Comparative effectiveness of 2nd-line targeted therapies for metastatic renal cell carcinoma: analysis of two practice-based chart reviews
J.E. SIGNOROVITCH*, N.J. VOGELZANG† , S.K. PAL‡, P.L. LIN*, D.J. GEORGE§, M.K. WONG¶, Z. LIU**, X. WANG**, K. CULVER**, J.A. SCOTT††and E. JONASCH‡‡
*Analysis Group, Inc., Boston, MA, USA;†US Oncology Research, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA;‡City of Hope Comprehensive Cancer Center, Duarte, CA, USA;§GU Oncology, Duke Cancer Institute, Durham, NC, USA;¶University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; **Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA;††Cardinal Health, Grand Prairie, TX, USA;‡‡MD Anderson Cancer Center, Houston, TX, USA
Background: Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study aimed to compare practice-based effectiveness of these therapies in a recent chart review, and to compare findings with a previous chart review (Yang et al. 2012. ASCO).
Methods: Community-based medical oncologists/hematologists (N = 36) reviewed charts for ≤15 patients each. Included patients were aged ≥18 years, received a 1st-line TKI and initiated 2nd-line targeted therapy in 2010 or later. The primary outcome was time from 2nd-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving 2nd-line everolimus (EVE), temsirolimus (TEM), or TKI as a class (sunitinib, sorafenib, pazopanib or axitinib), using a multivariable Cox proportional hazards model adjusting for characteristics including type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled with previously-reported HRs for progression-free survival (PFS) from a previous chart review in a meta-analysis.
Results: A total of 138, 64 and 79 patients received 2nd-line therapy with EVE, TEM or a TKI, respectively. Mean age was 63 years, mean duration of mRCC 13.5 months, and median follow-up 6 months. After adjusting for baseline characteristics, EVE was associated with a 28% and 26% reduction in the hazard of TTF compared to TEM and TKI, respectively. Pooling both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (Table). TTF differences between TEM and TKI were not significant.
Conclusions: In two retrospective chart reviews EVE was associated with consistently reduced hazards of 2nd-line treatment failure in mRCC compared to TEM and TKIs.
HR (95% Confidence Interval)
EVE vs. TEM
0.73 (0.54, 0.97)
0.72 (0.45, 1.16)
0.73 (0.57, 0.93)
EVE vs. TKI
0.76 (0.55, 1.04)
0.74 (0.48, 1.15)
0.75 (0.58, 0.97)
Survival following initiation of everolimus for 2nd-line treatment of metastatic renal cell carcinoma: prognostic factors in clinical practice and comparison to clinical trials
M.K. WONG*, E. JONASCH†, S.K. PAL‡, J.E. SIGNOROVITCH§, P.L. LIN§, Z. LIU¶, X. WANG¶, K. CULVER¶, J.A. SCOTT**, D.J. GEORGE††and N.J. VOGELZANG‡‡
*University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA;†MD Anderson Cancer Center, Houston, TX, USA;‡City of Hope Comprehensive Cancer Center, Duarte, CA, USA;§Analysis Group, Inc., Boston, MA, USA;¶Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; **Cardinal Health, Grand Prairie, TX, USA;††GU Oncology, Duke Cancer Institute, Durham, NC, USA;‡‡US Oncology Research, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA
Background: Current overall survival (OS) for metastatic renal cell carcinoma (mRCC) patients in clinical practice may differ from clinical trials. We aimed to identify and validate prognostic factors for OS in practice-based patients receiving 2nd-line everolimus (EVE), and to compare their OS vs. the RECORD-1 trial of EVE for mRCC.
Methods: Two separate samples of oncologists/hematologists reviewed charts for patients initiating 2nd-line EVE between 2009 and 2011 following a 1st-line tyrosine kinase inhibitor (TKI). OS was defined as time from EVE initiation to death (censored at last follow-up). In the 1st sample of charts (the study sample), prognostic factors were identified via multivariable Cox proportional hazards models with stepwise selection. Prognostic factors considered included age, duration of mRCC and 1st-line treatment, metastatic sites, diabetes, histological subtype, ECOG and KPS score, and progression during 1st-line treatment. Model performance was assessed in the 2nd sample (the validation sample). Kaplan-Meier (KM) estimates for OS were compared between chart data and RECORD-1.
Results: The study and validation samples included 220 and 97 patients, respectively. Significant prognostic factors were clear cell histology (hazard ratio (HR) = 2.9), KPS score <80% (HR = 2.9), duration of mRCC <1 year (HR = 2.7), progression on 1st-line TKI (HR = 2.2), and liver metastasis (HR = 1.9) (all P < 0.05). In the validation sample, KM estimates for 1-year OS were 90% for patients with 0–2 risk factors, 62% for patients with 3 risk factors, and 20% for patients with 4–5 risk factors (log-rank P < 0.001). OS estimates were consistent between both chart samples with 1-year OS probabilities of 67% and 68% and median OS of 19 and 23 months. In RECORD-1 1-year OS was 60% and median OS was 14.8 months (Motzer et al. 2010, Cancer).
Conclusions: Prognostic factors for OS following 2nd-line EVE for mRCC in clinical practice were consistent with those previously identified in trial data. However, OS with 2nd-line EVE in clinical practice was longer than observed in trial data, and was not associated with type of 1st-line TKI.
Association between guideline-adherent imaging and overall survival following 2nd-line targeted therapy for metastatic renal cell carcinoma
P.L. LIN*, S.K. PAL†, E. JONASCH‡, J.E. SIGNOROVITCH*, Z. LIU§, K. CULVER§, J.A. SCOTT¶and N.J. VOGELZANG**
*Analysis Group, Inc., Boston, MA, USA;†City of Hope Comprehensive Cancer Center, Duarte, CA, USA;‡MD Anderson Cancer Center, Houston, TX, USA;§Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA;¶Cardinal Health, Grand Prairie, TX, USA; **US Oncology Research, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA
Background: NCCN guidelines recommend imaging at 2–6 months after initiation of targeted therapy for metastatic renal cell carcinoma (mRCC). This study assessed the association between guideline-adherent imaging and overall survival in mRCC.
Methods: Thirty-six community-based medical oncologists/hematologists reviewed charts for ≤15 mRCC patients each. Included patients were aged ≥18 years and initiated 2nd targeted therapy in 2010 or later. Patients alive up to month 6 were categorized into 3 groups based on time of first imaging test: early (0–60 days), guideline-adherent (61–180 days), and delayed (>180 days). Overall survival (OS) was compared using multivariable Cox proportional hazards models adjusted for age, gender, duration of mRCC, prior treatments, comorbidities, metastatic sites, 1st targeted therapy, ECOG and MSKCC status, 2nd targeted therapy, and progression status (based on symptoms or imaging) in the first 6 months on 2nd line therapy. Reasons for imaging were also assessed.
Results: Among the 192 patients included in the analysis, 25 received early imaging, 136 received guideline-adherent imaging, and 31 received delayed imaging. First imaging tests were more likely due to worsening symptoms or changes in a palpable mass, as opposed to routine monitoring, among patients with delayed vs. guideline adherent imaging (20.0% vs. 7.1%, P = 0.005). After adjusting for baseline characteristics, guideline-adherent imaging was associated with a 64% lower hazard of death compared to delayed imaging (hazard ratio (HR) = 0.36, 95% confidence interval (CI) 0.14 to 0.93, P = 0.035). Adjusted 1-year survival was 82% in the guideline-adherent compared to 67% in the delayed imaging group. The hazard of death did not differ between those with early vs. guideline-adherent imaging (HR = 1.05, 95% CI 0.35–3.12, P = 0.927).
Conclusions: Among patients surviving 6 months after the initiation of 2nd targeted therapy for mRCC, timely first imaging within 2–6 months, consistent with guidelines, was associated with significantly prolonged overall survival compared to delayed imaging. Further investigation is warranted with larger samples.
Contrast enhancement on CT following renal cryoablation – does it represent treatment failure?
T.K.NIELSEN*, Ø. ØSTRAAT*, G. ANDERSEN†, S. HØYER‡and M. BORRE*
*Dep. Urology, Aarhus University Hospital;†Dep. Radiology, Aarhus University Hospital;‡Dep. Pathology, Aarhus University Hospital, Denmark
The project was kindly supported by The Danish Cancer Society.
Aim: Renal cryoablation is a valid treatment option for localized pT1a renal cancer. Treatment success is typically defined as absence of contrast enhancement (CE) on follow-up imaging. We investigate the development of lesions that demonstrate CE on follow-up CT after renal cryoablation.
Materials and Methods: A retrospective review of laparoscopic and percutaneous cryoablation procedures from 2005 to 2012 was conducted. A total of 113 patients with a localized pT1a biopsy verified malignant renal lesion was identified. Of these, 34 patients (12 females and 22 males) experienced postoperative CE. Mean patient age was 43 (59–66) yr. Mean tumor size was 25 (22–28) mm. RCC-subtypes: Clear cell (55%), Papillary (12%), Chromophobe (3%), Subtype not specified (30%). There was no statistically significant difference between the patient characteristics with or without CE lesions.
Results: A total of 28 patients (25%) were found to have CE on the initial follow-up CT and additional 6 patients had delayed CE (defined as no CE on prior CT). Spontaneous resolution of the CE was observed in 12 of the 34 patients (35%). Eleven percent of the patients with CE lesions had salvage therapy (including reablation) after the initial follow-up CT at 6 months compared with 44% and 33% after the second CT and third CT, respectively (p > 0.05). Two of the 6 patients with delayed CE were reablated, one had oncological treatment due to performance status and three are still awaiting the next follow-up CT.
Conclusion: CE is evident in about ¼ of patients on the initial follow-up CT. At 12 months CE had spontaneously resolved in more than ⅓ of patients, but was continuously observed as late as 31 months. There was a tendency towards intervention if persistent CE was evident at 12 months, but later interventions were not uncommon. As there are no clear-cut criteria for monitoring treatment failure, careful evaluation by an experienced radiologist and urologist is recommend. The significance of delayed contrast enhancement is not clearly evident and needs further investigation.
Fig. 1 Flow chart of patients with CE on follow-up imaging. Salvage therapy was defined as all secondary curative intended therapies, including reablation. *The patient with delayed CE in CT-3 had no CE on CT-2 but had CE on CT1.
The lifetime cost of everolimus vs. axitinib in metastatic renal cell carcinoma patients who have failed prior sunitinib therapy in the US
S. PAL*, A. PERRIN†, A. CHUA†, M. GORRITZ†, Z. LIU‡, X. WANG‡and L. GARRISON§
*City of Hope Comprehensive Cancer Center, Duarte, CA, USA;†LA-SER Analytica, New York, NY, USA;‡Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA;§University of Washington, Seattle, WA, USA
Background: Everolimus and axitinib are approved in the US to treat metastatic renal cell carcinoma (mRCC) patients after failure on sunitinib or sorafenib, and one prior systemic therapy (e.g., sunitinib), respectively. Based on their respective clinical trial data, everolimus and axitinib appear to have similar progression-free survival (PFS) efficacies in sunitinib-refractory patients. Therefore, the purpose of this study is to compare the lifetime cost and resource utilization of these two therapies among mRCC patients following failure of sunitinib from a US payer perspective.
Methods: A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and estimate the cost of treating patients with of everolimus vs. axitinib. The following health states were included: stable disease without adverse events (AEs), stable disease with AEs, disease progression (PD), and death. Lacking an overall survival (OS) comparison between the two drugs, the model base case assumed OS equivalency between the arms based on the demonstrated association between PFS and OS (Delea et al. 2012). The model included the following resources: anti-tumor treatments, post-progression treatments, adverse events, physician and nurse visits, scans, blood tests, and palliative care. For drugs, the wholesale acquisition cost was used. Visit, procedure, and test costs were obtained from the Physician's Fee & Coding Guide. Adverse event management and end-of-life care costs were based on the Healthcare Cost & Utilization Project, secondary literature, and expert opinion. Resource utilization was obtained from clinical trial data and an analysis of the MarketScan® Research Database. A 3% annual discount rate was applied to costs and survival estimates. Scenario analyses were performed to determine the model's robustness.
Results: Base case results demonstrated that sunitinib-refractory patients treated with everolimus cost an average of $15,880 (15%) less over their lifetimes than sunitinib-refractory patients treated with axitinib. The primary difference in costs was related to anti-tumor treatment, which was largely driven by axitinib's higher dose intensity. Results remained consistent across sensitivity analyses for AE and PD treatment costs, as well as dose intensity.
Conclusions: Model results suggest that everolimus likely leads to lower lifetime costs than axitinib for sunitinib-refractory mRCC patients in the US.
FGF-mediated angiogenesis as independent mechanism of resistance to VEGF/VEGFR targeting
I. TSIMAFEYEU*, L. DEMIDOV†and E. STEPANOVA†
*Kidney Cancer Research Bureau;†N.N. Blokhin Russian Cancer Research Center, Moscow, Russia
Background: The growth of new blood vessels is regulated at multiple steps by interactions between several pro- and antiangiogenic factors. FGF/FGFR pathway plays important role in renal cell carcinoma (Tsimafeyeu et al. 2010 ASCO meeting). We believe that the angiogenesis induced by basic fibroblast growth factor (bFGF) is resistant to anti-VEGF/R (vascular endothelial growth factor/receptor) therapy.
Methods: In our first study, angiogenesis was measured with subcutaneously implanted Matrigel plugs containing: bFGF; VEGF; bFGF + bevacizumab; VEGF + bevacizumab; bFGF + anti-FGFR1 monoclonal antibody OM-RCA-01 (Tsimafeyeu et al. 2012 ASCO meeting); VEGF + OM-RCA-01. Control group was without stimulation or treatment. In second study, Corneal Micro Pocket Assay (CMPA) was performed. 70 Charles River female C57BL/6 mice were randomized to 7 arms: 1) bFGF; 2) VEGF; 3) bFGF negative, VEGF negative; 4) bFGF + sunitinib; 5) VEGF + sunitinib; 6) bFGF + bevacizumab; 7) VEGF + bevacizumab. Hydron pellets preparation, surgical procedure, and quantification of angiogenesis (angiogenic score) were performed as previously reported (Kenyon BM et al.).
Doses of bFGF, VEGF-A (R&D Systems), sunitinib (Pfizer), bevacizumab (Roche), OM-RCA-01 (OncoMax) were 100 ng, 200 ng, 50 mg/kg, 10 mg/kg, 10 mg/kg per animal, respectively.
Results: There was no neovascularization in bFGF negative, VEGF negative group (mean, 0). bFGF and VEGF strongly induced angiogenesis (P < 0.001) in both studies. There were no vessels and endothelial cells in anti-FGFR1 antibody FGF-stimulated group. In bFGF-induced angiogenesis, sunitinib (mean, 3.9; SEM, 0.1; P = 0.2) and bevacizumab (mean, 4.71; SEM, 0.33; P = 0.85 for CMPA and P = 0.5 for Matrigel assay) did not impact on neovascularization in comparison with bFGF positive control. The angiogenic effect of VEGF was significantly inhibited by both sunitinib (mean, 0.38; SEM, 0.06; P = 0.001) and bevacizumab (mean, 0.75; SEM, 0.05; P = 0.001 for CMPA and P < 0.0001 for Matrigel assay) in comparison with VEGF positive control. OM-RCA-01 not significantly inhibited growth of vessels in VEGF positive group (P = 0.064).
Conclusion: Targeting FGFR1 inhibited FGF-induced angiogenesis. Targeting VEGF(R) significantly impacted on VEGF-induced angiogenesis and not on bFGF-induced neovascularization.
The study was supported by Terry Fox Foundation.
A phase 3 randomized study of cabozantinib (XL184) vs everolimus in subjects with clear cell renal cell carcinoma (METEOR)
T.K. CHOUEIRI*, B. ESCUDIER†, T. POWLES‡, D. CELLA§, Y. LEE¶, D. A. LAIRD¶, C. SCHEFFOLD¶and R.J. MOTZER**
*Dana-Farber Cancer Institute, Boston, MA, USA;†Institut Gustave Roussy, Medical Oncology Department, Villejuif, France;‡Queen Mary University, Barts Cancer Institute, London, United Kingdom;§Northwestern University Feinberg School of Medicine, Department of Medical Social Sciences, Chicago, IL, USA;¶Exelixis Inc, South San Francisco, CA, USA; **Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Background: Cabozantinib is an orally bioavailable tyrosine kinase inhibitor (TKI) with potent activity against MET and VEGFR2. Cabozantinib has demonstrated clinical activity in heavily pretreated subjects with clear cell carcinoma (ccRCC) in a single arm trial (Choueiri et al.; ASCO 2012, abstract 4504). VHL tumor suppressor gene dysfunction is commonly found in sporadic ccRCC and evident in all hereditary ccRCCs. This results in impaired HIF1α degradation and consequent activation of MET and VEGF pathways. Moreover, MET has been implicated in adaptive resistance to VEGF-pathway targeted agents. Based on clinical activity seen to date and scientific rationale, there is strong interest in the evaluation of cabozantinib in ccRCC.
Methods: We designed a Phase 3 randomized, open-label study to evaluate the effect of cabozantinib compared with everolimus in subjects with ccRCC (NCT01865747).The protocol-defined primary efficacy endpoint is progression-free survival (PFS) as determined by an independent radiology review committee (IRC). Secondary efficacy endpoints include overall survival (OS) and objective response rate (ORR). Exploratory analyses include safety and tolerability, tumor MET status, circulating tumor cells, bone markers, plasma biomarkers, skeletal-related events, and changes in health-related quality of life (HRQoL). Approximately 650 subjects will be randomized in 1:1 fashion to receive either cabozantinib or everolimus. Randomization will be stratified by number of prior VEGFR TKI therapy and MSKCC prognostic criteria (Motzer et al.; J Clin Oncol 22:454–463, 2004). Eligible subjects must have documented diagnosis of renal cell cancer with a clear-cell component and progressed after one or more prior VEGFR TKI therapy. Tumor assessments will include CT/MRI scans and technetium bone scans. Radiographic response will be evaluated by IRC using RECIST criteria (version 1.1). Skeletal related events are defined as radiation therapy to bone, pathological fracture, spinal cord compression, and surgery to bone. HRQoL will be assessed using the NCCN-Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) questionnaire and the EuroQol Health questionnaire (EQ-5D-5L). Survival of subjects will be followed at regular intervals.
Sunitinib expanded-access trial in metastatic renal cell carcinoma (mRCC) – final US results
T.E. HUTSON*, A.Z. DUDEK†, M.N. FISHMAN‡, J.A. THOMPSON§, N. AGARWAL¶, D.J. GEORGE**, K. ZHANG††, K. FLY‡‡, E. MATCZAK§§, M.J. LECHUGA¶¶and R. DREICER***
*Baylor Sammons Cancer Center-Texas Oncology, PA, Dallas, TX;†University of Minnesota Medical School, Minneapolis, MN;‡H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL;§Seattle Cancer Care Alliance, Seattle, WA;¶Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; **Duke University Medical Center, Durham, NC;††Pfizer Oncology, La Jolla, CA;‡‡Pfizer Oncology, Groton, CT;§§Pfizer Oncology, New York, NY, USA;¶¶Pfizer Oncology, Milan, Italy; ***Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
Background: Sunitinib is established as a reference standard of care and approved worldwide for mRCC patients. Prior to its regulatory approval, >4,500 patients were enrolled from 2005–2007 in a global mRCC expanded-access trial (ClinicalTrials.gov, NCT00130897; Pfizer) with sunitinib given to patients ineligible for other sunitinib trials. Sunitinib was shown to have a manageable safety profile and encouraging efficacy in this broad population of patients (Gore et al. 2009). Here we report final efficacy and safety results for the 320 patients in the US who enrolled in this trial.
Methods: Patients aged ≥18 years with treatment-naïve or previously treated mRCC received oral sunitinib at 50 mg/day on a 4-week-on/2-week-off schedule. Tumor measurements were scheduled per local practice and measured using RECIST. Safety was assessed regularly. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) are reported. Analyses included patients receiving ≥1 sunitinib dose.
Results: The treated patients included 30% aged ≥65 years, 7% with non-clear cell RCC, 8% with ECOG performance status (PS) ≥2, and 12% with baseline brain metastases. Median treatment duration and follow-up were 5.7 and 12.7 months. 305 patients (95%) discontinued treatment; reasons included lack of efficacy (32%), death (19%), or AEs (15%). Overall ORR was 14%, with ORR in subgroups of interest as follows: aged ≥65 years, 9%; non-clear cell RCC, 9%; ECOG PS ≥2, 0%; and baseline brain metastases, 5%. Median PFS was 9.4 months (95% CI: 7.9–12.0) and median OS was 16.6 months (95% CI: 13.7–20.7). The most common any-grade treatment-related AEs were fatigue (64%), diarrhea (54%), nausea (41%), dysgeusia (35%), decreased appetite (31%), vomiting and mucosal inflammation (both 29%), hand-foot syndrome (26%), stomatitis (23%), hypertension (22%), thrombocytopenia (21%), and rash (20%). The most common grade 3/4 treatment-related AEs were fatigue (11%), thrombocytopenia and neutropenia (both 8%), hypertension (7%), and diarrhea (5%).
Conclusions: Among patients from the US treated in an mRCC global expanded-access trial, efficacy with sunitinib was favorable and the safety experience was similar for a broader patient population than was eligible for clinical trials, comparable to results previously reported in the overall population.
Multiplexed tissue protein assay as a predictor of response to targeted therapy in advanced renal cell carcinoma
U.N. VAISHAMPAYAN, A. DERRIEN-COLEMYN, S. SETHI, W. CHEN, B. DICKOW, J.W. GILLESPIE, D.W. SMITH, V.RAIT and P. TUNON
Wayne State University, Detroit, MI; 20/20 Gene Systems Inc., Rockville, MD; Karmanos Cancer Institute, Wayne State University, Detroit, MI; 20/20 Gene Systems, Inc., Rockville, MD; 20/20 Gene Systems, Inc., Rockville, MA, USA
Background: Although a number of prognostic biomarkers have been explored in advanced renal cancer, to date none have been useful in therapeutic outcome prediction.
Methods: Following regulatory approval, formalin-fixed paraffin embedded pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The samples were analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Multiplexed panels of protein biomarkers were used to probe tissue sections for proteins along the PI3K/AKT/mTOR and/or the VEGFR/PDGFR signaling pathways. Expression of biomarkers in the cancer was scored, and predictive scores which correlated with the patient's clinical outcome status generated.
Results: Tissue samples of 51 pts treated with sunitinib were analyzed. A predictive score was generated by combining the scores assigned to VEGFR1 and VEGFR2 and multiplying the sum with the score of VEGFA. If the predictive score was equal to or above 24, pt was predicted to be a responder; to have an objective response (OR)/stable disease (SD). If score <24 the pt was predicted to have no benefit from sunitinib. 27 of 33 OR/SD pts and 15 of 18 with progressive disease (PD) were accurately predicted. The accuracy of the test was noted to be 83.3% and sensitivity and specificity were 81.8% and 83.3% respectively. Median times to treatment failure were 12 months (95%CI 8–24 months) and 3 months (95%CI 3–12 months), respectively on the patient groups with scores >24 or <24.
Tissue samples of 33 pts treated with mTOR inhibitor were analyzed. 3 biomarkers in the mTOR pathway (pmTOR (Ser 2448), p4EBP1 (Ser 65), p4EBP1 (Thr 37-46)) were used to create a predictive score. 8 of 12 OR/SD pts (sensitivity 67%) and 17 of 21 PD pts (specificity 76%) were accurately predicted using a score cutoff of 6.
Conclusions: These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information to help guide therapy. Prospective testing with a larger sample size is required. Funding source: Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by NCI SBIR Contract No. HHSN261201000135C.
Role of cytoreductive nephrectomy (CN) in patients with metastatic non-clear cell renal cell carcinoma (nccRCC): results from a surveillance, epidemiology, and end results (SEER) database analysis of over 4,900 patients
R.R. MCKAY*, A.A. AIZER†, Y. URUN*, A.S. KIBEL*, P.L. NGUYEN* and T.K. CHOUEIRI*
*Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA;†Harvard Radiation Oncology Program, Boston, MA, USA
Background: The role of CN in patients with metastatic nccRCC is largely unknown. Additionally, the impact of CN in these patients in the era of molecularly targeted therapy (MTT) is not defined. Herein, we determine the impact of CN on mortality in patients with metastatic nccRCC.
Methods: We used the SEER database to identify 4,914 patients diagnosed with metastatic RCC between 2000–2009. Of these patients, 2,994 (61%) underwent CN and 591 (12%) had NCC histology. The primary outcome was RCC-specific mortality (RSM) and secondary outcome was overall survival (OS).
Results: Patients with NCC histology undergoing CN had a lower likelihood of RSM (p < 0.001). This association was retained after adjustment for age at diagnosis, gender, race, marital status, year of diagnosis, geographic location, and different NCC histology, (Hazard Ratio (HR) 0.62, 95% Confidence Interval (CI) 0.48–0.80, p < 0.001) (Table 1). Additionally, patients having undergone CN had improved OS compared to those who did not (14 versus 6 months, p < 0.001). In multivariable analysis, CN was associated with a significant improvement in OS (HR 0.45, 95% CI 0.37–0.55, p < 0.001). The association between CN and improved RSM and OS in patients treated in the era of MTT (2006–2009) remained significant (HR 0.50 and HR 0.43, respectively).
Conclusions: CN in patients with metastatic nccRCC appears to be associated with a survival benefit in patients treated in the era of MTT and regardless of the underlying nccRCC histology. CN remains a treatment option for patients with metastatic RCC who are appropriate surgical candidates. Limitations of this data include the absence of information regarding comorbidities, performance status, and disease burden.
Table 1 RSM and OS, based on CN status, in metastatic RCC
N (No CN/CN)
1-Year RSM (No CN/CN) (%)
HR (95% CI)
N (No CN/CN)
Median OS (No CN/CN) (months)
HR (95% CI)
The initial experience with RENAL nephrometry in children, adolescents, and young adults with renal tumors
*Divisions of Urology,†Radiology, and‡Oncology at the Cincinnati Children's Hospital Medical Center, Cincinnati, OH,§Division of Urology at the University of Colorado Anschutz Medical Campus, Denver, CO, USA
Background: Currently, no standard manner exits to compare renal tumor complexity in children and adolescents, making it impossible to speak a “common language” when comparing lesions and the impact of tumor complexity on surgery and outcomes. Recently, such a standardized system has been developed in adults. The RENAL Nephrometry system is a valid instrument across institutions and between users which reliably predicts tumor complexity and clinical outcomes such as the ability to complete partial nephrectomy (PN) and the incidence of peri-operative complications. We propose that such a standardized system would be a useful in children, adolescents, and young adults with renal masses. Our goal was to describe RENAL Nephrometry in such a population and correlate this score with surgical and pathologic outcomes.
Methods: We reviewed all patients at our institution who underwent resection of a renal tumor between 2002–13, and who had pre-operative, contrast-enhanced, cross-sectional imaging available. We assessed the RENAL Nephrometry score for each affected kidney. RENAL Nephrometry is based on 5 features characterizing renal tumor anatomy as they relate to resectability. The mass is assigned low (4–6), moderate (7–9) or high (10–12) complexity based on the sum score. We then compared tumor characteristics and outcomes between the groups of low, moderate, and high complexity masses.
Results: We identified 65 patients and 67 kidneys meeting study criteria. Median age at diagnosis was 3.5 yr (0.1–27.6). We identified 5 low-complexity, 10 moderate-complexity, and 52 high-complexity lesions (Table). In comparing the clinical and pathologic features between groups, we observed that less complex masses were observed in older patients, more commonly managed with PN, and more often represented Renal Cell Carcinoma (RCC), and non-Wilms Tumor (WT) pathology. We did not observe a statistically significant correlation between tumor complexity and EBL, Operative time, Intraoperative transfusion, Positive margins, or Tumor rupture.
Conclusion: Typically, renal lesions in this population are highly complex. RENAL Nephrometry appears most useful in evaluating and discriminating RCC and masses in older children and adolescents. However, it requires further refinement to capture nuances in distinguishing the complexity of other pediatric renal malignancies such as WT.
Table Comparison of Renal Masses with Low, Moderate and High Complexity RENAL Nephrometry Scores
Low Complexity N = 5
Moderate Complexity N = 10
High Complexity N = 52
Low vs. Mod p-value
Mod vs. High p-value
Low vs. High p-value
Median Age at Dx (Years)
R – Largest tumor diameter
1: ≤4 cm
2: 4 to 7 cm
3: ≥7 cm
E – % Exophytic
3: Entirely Endophytic
Low Complexity N = 5
Moderate Complexity N = 10
High Complexity N = 52
Low vs. Mod p-value
Mod vs. High p-value
Low vs. High p-value
N – Nearness to CS/Sinus
1: ≥7 mm
2: 4 to 7 mm
3: ≤4 mm
A – Ant vs. Post Location
a: Completely Anterior
p: Completely Posterior
L – Location to PLs
1: Entirely above or below
2: Crosses the PL
3: >50% across or between
4: 2 (40%)
7: 0 (0%)
10: 6 (11.5%)
5: 2 (40%)
8: 2 (20%)
11: 11 (21.2%)
6: 1 (20%)
9: 8 (80%)
12: 35 (67.3%)
Radical Nephrectomy (RN)
Partial Nephrectomy (PN)
Completed Case as PN
3 of 3 (100%)
7 of 7 (100%)
1 of 1 (100%)
Operative Time (min)
Wilms Tumor (WT)
Renal Cell Carcinoma
Clear Cell Sarcoma (CCSK)
Inf. Myofibroblastic Tumor
All other pathologies
Wilms Tumor/CCSK vs.
All other pathologies
Quadrant biopsy technique improves diagnostic ability for large renal masses
J.E. HECKMAN, A. DREWRY, S. BEST, T. ZIEMLEWICZ, M.G. LUBNER, T.M. DOWNS, D.F. JARRARD, S.Y. NAKADA, W. HUANG and E.J. ABEL
University of Wisconsin School of Medicine and Public Health
Objectives: Standard percutaneous biopsy is generally obtained from one location within a renal mass and thus prone to sampling error, particularly in large heterogeneous tumors. Indeterminate results or failure to detect poor prognostic features is common even when several samples are obtained from a single area. The purpose of this study was to evaluate the accuracy of percutaneous biopsy for large renal masses using a modified technique that includes core biopsies from multiple locations within each tumor compared with standard biopsy.
Patients and Methods: Clinical and pathologic data for all patients with ≥cT2 renal masses who underwent percutaneous biopsy at a single institution from 5/2009–6/2013 was reviewed. The quadrant biopsy technique was developed in 2011 and includes core biopsies from four separate solid enhancing areas within the tumor using an 18-gauge needle. An expert genitourinary pathologist performed a blinded central review of each core and nephrectomy specimen. Results from quadrant biopsy technique were compared with those from standard biopsy.
Results: Of 72 biopsies performed in 68 patients, 30 used standard and 42 utilized a quadrant technique. Median number of cores obtained in standard technique and quadrant technique was 2 and 5 respectively. Biopsy was diagnostic in 26/30 (86.6%) standard biopsies and 42/42 (100%) quadrant biopsies. When evaluating individual cores, fibrotic/necrotic material or benign kidney was present in 18.3% of quadrant biopsy specimens. Nephrectomy was performed in 37/68 (54.4%) of patients after biopsy. When comparing nephrectomy to standard or quadrant biopsy technique, 2/8 (25%) and 0/29 (0%) patients had an inaccurate diagnosis of the presence of malignancy made from each technique respectively. Sarcomatoid de-differentiation was identified in 1/30 (3.3%) standard and 7/42 (16.6%) quadrant biopsies. Using the quadrant technique, sensitivity for detecting sarcomatoid features was 85% and 81% when compared to nephrectomy specimens or among all biopsy cores, respectively. Post-procedure complications were reported in 1/72 (1.4%) patients. One patient was admitted to the hospital after standard technique biopsy for hematoma and required no further intervention.
Conclusions: Sampling multiple locations in large renal tumors may increase diagnostic capability to guide entrance into pre-surgical clinical trials for metastatic RCC, facilitate surgical planning or improve informed consent. Sensitivity for detecting poor prognostic features is increased using quadrant technique when compared with historical series.
Proposal of an algorithm for utilization of percutaneous renal mass biopsy based on the results of 1000 case series
A.S. FELDMAN*, S.M. DESHMUKH*, M. DHYANI†, G. BARRISFORD*, D. RODRIGUEZ*, F.J. MCGOVERN*, W.S. MCDOUGAL*, A. OLUMI*, D.M. DAHL*, A. SAMIR†and M.L. BLUTE*
*Department of Urology, Massachusetts General Hospital, Boston, MA;†Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
Introduction: Renal mass biopsy (RMB) is a diagnostic option for evaluation of suspicious renal masses. Current guidelines offer little guidance about selection of appropriate masses for diagnostic biopsy and management after RMB results have been obtained. We propose an algorithm for utilization of RMB based on our database of 1000 RMBs.
Methods: Under IRB approval, we performed a retrospective review of our database of 1000 adult patients who underwent a RMB at Massachusetts General Hospital (1997–2010). The decision for RMB was at the discretion of the urologist and patient, although all masses considered for ablative therapy were biopsied routinely. Core biopsies were performed using 15–18 gauge coaxial needles and fine needle aspirations (FNA) were performed with 20–23 gauge Chiba needles.
Results: 80% of tumors were 0–4 cm, 16% were >4–7 cm, 4% were >7 cm. 82% were solid and 18% were cystic. 94% underwent core biopsies + FNA, 5% had core biopsies only and 1% had FNA only. 216/1000 (22%) biopsies were non-diagnostic. Solid lesions had a non-diagnostic rate of 13% (104/821) compared with 63% (112/179) in cystic lesions (p < 0.0001). The non-diagnostic rate increased with a decrease in tumor size (<2 cm: 21%, 2–4 cm: 9.5%, >4–7 cm: 11%, >7 cm: 6.3%; p < 0.0001) and the non-diagnostic rate for tumors <1.5 cm was 42%. Of diagnostic biopsies, the identification of RCC increased with tumor size (<2 cm: 65%, 2–4 cm: 73%, >4–7 cm: 79%; >7 cm: 87%; p < 0.0001). Of the 216 tumors with an initial non-diagnostic RMB, 55 underwent eventual repeat biopsy, revealing 26 (47%) RCC or other malignancy, 32 (58%) non-diagnostic, 3 (5.5%) oncocytoma and 2 (3.6%) angiomyolipoma. 33/216 non-diagnostic RMB eventually had surgery, with 30 being RCC or other malignancy on pathology. Based on our results we propose an algorithm (see Figure opposite) for selection of small renal masses for biopsy and management after RMB.
Conclusions: RMB can be an effective method for diagnostic evaluation of a suspicious renal mass. However, utilization of RMB and management afterwards should be based on both the properties of the mass as well as the clinical history of the patient. We present an effective algorithm for approaching the suspicious cT1a renal mass.
Safety, durable clinical benefit, and remission resulting from nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase 1 trial in patients with previously treated metastatic renal cell carcinoma (mRCC); long-term patient follow-up
C.G. DRAKE*, D.F. MCDERMOTT†, M. SZNOL‡, T.K. CHOUEIRI†, H.M. KLUGER‡, J.D. POWDERLY§, D.C. SMITH¶, V. SANKAR**, A.A. GUTIERREZ**, J.M. WIGGINTON**, A. GUPTA** and M.B. ATKINS††
*Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA;†Dana-Farber Cancer Institute, Boston, MA, USA;‡Yale Cancer Center, New Haven, CT, USA;§Carolina BioOncology Institute, Huntersville, NC, USA;¶University of Michigan, Ann Arbor, MI, USA; **Bristol-Myers Squibb, Princeton, NJ, USA;††Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA
Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation. PD-L1, a PD-1 ligand, is associated with poor prognosis in mRCC. In a phase 1 study, the PD-1 receptor-blocking antibody nivolumab was generally well tolerated and showed encouraging antitumor activity in patients with previously treated mRCC and other solid tumors. We report overall survival (OS), long-term safety, and updated response data after a minimum 1-year follow-up for the mRCC cohort.
Methods: Patients received nivolumab 0.1–10 mg/kg every 2 weeks intravenously in 8-week treatment cycles for 24 months or until discontinuation criteria were met. A maximum tolerated dose was not reached up to 10 mg/kg; cohorts were expanded at the 1- and 10-mg/kg dose levels.
Results: 34 patients received nivolumab at 1 mg/kg (n = 18) or 10 mg/kg (n = 16). Of these, 15 patients (44%) had received ≥3 prior therapies. Responses were noted in 10/34 patients (Table). An additional 3 patients showed unconventional “immune-related” responses. Among responding patients, 40% had responses at first tumor assessment (8 weeks). As of March 2013, 4/10 patients continued to respond. Median duration of response was 56.1 weeks for both doses (range: 36.6–126.7+). Among 7 patients who discontinued treatment while responding for reasons other than progressive disease, responses persisted in 4 patients for ≥19 weeks off treatment (19, 45+, 51+, and 59+ weeks). OS rates at 1 and 2 years were 70% and 50%, respectively, with 19 patients alive after 24 months median follow-up. The incidence of all-grade and grade 3–4 treatment-related adverse events (AEs) was 85% and 18%, respectively. The most common AEs included fatigue, rash, diarrhea, and pruritus. Treatment-related pneumonitis occurred in 1 patient (grade 1). Select, potentially immune-related AEs requiring more frequent monitoring and/or specific intervention included skin (35%), endocrinopathies (18%), gastrointestinal (18%), and hepatic (12%).
Conclusions: In a cohort of heavily pretreated patients with mRCC, long-term continuous dosing of nivolumab was generally well tolerated and produced durable clinical benefit, which was maintained off therapy in a subset of patients. These findings provide the basis for an ongoing randomized phase 3 trial of nivolumab in mRCC (NCT01668784).
Objective Response Rate, % (n/N)
Stable Disease Rate, % (n/N)
Median Progression-Free Survival, Months
Median OS, Months
aMedian OS not reached at 22 months (the longest time to death so far)
A phase 3 comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients with advanced or metastatic renal cell carcinoma (mRCC) previously treated with anti-angiogenic therapy
R.J. MOTZER*, P. BONO†, Y. TOMITA‡, A. RAVAUD§, I. WAXMAN¶and M.E. GORE**
*Memorial Sloan-Kettering Cancer Center, New York, NY, USA;†Helsinki University Central Hospital, Helsinki, Finland;‡Yamagata University, Yamagata, Japan;§Bordeaux University Hospital, Hôpital Saint André, Bordeaux, France;¶Bristol-Myers Squibb, Princeton, NJ, USA; **The Institute of Cancer Research & The Royal Marsden Foundation Trust, London, UK
Background: Standard approved treatments for patients with mRCC include interleukin-2, VEGF TKIs (e.g. sunitinib, pazopanib, axitinib, sorafenib) or mTOR inhibitors (temsirolimus, everolimus). However, many patients develop resistance, and overall survival (OS) improvement has only been shown in one phase 3 trial in poor-risk, untreated patients. Although sequential treatment with targeted therapies may improve OS for some patients with mRCC, more data are needed to confirm this finding. Everolimus demonstrated a 3-month improvement in median progression-free survival (PFS) but showed no improvement in OS versus placebo in patients who progressed following VEGF-targeted therapy (Motzer RJ, et al. Lancet. 2008;372:449–56). Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation and PD-1 overexpression by tumor infiltrating lymphocytes has been associated with poor prognosis in multiple tumor types including mRCC. A phase 1 study of the fully human PD-1 receptor blocking monoclonal antibody nivolumab showed encouraging antitumor activity in previously treated mRCC (objective response rate [ORR], 29% (10/34); stable disease at ≥24 weeks, 27% [9/34]; poster presentation at ASCO 2013; JCO 2013:31(15 suppl):abstract 4514). Therefore, an ongoing, randomized, open-label, global phase 3 trial was developed to evaluate the clinical benefit of nivolumab in patients with mRCC previously treated with anti-angiogenic therapy.
Methods: 822 patients with advanced or metastatic clear-cell mRCC who have received ≤2 prior anti-angiogenic therapies and ≤3 total prior systemic regimens will be randomized 1:1 to receive nivolumab 3 mg/kg intravenously every 2 weeks (Arm A) or everolimus 10 mg orally daily (Arm B). Patients will be stratified by region, MSKCC risk group, and number of prior anti-angiogenic therapy regimens. Tumor response will be assessed using RECIST 1.1 every 8 weeks following randomization for the first year and then every 12 weeks until disease progression or treatment discontinuation, whichever occurs later. The primary endpoint is OS. Secondary endpoints include PFS, ORR, OR duration, adverse events, OS in PD ligand 1 (PD-L1) positive or negative subgroups, and patient-reported outcomes. The trial is open and enrolling patients.
Impact of bone metastases (BM) and bisphosphonate use in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy: Results from a pooled clinical trials database
*Dana-Farber Cancer Institute, Boston, United States;†Pfizer Oncology, New York, United States;‡Tom Baker Cancer Center, Calgary, Canada
Background: BM are frequently present in patients with mRCC and are associated with high rates of skeletal-related events (SREs), defined as pathologic fractures, need for bone radiotherapy or surgery, and spinal cord compression. The objective of this study was to investigate the prognostic significance of BM and to analyze the role of bisphosphonate therapy in patients with mRCC treated with targeted therapy.
Methods: We conducted a pooled retrospective analysis of patients with mRCC treated from 2003–2011 on phase III (NCT00083889, NCT00065468, NCT00678392) and phase II clinical trials (NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423). Statistical analyses were performed using Cox regression and the Kaplan-Meier method.
Results: We identified 2,749 patients treated with sunitinib (n = 1,059), sorafenib (n = 355), axitinib (n = 359), temsirolimus (n = 208), temsirolimus + interferon-alfa (IFN-α) (n = 208), or IFN-α (n = 560), of whom 28% had BM. Most patients were less than 65 years of age (66.5%), with clear-cell histology (89.1%), and prior nephrectomy (83.6%). 285 patients (10.4%) received treatment with bisphosphonate therapy. No patient received denosumab. The presence of BM was associated with a shorter progression-free survival (PFS) and overall survival (OS) when compared to those without BM (Table 1). The use of bisphosphonate therapy was not independently associated with improved survival. The rate of SREs in patients with BM receiving treatment with a bisphosphonate was 1.8% (n = 14) compared to 4.6% (n = 36) in patients not receiving a bisphosphonate (p = 0.191). Adverse events for patients treated with bisphosphonate therapy compared to patients not receiving bisphosphonate therapy included: osteonecrosis of the jaw (2.1% versus <0.1%), hypocalcemia (7.4% versus 3.0%), and renal insufficiency (4.9% versus 2.5%).
Conclusions: In this analysis, we confirm that the presence of bone metastases is associated with shorter survival in patients with mRCC. Bisphosphonate therapy did not have an impact on survival.
Table 1 PFS and OS based on presence of BM and treatment with bisphosphonate therapy
Not treated with bisphosphonate therapy (n = 619)*
p = 0.1785
p = 0.3801
HR = 1.154
HR = 1.106
Combinedlow activity GSTA1andactive GSTT1genotypes modify risk for renal cell carcinoma
M. PLJESA-ERCEGOVAC*†, V. CORIC*†, D. DRAGICEVIC*‡, A. SAVIC-RADOJEVIC*†, M. MATIC*†, Z. DZAMIC*‡and T. SIMIC*†
*Faculty of Medicine, University of Belgrade, Serbia;†Institute of Medical and Clinical Biochemistry;‡Clinical center of Serbia, Urology clinic, Belgrade
Objective: Obesity, hypertension, smoking and professional exposure to carcinogens are the recognized risk factors for clear renal cell carcinoma (cRCC). Cytosolic glutathione transferases (GST) catalyze conjugation reaction of electrophylic compounds to glutathione. Although polymorphic expression of GST enzymes confers increased risk for various cancers, the role of GST polymorphisms in susceptibility to cRCC is still controversial. We aimed to assess whether common GST polymorphisms are associated with higher risk for cRCC, independently or in conjunction with recognized risk factors, as well as, to identify their value in tumor progression.
Methods: A hospital-based case-control study recruited 98 patients with cRCC and 240 healthy controls. GSTA1, GSTT1, GSTP1 and GSTO1 genotypes were determined by PCR. The associations between the genotypes and cRCC risk were examined by using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
Results: Regression analysis showed that low activity GSTA1 (CT/TT) and active GSTT1 genotypes were associated with higher, but statistically non-significant effect on risk for cRCC (OR = 1.4 CI:0.7–2.4 and OR = 1.8 CI:0.9–3.5, respectively) after adjustment for age, gender and obesity. However, when the effect of these two genotypes was analyzed in combination, patients with combined low activity GSTA1/active GSTT1 genotype exhibited 5–fold higher risk (CI:1.1–22.9, p = 0.034) than those with GSTA1 CC/GSTT1 null genotype. Patients homozygous for GSTO1 A and GSTP1 Ile alleles exhibited higher, but non-significant risk compared to the patients homozygous for GSTO1 C and GSTP1 Val alleles (OR = 1.6, CI:0.7–3.8, OR = 1.5 CI:0.6–3.6, respectively). Concerning the association of GST genotypes with cRCC progression, patients with active GSTT1 genotype, or carrying GSTO1 A and GSTP1 Ile alleles had tumors of higher grade than those with GSTT1 null genotype or homozygous for GSTO1 C or GSTP1 Val alleles.
Conclusions: Patients with combined low activity GSTA1 and active GSTT1 genotypes are at higher risk of developing cRCC.
ADAPT: An Ongoing international phase 3 randomized trial of autologous dendritic cell Immunotherapy (AGS 003) plus standard treatment in advanced renal cell carcinoma (RCC)
C.G. WOOD* and R.A. FIGLIN†on behalf of THE ADAPT STUDY GROUP
*Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX;†Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Background: AGS-003 is an autologous immunotherapy designed to induce a T-cell response specific to a patient's tumor antigens. It is prepared from matured monocyte-derived dendritic cells co-electroporated with patients’ amplified tumor RNA plus synthetic CD40L RNA. Sunitinib is a tyrosine kinase inhibitor (TKI) that has been well established as a standard first-line treatment for advanced RCC. The antitumor activity of sunitinib combined with its ability to reverse the immune suppression observed in RCC patients provides strong rationale to combine sunitinib with AGS-003. In a single arm phase 2 study, AGS-003 plus sunitinib was safe and yielded a median overall survival (OS) of over 30 months in newly diagnosed, synchronous, unfavorable risk mRCC patients.
Methods: The ADAPT study is a randomized (2:1), international phase 3 study comparing standard targeted therapy ± AGS-003. While standard targeted therapy initiates with sunitinib for all subjects, changes to other TKIs or mTOR inhibitors is permitted for early progression or toxicity. Patients randomized to the combination arm will receive AGS-003 once every 3 weeks for 5 doses, followed by quarterly booster doses. At week 48, patients with stable disease or better will continue booster dosing every 12 weeks until progression.
The primary objective is to compare the median OS between treatment arms. Additional endpoints include PFS, safety, immunologic and tumor response.
The study is enrolling adults with synchronous, metastatic clear cell RCC who are good candidates for surgery and targeted therapy initiating with sunitinib, 1–4 Heng risk factors (intermediate or poor risk), KPS ≥ 70%, life expectancy of at least 6 months and adequate end organ function. Patients will be excluded for prior systemic RCC treatment, brain metastases or if they require chronic immunosuppressive therapy.
More than 120 sites in North America, Europe and Israel will participate to recruit approximately 900 subjects for tumor collection. Currently, 78 global sites have been activated with 70 tumors collected and 16 subjects randomized. Further details regarding enrollment and study progress will be presented.
A.M. CZARNECKA* , D. MATAK*†, W. SOLAREK*†, M.I. KHAN* and C. SZCZYLIK*
*Laboratory of Molecular Oncology, Department of Oncology, Military Institute of Medicine, ul. Szaserow 128, 04-141 Warsaw, Poland;†School of Molecular Medicine, ul. Zwirki i Wigury 61, 02-091 Warsaw, Poland
Scientific Background: Clear cell renal cancer (ccRCC) is associated with VHL gene mutations that lead to stabilization of hypoxia inducible factors (HIF-1α and HIF-2α). In turn, this activates the transcription of a palette of genes involved in glucose uptake and metabolism, angiogenesis and cell cycle. Tumor initiating cells (TICs), often referred as to cancer stem cells, are neoplastic cells characterized by self-renewal, multilineage differentiation and initiation of tumor growth in vivo abilities. Previous reports have indicated ccRCC CD105+ cells population to harbor stem cell properties, including clonogenic ability, expression of nestin, Nanog, Oct4, lack of differentiative epithelial markers expression, ability to grow in nonadhesive spheroids, in vitro differentiation into epithelial and endothelial cell types, and finally generation of transplantable carcinomas in vivo. At the same time ccRCC CD133+ cells are to significantly enhance tumor development and growth as they differentiate into endothelial and epithelial cells and contribute to tumor vascularization. Moreover hypoxia was pointed as a critical microenvironmental factor regulating cancer stem cells’ self-renewal potential, enhancing the activity of stem cell factors and maintaining stem cell populations but its roles in ccRCC stem cells biology is largely unknown.
Research design: The present study was to evaluate the influence of hypoxia on propagation of CD105+ and CD133+ ccRCC cells. In the first step viability and proliferation of ccRCC cells carrying wild type and mutant VHL gene was analyzed in 21% and 2% oxygene tension. In the second step the presence of CD105+ and CD133+ ccRCC cells was verified in these conditions. Clonogenicity – colony formation potential – (anchorage-independent growth) and aggregation (metastatic potential) property of cancer cells was measured. The anti-proliferative effects of selected TKI on ccRCC and ccRCC TICs in 2D and 3D cultures under 21% and 2% oxygene tension was verified. In 3D approach ccRCC and TICs were grown in aggregates and in hanging drop culture. ccRCC spheroids were also treated with TKI under normoxic or hypoxic conditions.
Current research: Tumor micro-environmental hypoxia and VHL gene status concordantly influence propagation of CD105+ and CD133+ ccRCC cells. TICs are targets of TKI and hypoxia modulates its’ effect.
Grant registry number: This project was supported by the National Science Centre research grant NCN – UMO-2011/01/B/NZ5/02822, Foundation for Polish Science research grant TEAM 6/2011 and Military Institute of Medicine statutory funding.
Chronic myeloid leukaemia development in the course of ccRCC treatment with tyrosine kinase inhibitors
A.M. CZARNECKA*, S. OBORSKA†, P. RZEPECKI†and C. SZCZYLIK*
*Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Warsaw, Poland;†Department of Hematology with Stem Cell Transplant Unit, Military Institute of Medicine, Warsaw, Poland
Scientific Background: Targeted agents are a novel therapeutic approach developed to disrupt different cellular signalling pathways. Tyrosine kinase inhibitors (TKIs), including sunitinib and sorafenib, block multiple tyrosine kinase receptors that are involved in the progression of many tumours, including clear cell renal cell cancer (ccRCC). Although TKIs are primarily designed to target defined receptor tyrosine kinases (RTKs), it is increasingly apparent that many TKIs may also unexpectedly inhibit other targeted kinases and trigger the appearance of undesirable side effects by influencing kinases on non-cancerous cells. Patients should be examined for the presence and development of comorbidities before starting TKI treatment as well as during the therapy.
Treatment and eligibility criteria: 259 patients with clear cell renal cancer (ccRCC) were treated with sunitinib or sorafenib as I line ccRCC treatment in standard dose and schedule in the Military Institute of Medicine in Warsaw. Patients were eligible for treatment under standard MSKCC criteria. Treatment was initialized between March 2004 and July 2009 and monitoring ended in May 2013. Analyzed cohort represent typical patients in oncology ward hospitalized care in large oncology center.
Main Outcome: Development of 3 cases of chronic myeloid leukemia (CML) during tyrosine kinase inhibitor treatment was observed and defined as unexpected medical coincidence.
Current research: Hypothetical model picturing inhibition of multiple molecular pathways in bone marrow stem cells by TKIs has been proposed to explain co-incidence of TKI treatment and CML development.
Grant registry number: This study was supported by Military Institute of Medicine statutory founding, treatment was covered according to National Health Fund regulations.
Survival, safety and treatment response duration in “real world” patients with metastatic clear cell renal cancer – an update from clinical practice
A.M. CZARNECKA*, P. SOBCZUK*†, K. BOGUSZ*†, M. SPYCHALSKA*†and C. SZCZYLIK*
*Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Warsaw, Poland;†Medical University of Warsaw, Warsaw, Poland
Scientific Background: Clinical trials are considered the gold standard to assess the efficacy and safety of treatment. However, because trials are conducted in standardized conditions, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks of treatment. Progression-free survival (PFS) durations reported from randomized trials of targeted therapies may also vary considerably from the real world of prescription and use. Level 1 evidence supports sequential use of tyrosine kinase inhibitors, as well as these agents followed by everolimus and sequential therapy with targeted agents provides significant benefit. Classical scheme of treatment, approved in Poland, combines nephrectomy and sequential treatment of metastatic disease with Sunitinib (TKI) and Everolimus (mTOR inhibitor).
Treatment and eligibility criteria: 153 (117M, 36F) patients with metastatic ccRCC were treated in the Department of Oncology of Military Institute of Medicine in Warsaw. Patients stared therapy between January 2007 and December 2011. Overall Survival (OS) since nephrectomy was evaluated and duration of first-line therapy (Sunitinib) and second-line therapy (Everolimus) was estimated. Analyzed cohort represent typical patients in oncology ward hospitalized care in large oncology center. Common side effects were monitored and treated accordingly. Cardiovascular risk associated with sunitinib treatment was investigated.
Current research: On-treatment patients are monitored. PFS on Sunitinib vary favorably form reported in clinical trials. Negative and positive predictive factors of TKI treatment are recognized.
Grant registry number: This study was supported by Military Institute of Medicine statutory founding, treatment was covered according to National Health Fund regulations.
Brain metastasis from renal cell carcinoma, are we missing our chance to treat?
M. HANZLY, A. ABOUMOHAMED, K. ATTWOOD, D. MEHEDINT, E. KAUFFMAN and T. SCHWAAB
Roswell Park Cancer Institute
Introduction: Brain metastasis occurs in approximately 8% of patients with primary renal cell carcinoma . Current guidelines from the NCCN, European Association of Urology, and American Urologic Association recommend cerebral imaging only in patients who have symptomatology [2–4]. The purpose of our study was to examine characteristics of RCC patients with brain metastasis, including symptomatology at diagnosis, treatment and overall survival.
Methods: An IRB-approved prospectively-maintained kidney cancer data base at Roswell Park Cancer Institute was reviewed for cases of primary RCC from 1995 to 2012. Brain metastases from a primary RCC was identified in 52 patients. Clinical and perioperative variables examined include family and social history, primary tumor histology and treatment modality, time between primary tumor diagnosis and brain metastasis, symptomatology, metastasis treatment modality and overall survival from the time of brain metastasis diagnosis.
Results: Primary RCC was diagnosed in 898 patients. Among the 52 patients with brain metastasis, 79% were male and 100% were Caucasian, 87% had no family history of renal malignancy and 51% had a history of tobacco abuse, with a 39 pack-year average. Primary treatment for RCC included 75% radical nephrectomy, 10% observation, 7.6% cytoreductive nephrectomy, 5.4% sunitinib, 2% interleukin-2 treatment. Histological examination of the primary tumors identified 88% pure clear cell, 6% clear cell with sarcomatoid features, 4% clear cell with granular features and 2% were poorly differentiated. Central nervous system (CNS) symptoms were absent in 37% of patients diagnosed with brain metastases, while 73% presented with symptoms. The average number of metastases was 1.78 per patient in the asymptomatic group, and 2.7 metastases in patients with CNS symptoms (p = 0.18). Elapsed time from primary RCC treatment to diagnosis of brain metastases was an average of 730 days in the asymptomatic group and 1170 days for the symptomatic group (p = 0.02). The symptomatic group overall survival (OS) at one and three years was 81% and 69%, respectively, while the asymptomatic group was 81% and 31%, respectively. Pulmonary metastasis was present in 75% of both cohorts (p = 0.002). Two patients had only brain metastases and no other sites of metastasis. Clinical trial enrolment was cited as the number one reason for brain imaging and diagnosed 75% of asymptomatic patients.
Conclusion: Patients without CNS symptoms with brain metastases may have a worse overall survival. Patients with pulmonary metastasis are more likely to have brain metastases. Urologic guidelines recommending CNS imaging only in patients with symptoms may be missing a subset of the metastatic RCC population who could potentially benefit from early therapeutic intervention.
1 Bianchi Met al.Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol2012; 23: 973–980
3 Motzer RJet al.NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw2009; 7: 618–630
4 Ljungberg Bet al.EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol2010; 58: 398–406
Utilization of renal mass biopsy in patients with renal cell carcinoma
J.T. LEPPERT*†, J. HANLEY‡, T.H. WAGNER†§, B.I. CHUNG*, S. SRINIVAS¶, G.M. CHERTOW¶, J.D. BROOKS*, C.S. SAIGAL** and THE UROLOGIC DISEASES IN AMERICA PROJECT
*Department of Urology, Stanford University School of Medicine, Stanford, CA;†Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA;‡Rand Corporation, Santa Monica, CA;§Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA;¶Department of Medicine, Stanford University School of Medicine, Stanford, CA; **Departments of Urology and Health Services, UCLA School of Medicine, Los Angeles, CA, USA
Acknowledgements: The Urologic Diseases in America Project is sponsored by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). Dr. Leppert is supported by K23 DK089086. Dr. Chertow is supported by K24 DK085446. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH/NIDDK.
Purpose: Renal mass biopsy (RMB) may play an important role in personalized treatment for patients with renal cell carcinoma (RCC). We examined the patient, tumor, and temporal factors associated with receipt of RMB in a contemporary nationally representative sample.
Materials and Methods: We queried the Surveillance, Epidemiology, and End Results-Medicare dataset for incident cases of RCC diagnosed between 1992 and 2007. We tested for associations among receipt of RMB and patient and tumor characteristics, type of therapy, and procedure type. Temporal trends in receipt of RMB were characterized over the study period.
Results: Approximately one in five (20.7%) patients diagnosed with RCC (n = 24,702) underwent RMB before instituting therapy. There was a steady and modest increase in RMB utilization, with the highest utilization (30%) occurring in the final study year. Among patients who underwent radical (n = 15,666) or partial (n = 2,211) nephrectomy, 17% and 20%, respectively, underwent RMB in advance of surgery. Sixty-five percent of patients who underwent ablation (n = 314) underwent RMB before or in conjunction with the procedure. Roughly half of patients (50.4%) treated with systemic therapy alone underwent RMB. Factors independently associated with use of RMB included younger age, black race, Hispanic ethnicity, tumor size >7 cm, and metastatic disease at presentation.
Conclusions: At present, most patients who eventually undergo radical or partial nephrectomy do not undergo RMB, whereas most patients who eventually undergo ablation or systemic therapy do. The optimal use of RMB in the evaluation of kidney tumors has yet to be determined.
Nano-scale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC
J.T. LEPPERT*†‡, A.C. FAN*§, T. METZNER†, J.E. LILIENTAL*¶, L. XU§, A.E. THONG†, C. YOST¶, ALIA YAGHI¶, J.D. BROOKS*†, L.C. HARSHMAN**, C. SABATTI†, S. SRINIVAS*§and D.W. FELSHER*§
*The Stanford Kidney Cancer Research Program;†Department of Urology, Stanford University School of Medicine;‡Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA;§Department of Medicine, Stanford University School of Medicine;¶Translational Research and Applied Medicine Laboratory, Stanford University School of Medicine; **Department of Medicine, Harvard Medical School;†Department of Statistics, Stanford University School of Medicine
Acknowledgements: This work is supported by the NCI/NIH (R21 CA169964), by a Stanford Cancer Institute 2012 Developmental Cancer Research Award Grant, and by a Translational Research and Applied Medicine Pilot Grant Award. Dr. Leppert is supported by K23 DK089086 from the NIDDK/NIH.
Background: Novel agents that inhibit kinases in the hypoxia and MTOR pathways can achieve response rates of 30–60% in renal cell carcinoma (RCC); however, protein biomarkers to diagnose RCC and guide treatment have not been identified.
Methods: We developed the use of two high-throughput, nanoscale immunoassays to profile hypoxia and downstream signaling in clinical specimens from patients with RCC. These automated technologies minimize errors due to manual variability, and make 96 independent measurements per overnight experiment. We used size-based protein separation (Sally Instrument, Protein Simple) to quantify proteins using antibody-specific detection, normalized to loading control. Next, we used a nano-immunoassay with charge-based separation (NIA, Nanopro1000 Instrument, Protein Simple) to distinguish multiple charged modifications of individual proteins, and measure relative ratios of individual unphosphorylated and phosphorylated isoforms.
Results: We first optimized assays for proteins in MAPK, PI3K and STAT pathways, and loading controls, to analyze frozen surgical specimens and ex-vivo fine needle aspirates (FNA's) performed immediately following nephrectomy. We analyzed more than 200 FNA's from solid tumors, comparing RCC with paired adjacent non-tumor tissue, and other epithelial malignancies. Basal MAPK signaling of tumors varied across 3 logs of expression. Unique to NIA, we analyzed percent phosphorylation and resolved differences in single phosphorylations. Subtle differences in basal MAPK signaling between tumor calls and adjacent non-tumor tissue can distinguish RCC from other malignancies. Lastly, we prospectively collected and analyzed blood peripheral mononuclear cells from 20 RCC patients before and during treatment with standard targeted therapies. Kinase inhibitors can preferentially inhibit or activate specific protein phospho-isoforms.
Conclusions: Our studies demonstrate that rapid and quantitative nanoproteomic profiling in very small amounts of clinical specimen may accelerate translational studies for novel diagnostic and predictive biomarkers.
Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era
*Stanford Kidney Cancer Research Program;†Department of Urology, Stanford University School of Medicine;‡Department of Medicine, Stanford University School of Medicine;§Department of Health Research and Policy, Stanford University School of Medicine;¶Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
Acknowledgements: Dr. Leppert is supported by Award Number DK089086 from the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Chertow is supported by K24 DK085446. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH/NIDDK.
Background: We sought to analyze utilization and survival outcomes of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) before and after introduction of targeted therapy.
Methods: We identified patients with metastatic RCC between 1993 and 2010 in the SEER registry and examined temporal trends in utilization, as well as patient and tumor characteristics associated with receipt of cytoreductive nephrectomy. We performed a joinpoint regression to determine when changes in utilization of cytoreductive nephrectomy occurred. We fitted multivariable proportional hazard models to determine the association of cytoreductive nephrectomy with mortality in full and propensity score-matched cohorts. We performed a difference-in-difference analysis to compare survival outcomes before and after introduction of targeted therapy.
Results: The proportion of patients undergoing cytoreductive nephrectomy increased from 1993 to 2004, from 29% to 39%. We identified a primary joinpoint of 2004, just prior to the introduction of targeted therapy. Beginning in 2005, there was a modest decrease in utilization of CN. Cytoreductive nephrectomy was associated with a lower adjusted relative hazard (0·41, 95% confidence interval 0·34 to 0·43). Median survival among patients receiving cytoreductive nephrectomy increased in the targeted therapy era (19 versus 13 months), while median survival among patients not receiving cytoreductive nephrectomy increased only slightly (4 versus 3 months). Difference in difference analysis showed that there was a significant decrease in hazard of death among patients who received cytoreductive nephrectomy in the targeted therapy era.
Conclusions: Despite decreased utilization in the targeted therapy era, cytoreductive nephrectomy remains associated with improved survival. Prospective randomized trials are needed to confirm the benefit of cytoreductive nephrectomy among patients with metastatic RCC treated with novel targeted therapies.
Fig. 1 Proportion of patients with metastatic RCC receiving cytoreductive nephrectomy by year of diagnosis. We identified 2004 as the year when utilization trends changed (joinpoint). This coincides with the introduction of targeted therapies in 2005, represented by the vertical dotted reference line.
Fig. 2 Product-limit survival estimates stratified by treatment era in the full (A) and propensity score-matched (B) cohorts. Patients treated in the targeted therapy era (≥2005) are shown in red. Patients treated before 2005 are shown in blue. Survival curves of patients treated with cytoreductive nephrectomy are represented as a solid line, while those not receiving cytoreductive nephrectomy are represented as dotted lines. Median overall survival of patients treated with CN increased to 19 months from 13 months in the targeted therapy era. Median overall survival of patients not receiving CN, increased to 4 from 3 months. (C) The temporal trend of the adjusted hazard of mortality associated with cytoreductive nephrectomy by diagnosis year with 95% CI. (D) The increasing difference in median survival for patients receiving cytoreductive nephrectomy. The beginning of the targeted therapy era is represented by the vertical dotted reference line.
Poorly functioning kidneys recover from ischemia during partial nephrectomy as well as strongly functioning kidneys
M.C. MIR, T. TAKAGI, R.A. CAMPBELL, N. SHARMA, E. REMER, J. LI, S. DEMIRJIAN, J. KAOUK and S.C. CAMPBELL
Department of Urology, Glickman Urological and Kidney Institute, Cleveland OH
Objective: Some authors have proposed that poorly functioning kidneys may not recover from ischemia as well as strongly functioning kidneys, which would have impact on the surgical approaches to partial nephrectomy (PN).
Materials and Methods: A total of 122 consecutive patients undergoing PN at our institution with appropriate studies to facilitate analysis of function and parenchymal mass volume in the operated kidney (CT and SCr within 2 months prior and 4–12 months postoperative) were analyzed. Patients with a contralateral kidney also required renal scans in the same time frame to provide split renal function. Volumetric CT was utilized to measure the volume of functional parenchyma pre and post PN in the operated kidney and the contralateral kidney. GFR was determined by the MDRD2 equation. Recovery of nephron function (GP/VS = % GFR preserved/% volume saved) would be 100% if all nephrons recovered from the ischemic insult.
Results: Median age was 61 years with approximately 50% of patients having open procedures. Median RENAL score was 7. Cold ischemia was used in 50 patients (median 26 min), while 72 had limited warm ischemia (median 20 min). Median %GFR preserved in the operated kidney was 79.5%. Median parenchymal volume saved was 84%. Function in the contralateral kidney remained stable without significant increase. Overall recovery of nephron function (GP/VS) was 95.5%, and was 100.7% for the cold ischemia subgroup and 93% in the limited warm ischemia subgroup. Recovery of nephron function (GP/VS) was similar for all strata of preoperative eGFR in the operated kidney (<30, 21–45, 46–60, and >60) as detailed in the table (p > 0.18 for all comparisons), even in the limited warm ischemia subgroup.
Conclusion: Preoperative GFR at PN does not correlate with how well the kidney will recover from the ischemia insult. Our results suggest that the amount vascularized parenchyma preserved by the PN is the main determinant of the postoperative GFR. Even poorly functioning kidneys recover well from the ischemic insult as long as limited warm ischemia or hypothermia are utilized.
Recovery Nephron Function (GP/VS).
Overall (n = 122)
Cold Ischemia (n = 50)
Warm Ischemia (n = 72)
p = 0.206
p = 0.181
p = 0.679
All analyses refer specifically to the operated kidney.