regulatory subunits of Class IA PIK3s. Germline PIK3R1 variant M326I(c.978G&amp;gt;A) might affect the sensitivity of receptor tyrosine kinase (RTK) inhibitors and its downstream pathway inhibitors. We evaluated the possibility of BIM, PIK3R1 as a potential biomarker for VEGFR TKIs in mRCC. BIM deletion polymorphism status of gDNA from formalin fixed paraffin embedded (FFPE) tumor tissues and peripheral blood mononucleated cells (PBMC) of mRCC patients was determined by separated PCR. And we evaluated BIM protein expression by immunohistochemistry. We also evaluated PIK3R1 germline mutation by pyrosequencing in PBMC of mRCC patients.Germline BIM deletion accounted for 17.8% of total 124 mRCC patients. Unlike with previous other studies, our data suggested that BIM wild type showed tendency to poor prognosis with sunitinib or sorafenib treatments for clear cell type RCC (median OS of BIM wild and deleted type: 44.9 vs 67.3 months, p = 0.279), and high expression of BIM (median OS of BIM low(&amp;lt;10%), median(10-50%) and high(&amp;gt;50%) respectively: 76.5 vs 60.0 vs 21.3 months, p = 0.005). In addition, we found 26% (19/71) of the germline PIK3R1 variant in mRCC. Patients with PIK3R1 germline variant showed a tendency of poor prognosis to 1st line VEGFR TKI treatment than wild type (median PFS: 7.78 vs 15.87months, p = 0.342). Especially PFS of 1st line sunitinib treatment was significantly shorter in PIK3R1 variant compared to wild type (median PFS 7.78 vs 16.33 months, p = 0.004). But, there is no difference in mTOR inhibitor sensitivity both with PIK3R1 or BIM polymorphism.In conclusion, BIM expression and germline variants of BIM and PIK3R1 might be candidate biomarkers for VEGFR TKIs in mRCC. Citation Format: Jee Hung Kim, Woo Sun Kwon, Won Suk Lee, Tae Soo Kim, Kyu Hyun Park, Jae Kyung Roh, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. Novel biomarkers for VEGFR inhibitors in metastatic renal cell carcinoma: BIM expression, and germline polymorphisms of BIM and PIK3R1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 430.

610TiP - Lume-Colon 1: Double-Blind, Randomised Phase III Study of Nintedanib (Bibf 1120) Plus Best Supportive Care (Bsc) Versus Placebo Plus Bsc in Patients (Pts) with Refractory Colorectal Cancer

ABSTRACT Background: Clinical studies with anti-VEGF agents demonstrate that angiogenesis is critical to colorectal (CRC) tumour growth and metastasis. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF and FGF signalling. Phase II studies showed that 1st-line N monotherapy has similar efficacy to 1st-line sunitinib or sorafenib in VEGF-sensitive cancers like renal cell carcinoma (NCT01024920; 1199.26) and hepatocellular cancer (NCT01004003; 1199.37), respectively. N has also shown clinical activity and a manageable safety profile in phase III trials with NSCLC (NCT00805194; 1199.13 and NCT00806819; 1199.14) and ovarian cancer (NCT01015118, 1199.15). These findings provide a rationale to examine N in refractory CRC. The objective of this study is to evaluate PFS, OS and safety of N in pts with metastatic CRC after failure with standard chemotherapy and biological agents. Trial design: 764 pts from approximately 150 sites worldwide—at least 18 years of age, ECOG score 0–1, and histologically/cytologically confirmed CRC adenocarcinoma not amenable to surgery and/or radiotherapy—will be randomised 1:1 to receive either N (200 mg bid) + BSC or placebo (bid) + BSC in 21-day courses until disease progression or undue toxicity. The study is adequately designed and powered for distinguishing a clinically meaningful effect in the primary endpoint PFS and the key secondary endpoint OS. Other secondary endpoints are objective tumour response and disease control. Pts will be stratified at randomisation based on previous regorafenib treatment (yes vs no), time from onset of metastatic disease until randomisation in the trial ( Disclosure: E. Van Cutsem: Research Grants: Boehringer Ingelheim; J. Tabernero: Consultant: Amgen, Celgene, Chugai, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Roche, Sanofi, Taiho; T. Yoshino: Consultant/Honoraria: Chugai, Merck Serono, Takeda; Research Grants: Bayer, Chugai, Daiichi Sankyo, Lilly, Pfizer, Taiho, Yakult; M. Sassi: Employee: Boehringer Ingelheim France S.A.S., France; Z. Oum'Hamed-Mansour: Employee: Boehringer Ingelheim France S.A.S., France; M. Studeny: Employee: Boehringer Ingelheim, Austria; H. Lenz: Consultant: Boehringer Ingelheim

Body composition as a predictor of sunitinib toxicity in patients with renal cell carcinoma.

e15566 Background: Sunitinib is a standard first-line option for metastatic renal cell cancer (mRCC). Identification of biomarkers associated with outcome or toxicity is a challenge. Body composition is a prognostic factor in cancer and sarcopenia is associated with treatment toxicity and survival. We investigated if body composition by CT scan predicted dose limiting toxicity (DLT) from sunitinib in mRCC. Methods: Patients (pts) with mRCC receiving sunitinib 50mg as 1stline therapy between 2007-2012 were included. Ethical approval was obtained and prospectively maintained databases analysed. Skeletal muscle cross-sectional area at L3 was measured by CT. Sarcopenia was defined using published cut offs. Toxicity was assessed after 4 cycles of drug (CTCAE, v4.0). Results: 55 pts (43 male), mean age 64yrs (±10.6) were included. 67% were overweight/obese (BMI&gt;25kg/m2). Sarcopenia was present in 33% (56% of normal BMI, 44% overweight group). Overall 40 pts (73%) experienced DLT (51% M, 100% F, p&lt;0.016). DLT occurred in &lt;6 months in 53% (44% M vs 83% F, p&lt;0.016) and these pts were older (mean 68 yrs vs 60 yrs, p&lt;0.01), had lower skeletal muscle mass (51.8 cm2/m2 vs 59.4 cm2/m2, p&lt;0.012), and fat free mass (FFM) (51.4kg vs 57.7kg, p&lt;0.03), and received higher drug dose in mg/kg FFM (1.01 vs 0.89, p&lt;0.02). Common toxicities were GI (65%) and fatigue (47%). Of pts &lt;25th percentile skeletal muscle mass 92% experienced DLT, higher than pts &gt;75th percentile (p&lt;0.05). Pts &lt;25th percentile had an average of 5 toxicities vs 2 in those &gt;75th percentile (p&lt;0.003). All toxicities were more common in muscle wasted patients (p&lt;0.05). 77% (n=10) of pts receiving a drug dose &gt;75th percentile (1.105mg/FFM) experienced DLT in &lt;6 months vs 44% (n=17) receiving a dose &lt;75thpercentile (&lt;1.099mg/FFM; p&lt;0.037). Conclusions: Sarcopenia is prevalent in patients with mRCC, is easily measured, is an occult condition in pts with normal/high BMI, and is a significant predictor of DLT in pts receiving 1st line sunitinib. Our results highlight the potential use of baseline body composition to predict toxicity. The role of sarcopenia in targeted therapy is evolving and its potential to predict toxicity should be further studied.

Reversible posterior leucoencephalopathy syndrome (RPLS) associated with pazopanib.

e15574 Background: Tyrosine kinase inhibitors (TKI) are a relatively new modality for the therapy of metastatic renal cell carcinoma (MRCC). Although there are promising results, their use is often limited due to adverse reactions. We report on a case of malignant hypertension (HTN) and RPLS in a patient (PT) treated with pazopanib for MRCC. Methods: Case report. Results: A 62 year old woman with MRCC and since 8 weeks under 3rd-line therapy with pazopanib had suddenly developed headaches, grand-mal seizures, paresis of the left arm, gait instability and nausea during her vacation. The emergency physician measured blood pressure (BP) values &gt;300 mmHG systolic and suspected a stroke. A CT without contrast agent in a local hospital only showed bone metastases. Suspecting cerebral metastases or meningeosis carcinomatosa (MC) the colleagues referred her to our radiooncologic department for diagnostics and treatment planning. At admission the PT was somnolent and unable to communicate because she had received larger quantities of diazepam as an anticonvulsive on the plane. The next day the PT was fully awake but showed significant anterograde amnesia from the onset of the headaches, psychomotoric deceleration and persistent gait instability. Brain metastases and MC were ruled out in an MRI which showed signs of RPLS in the form of band-like hyperintensities in the left parietal lob. HTN up to 220/120 mmHg persisted under 3x antihypertensive therapy and the PT reported that similar values were measured after the start of 1st-line sunitinib 1 year ago. We discontinued pazopanib. Within 1 week the neurologic findings vanished and we discharged her. An MRI 3 weeks later showed RPLS-typical cortical infarctions in the affected area. The PT remained without any neurologic symptoms but intermittent HTN persisted. Conclusions: Vascular endothelial growth factor (VEGF) inhibitors and TKI are associated with HTN. Currently the exact mechanism remains unknown. HTN is an indicator for improved outcome under TKI therapy. BP should be closely monitored under TKI therapy. RPLS clinically mimicking cerebral metastases should always be considered as the actual reason for neurologic findings in patients with known metastatic cancers under TKI therapy.

LBA22_PR - Temsirolimus vs Sorafenib As Second Line Therapy in Metastatic Renal Cell Carcinoma: Results from the Intorsect Trial

ABSTRACT Background Temsirolimus (TEM) demonstrated an overall survival (OS) benefit vs interferon alfa in previously untreated patients (pts) with advanced renal cell carcinoma (RCC) and poor prognostic features. The efficacy of temsirolimus after VEGF inhibitor therapy is not known. This multicenter, randomized, open-label phase 3 trial compared the efficacy and safety of TEM vs sorafenib (SOR) in pts with metastatic RCC (mRCC) who failed prior sunitinib therapy. Methods RCC pts with disease progression after 1st-line sunitinib therapy and ECOG performance status 0 or 1 were enrolled. Eligible pts, stratified by duration of prior sunitinib therapy (≤ or >6 mo), prognostic risk, histology (clear cell or non–clear cell), and nephrectomy status, were randomized 1:1 to receive TEM 25 mg/wk intravenously or SOR 400 mg bid. Dose reductions were allowed for TEM (to 20 then 15 mg) and for SOR (to 400 mg/d then every other day). Study was powered to detect a 33% improvement in progression-free survival (PFS), the primary end point, by independent central review. Results From Sept 2007 to March 2011, 112 sites in 20 countries enrolled 512 pts; 259 received TEM and 253 received SOR. Baseline demographics were balanced. Median age was 60 y, 75% were male, and 67% were white (Asian, 17%). Histology was clear cell in 422 pts, non–clear cell in 90 pts. At data cutoff for final analysis (May 2012), 389 pts had independently assessed PFS events; 351 pts had died. Median PFS with TEM was 4.28 mo (95% confidence interval [CI]: 4.01, 5.43) and with SOR, 3.91 mo (95% CI: 2.80, 4.21); hazard ratio [HR] = 0.87 (95% CI: 0.71, 1.07; 2-sided P value = 0.1933). Median OS for the TEM group was 12.27 mo (95% CI: 10.13, 14.80); for the SOR group, 16.64 mo (95% CI: 13.55, 18.72); HR= 1.31 (95% CI: 1.05, 1.63; 2-sided P value = .0144). The most common adverse events (all grade, all cause) with TEM were rash, fatigue, diarrhea, anemia, and hyperglycemia; with SOR, they were diarrhea, rash, hand-foot syndrome, and decreased appetite. Conclusions TEM did not show superiority to SOR in the primary end point (PFS [independent]) or in the secondary end point of OS. Safety data were as expected for both agents. Further evaluation is needed to define the optimal sequence after prior sunitinib in advanced RCC pts. Disclosure This study was sponsored by Pfizer Inc. T. Hutson: Dr. Hutson is a Study Investigator for Pfizer Inc. B. Escudier: Advisory role for Aveo, Bayer, GSK, Novartis, Pfizer Inc G.A. Bjarnason: Has received honoraria for talks given, support for travel to meetings and advisory boards, and funding for investigator initiated trials from Pfizer Inc. P. Senico: Employee and stock owner of Pfizer Inc. A. Niethammer: Employee and stock owner of Pfizer Inc. D. Lu: Employee and stock owner of Pfizer Inc. S. Hariharan: Employee and stock owner of Pfizer Inc. R.J. Motzer: Research Funding and Consultancy with Pfizer Inc. All other authors have declared no conflicts of interest.

Development and validation of prognostic models in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib: A Greek-French collaboration.

e15040 Background: The use of tyrosine kinase inhibitors (TKIs) in mRCC has improved prognosis but the individual outcome remains largely unpredictable. The MSKCC model, used to identify risk groups, was developed in cytokine-treated patients and has not been externally validated in the TKI era. It contains 3 laboratory factors (total 5), making its application to retrospective series somewhat problematic. Subsequently, a more complicated model, using 4 laboratory factors (total 6) has been described. The Hellenic Cooperative Oncology Group recently described a simpler model with only 3 clinical factors. We are describing the application and external validation of this model. Methods: 128 Greek patients with mRCC treated with 1st line sunitinib were included. All had had nephrectomy. Previous interferon was allowed. Cox regression was used to develop a predictive model for overall survival (OS). Our model was compared to that of MSKCC and Heng’s using ROC curves and Harrell’s Concordance Index. Risk groups were defined by the calculated prognostic index and by clinical factors. External validation was done using a sample of 226 French patients. The Royston and Sauerbrei D statistic was used as a measure of discrimination of the survival model. Results: Time from diagnosis of RCC to start of sunitinib (&lt;12), PS (&gt;1) and number of metastatic sites (&gt;1) were independent adverse prognostic factors in the Greek dataset. The co-efficients for each factor were: 0.51, 0.97, 0.61, respectively. The 3 risk groups were defined by the 25th and 75th percentiles of the prognostic index values (Table 1). The model was of equal prognostic value to the MSKCC (p=.272) and Heng’s (p=.075). French had better survival than Greek patients especially in the high risk group (for all models). Validation of our model in the French data showed that it was applicable (R2 D: 0.14, SE: 0.09), especially for the low/medium risk groups. Conclusions: Our model is the only one externally validated in TKI-treated patients. It may be considered as a simpler alternative to those currently applied. [Table: see text]

Risk of treatment failure after first-line sunitinib therapy in patients with metastatic renal cell carcinoma.

438 Background: Treatment options for metastatic renal cell carcinoma (mRCC) are rapidly evolving. Current treatment options include surgery, immunotherapy, and several targeted therapies including kinase inhibitors, mTOR inhibitors and anti-VEGF agents. The aim of this study was to inform choices and outcomes on the sequential use of targeted therapies for mRCC through the evaluation of the comparative effectiveness of common second-line targeted therapies following 1st line sunitinib treatment. Methods: A retrospective observational study using claims data was conducted. Final study subjects were mRCC patients who received everolimus, sorafenib or temsirolimus from 4/1/2008 to 2/29/2011 following 1st line sunitinib treatment. Patients were followed from the start of second-line treatment until treatment failure or last observation in the database. Treatment failure was defined as advancement to a third-line of mRCC therapy, or mortality. Results were analyzed using Cox proportional hazards model controlling for baseline clinical and demographic factors. Results: The study sample consisted of 257 mRCC patients who received everolimus (n=117), temsirolimus (n=75) and sorafenib (n=65) following 1st line sunitinib treatment. Patients had a mean age of 63 years, and 72% were male. The mean observation period from the start of second-line treatment was ∼6.4 months. Treatment failure was observed in 38.5% (20.2% advanced from 2nd to 3rd line and 18.3% died) of the study sample and 61.5% of patients were censored at last observation without any treatment failure event. Results from the Cox proportional hazards model indicated that, compared to everolimus, both sorafenib and temsirolimus patients experienced a statistically significant higher adjusted risk of treatment failure (sorafenib: HR=1.77, p=0.043; temsirolimus: HR=2.05, p=0.004). Conclusions: Following systemic treatment for mRCC with first-line sunitinib, patients on second-line targeted therapies were observed with differential risks of treatment failure, as defined by line advancement or death. The risk of treatment failure was significantly higher with sorafenib and temsirolimus as compared to everolimus.

Treatment and overall survival (OS) in metastatic renal cell carcinoma (mRCC): A Swedish population-based study (2000–2008).

389 Background: This retrospective register study assessed OS in all mRCC patients in Sweden diagnosed before (2000–2005) and after (2006–2008) the introduction of targeted therapies, plus factors and treatment options influencing OS. Methods: Three Swedish national health registers were used: the Swedish Cancer register (diagnosis and death), the National Patient Register (in-/out-patient data), and the Swedish Prescribed Drug Register. From 2000-2008, 3,243 patients were identified with mRCC; 602 were recorded as receiving 1st-line treatment. Cox proportional hazards regression analysis, including estimation of adjusted OS, was used in three models with the covariates: diagnosis period, age, gender, institution size, nephrectomy status, geographic region (all models); mRCC treatments, defined as any tyrosine kinase inhibitor (TKI; Model 1; n=417); sunitinib (SU), sorafenib (SO), and interferon-alfa (IFN-α) in the 1st-line setting (Model 2; n=602 [SU=244, SO=110, IFN-α=248]); and variations of these drugs as 1st- and 2nd-line treatment sequences (Model 3; n=602). Results: Amongst mRCC patients diagnosed from 2006–2008 compared with 2000–2005, median adjusted OS was 16.1 vs. 10.9 months, respectively (HR=0.76, 95% CI: 0.69, 0.83; P&lt;0.001). In all three models, factors independently associated with significantly improved OS included female gender, large institution, and prior nephrectomy. Prescription of any TKI (Model 1: HR=0.82, 95% CI: 0.73, 0.93; P=0.002) and 1st-line SU treatment (Model 2: HR=0.79, 95% CI: 0.67, 0.94; P=0.007) were associated with significantly improved OS compared with other or no treatments. A similar significant improvement in OS was also confirmed for patients treated with SU only in Model 3; however, due to a low number of observations, the model had insufficient statistical power to be appropriate for all sequences. Conclusions: An improved OS for mRCC patients was demonstrated for the period 2006-2008 compared with 2000-2005. Although the observed survival advantage is multifactorial in origin, contribution of targeted therapies is highly probable. Of the drugs studied, given design limitations, only SU was associated with improved OS.

Risk of treatment failure after first-line tyrosine kinase inhibitors (TKI) therapy in patients with metastatic renal cell carcinoma.

e15114 Background: Treatment for metastatic renal cell carcinoma (mRCC) includes surgery, immunotherapy, and/or targeted therapy: kinase inhibitors (including mTOR) and anti-VEGF agents. This analysis utilizes recent data to provide insight on comparative treatment effectiveness among common therapies after 1st line sunitinib or sorafenib (TKI). Methods: A retrospective observational study using claims data was conducted. Qualifying subjects were mRCC patients receiving targeted therapies from 4/1/2008 to 2/28/2010 following 1st line sunitinib or sorafenib (TKI) treatment. Following TKI treatments, 2nd line post mRCC observed therapies of interest included sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab, and pazopanib. Patients were followed from the start of 2nd-line until treatment failure or last observation in the database. Treatment failure was defined as advancement to a 3rd line of post mRCC therapy, or mortality. Results were analyzed using Cox proportional hazards model controlling for baseline clinical and demographic factors. Results: The study sample consisted of 283 mRCC patients post 1st line TKI therapy. Second line treatment included: everolimus (n=81), temsirolimus (n=46), sunitinib (n=83), sorafenib (n=50), and All Others (n=23 miscellaneous regimens, generally including bevacizumab or pazopanib). Patients had a median age of 65 years, and 71% were male. The mean observation period from the start of 2nd line treatment post mRCC, was ~4.5 months. Overall treatment failure rate was 32.9% (16.6% advanced line and 16.3% died) and 67.1% of patients were censored at last observation without any treatment failure event. Compared to everolimus: temsirolimus was associated with a statistically significant, higher, adjusted risk of treatment failure (HR=2.51 p=0.008); Sorafenib trended toward a higher adjusted risk (HR=1.91, p=0.069); and sunitinib’s adjusted risk of treatment failure was statistically equivalent. Conclusions: Following treatment post mRCC with 1st line sunitinib or sorafenib (TKI), patients on 2nd line therapies were observed with differential risks of treatment failure, as defined by line advancement or death.