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Sorafenib Versus Observation Following Radical Metastasectomy for Clear-cell Renal Cell Carcinoma: Results from the Phase 2 Randomized Open-label RESORT Study.
Procopio, G, Apollonio, G, Cognetti, F, Miceli, R, Milella, M, Mosca, A, Chiuri, VE, Bearz, A, Morelli, F, Ortega, C, et al
European urology oncology. 2019;(6):699-707
Abstract
BACKGROUND In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. OBJECTIVE To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. RESULTS AND LIMITATIONS At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test p = 0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3 AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. CONCLUSIONS This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. PATIENT SUMMARY This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.
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Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial.
Bracarda, S, Bamias, A, Casper, J, Negrier, S, Sella, A, Staehler, M, Tarazi, J, Felici, A, Rosbrook, B, Jardinaud-Lopez, M, et al
Clinical genitourinary cancer. 2019;(3):e689-e703
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Abstract
BACKGROUND Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting. PATIENTS AND METHODS AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors. RESULTS Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments. CONCLUSION In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.
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Efficacy of tivozanib treatment after sorafenib in patients with advanced renal cell carcinoma: crossover of a phase 3 study.
Molina, AM, Hutson, TE, Nosov, D, Tomczak, P, Lipatov, O, Sternberg, CN, Motzer, R, Eisen, T
European journal of cancer (Oxford, England : 1990). 2018;:87-94
Abstract
BACKGROUND Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC). METHODS Patients enrolled in this single-arm, phase 2 crossover study were previously randomised to sorafenib on TIVO-1, progressed and then crossed over to tivozanib. Patients received tivozanib (1.5 mg/day orally; 3 weeks on/1 week off) within 4 weeks after their last sorafenib dose. FINDINGS Crossover patients were exposed to tivozanib for a median of eight cycles. From the start of tivozanib treatment, median progression-free survival was 11.0 months (95% confidence interval [CI]: 7.3-12.7) and median overall survival was 21.6 months (95% CI: 17.0-27.6). Best overall response was partial response in 29 (18%) patients and stable disease in 83 (52%) patients, with a median duration of response of 15.2 and 12.7 months, respectively. About 77% of patients experienced adverse events, most frequently hypertension (26%), followed by diarrhoea (14%) and fatigue (13%); 53% of patients had treatment-related adverse events, including 24% grade ≥3. About 9% and 16% of patients had dose reductions and dose interruptions due to adverse events, respectively. A total of 30% of patients had serious adverse events, and 4% had treatment-related serious adverse events. INTERPRETATION This crossover study of patients with advanced RCC demonstrated potent tivozanib anti-tumour activity. Safety and tolerability profiles were acceptable and consistent with the established adverse event profile of tivozanib.
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Phase I/II study of S-1 in combination with sorafenib for metastatic renal cell carcinoma.
Naito, S, Sakai, H, Hashine, K, Tomita, Y, Shinohara, N, Fujisawa, M, Eto, M, Ozono, S, Akaza, H
Annals of oncology : official journal of the European Society for Medical Oncology. 2015;(9):1871-1876
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BACKGROUND The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC. PATIENTS AND METHODS In this multicenter, single-arm, open-label, phase I/II study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior cytokine-based regimen. The phase I primary end points were the maximum tolerated dose (MTD) and recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1-28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase II, the primary end point was to assess the overall response rate (ORR) at the RD. RESULTS Nine patients were enrolled into phase I and 21 (including 6 patients who received the RD in the phase I portion) were enrolled into phase II. In the phase I portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m(2)/day on days 1-28 + sorafenib 800 mg/day on days 1-42. In the phase II portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% [95% confidence interval (CI) 29.8-74.3], including one complete response (5%) and 10 partial responses (48%). The median progression-free survival was 9.9 (95% CI 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%). CONCLUSION Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy.
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The Relationship Between the Adverse Events and Efficacy of Sorafenib in Patients With Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Study from Northwest China.
Zheng, Y, Wang, F, Wu, G, Zhang, L, Wang, Y, Wang, Z, Chen, P, Wang, Q, Lu, J, Wang, Y, et al
Medicine. 2015;(49):e2222
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The aim of the study is to evaluate the relationship between the adverse events and efficacy of sorafenib in patients with metastatic renal cell carcinoma (mRCC), with a purpose to guide the judgment of efficacy in sorafenib treatment.Eighty-three mRCC patients who received sorafenib therapy at northwest China were studied retrospectively. Univariate and multivariate analyses were performed to correlate tumor response, progression-free survival (PFS), and overall survival (OS) with adverse event types and grades.Among 83 patients who underwent sorafenib therapy, 2 cases (2.4%) had completed response (CR), 14 cases (16.9%) had partial response (PR), 57 cases (68.7%) had stable disease (SD), and 10 cases (12.0%) developed progressive disease (PD). The median PFS and OS were 15.0 and 29.0 months, respectively. The most frequent grade 1 or 2 adverse events included hand-foot syndrome (68.7%), diarrhea (54.2%), and alopecia (51.8%). The most common grade 3 or 4 adverse events were hand-foot syndrome (6.0%), hypertension (4.8%), and diarrhea (3.6%). The frequency and severity of adverse events correlated with tumor response rate (both with P < 0.05). Multivariate analysis showed the independent predictors of better PFS included rash (OR 0.307, 95%CI 0.148-0.636, P = 0.001) and diarrhea (OR 0.391, 95%CI 0.169-0.783, P = 0.008). Elevated transaminase was the independent predictor of poor PFS (OR 2.606, 95%CI 1.299-5.532, P = 0.012). For OS, rash (OR 0.473, 95%CI 0.253-0.886, P = 0.019) and diarrhea (OR 0.321, 95%CI 0.171-0.605, P = 0.000) correlated with better OS.Sorafenib-related adverse events are associated with efficacy in patients with mRCC from northwest China. Rash and diarrhea are independent protective factors of both PFS and OS, and elevated transaminase is an independent risk factor of PFS. A large prospective study is warranted.
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A cross-sectional investigation of fatigue in advanced renal cell carcinoma treatment: results from the FAMOUS study.
P J, G, A, M, L, M, H J, H, M, K, S, B, N, M
Urologic oncology. 2014;(3):362-70
Abstract
OBJECTIVE With an increasing choice of new treatment options, the management of side effects to maintain a chosen treatment if likely to be effective on the tumor remains important. The perception of side effects however varies between the physician and the patient, leading to possible wrong assumptions on tolerability that result in dose modifications, which may ultimately affect effectiveness. The aim was to assess fatigue in patients with advanced or metastatic renal cell carcinoma (RCC) by comparing the evaluation of the physician to the one provided by their respective patient. In addition, we aimed to assess possible influences of fatigue on parameters of quality of life. METHODS Patients receiving systemic treatment for advanced RCC and their physicians were questioned independently regarding incidence and severity of fatigue and its effect on quality of life. RESULTS Both physicians and patients completed 98 matching questionnaires. Patients were treated with sunitinib, sorafenib, bevacizumab combined with interferon alpha, temsirolimus, everolimus, or interferon alpha alone. Incidence and severity of fatigue was differently assessed by patients and physicians, with fatigue being more severe when reported by the patient. The severity of fatigue increased with progressing treatment lines. Quality of life was significantly lower in patients experiencing fatigue compared with patients without fatigue. Emotional, functional, and physical well-being were all affected by fatigue, the latter being the most affected subscale. Social well-being was least affected. CONCLUSION Fatigue is a complex and cumulative condition of patients treated for advanced RCC, and it considerably affects patient's quality of life. As many of its underlying causes may be treated, the divergent perception of occurrence and severity of fatigue should be integrated in treatment concepts. The active role of the patient in helping to manage ailments through assessment should be implemented when optimizing treatment of RCC.
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Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
Rini, BI, Escudier, B, Tomczak, P, Kaprin, A, Szczylik, C, Hutson, TE, Michaelson, MD, Gorbunova, VA, Gore, ME, Rusakov, IG, et al
Lancet (London, England). 2011;(9807):1931-9
Abstract
BACKGROUND The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. METHODS We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. FINDINGS A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. INTERPRETATION Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. FUNDING Pfizer Inc.
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Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a subanalysis of TARGET.
Negrier, S, Jäger, E, Porta, C, McDermott, D, Moore, M, Bellmunt, J, Anderson, S, Cihon, F, Lewis, J, Escudier, B, et al
Medical oncology (Northwood, London, England). 2010;(3):899-906
Abstract
Before the development of targeted therapies, administration of cytokines (e.g., interleukin-2, interferon-alpha) was the primary systemic treatment option for advanced renal cell carcinoma. Sorafenib, an oral targeted, multikinase inhibitor, significantly prolonged progression-free survival and overall survival in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a large (N = 903) phase III, double-blind, randomised, placebo-controlled study of patients with advanced renal cell carcinoma resistant to standard therapy. This analysis of a patient subgroup from TARGET evaluated the safety and efficacy of sorafenib in patients who had received prior cytokine therapy (sorafenib: n = 374; placebo: n = 368) and in patients who were cytokine-naïve (sorafenib: n = 77; placebo: n = 84). Progression-free survival was significantly prolonged with sorafenib therapy compared with placebo among patients with and without prior cytokine therapy (respectively 5.5 vs. 2.7 months; hazard ratio, 0.54; 95% confidence interval, 0.45-0.64 and 5.8 vs. 2.8 months; hazard ratio, 0.48; 95% confidence interval, 0.32-0.73). Clinical benefit rates for sorafenib-treated patients compared with placebo patients were also higher (cytokine-treated: 83 vs. 54.3%; cytokine-naïve: 85.7 vs. 56.0%). Sorafenib was well tolerated in both subgroups (grade 3/4: 20 and 22%, respectively). Sorafenib demonstrated a consistent, significant clinical benefit against advanced renal cell carcinoma, with a twofold improvement in progression-free survival and disease control rate, with similar toxicities in patients with or without prior cytokine treatment.
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Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET.
Hutson, TE, Bellmunt, J, Porta, C, Szczylik, C, Staehler, M, Nadel, A, Anderson, S, Bukowski, R, Eisen, T, Escudier, B, et al
European journal of cancer (Oxford, England : 1990). 2010;(13):2432-40
Abstract
BACKGROUND The phase III Treatment Approaches in Renal cancer Global Evaluation Trial (TARGET) indicated that sorafenib is effective and well tolerated in advanced renal cell carcinoma patients. However, few data have been published on the safety of long-term sorafenib treatment. A retrospective subgroup analysis was performed to evaluate the efficacy and safety of sorafenib in patients in TARGET who received treatment for >1 year. METHODS The present subgroup analysis (based on the September 2006 database with updated safety analysis) evaluated the efficacy and safety of sorafenib in all patients in the sorafenib arm of TARGET who were treated for >1 year. The assessments included the overall survival, progression-free survival (PFS), disease control rate (DCR), and safety. The patients remained on therapy post-progression at the discretion of the investigator. RESULTS In TARGET, 169 patients received treatment with sorafenib for >1 year. The median PFS of patients in this subpopulation was 10.9 months from the date of randomisation, with a DCR of 92%. The most commonly reported treatment-related adverse events of any grade were diarrhoea (74%), rash/desquamation (51%), hand-foot skin reaction (49%), alopecia (39%), and fatigue (38%). Adverse events were mild to moderate, and presented early in the course of the treatment; there were no unexpected toxicities associated with the long-term administration of sorafenib. CONCLUSIONS Results of this subgroup analysis of patients enrolled in TARGET who received treatment for >1 year indicate that long-term treatment with sorafenib is associated with continued efficacy and a well-tolerated safety profile.
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Phase II randomized study of Plitidepsin (Aplidin), alone or in association with L-carnitine, in patients with unresectable advanced renal cell carcinoma.
Schöffski, P, Guillem, V, Garcia, M, Rivera, F, Tabernero, J, Cullell, M, Lopez-Martin, JA, Pollard, P, Dumez, H, del Muro, XG, et al
Marine drugs. 2009;(1):57-70
Abstract
This randomized phase II study evaluated two schedules of the marine compound Plitidepsin with or without co-administration of L-carnitine in patients with renal cell carcinoma. Patients had adequate performance status and organ function. The primary endpoint was the rate of disease control (no progression) at 12 weeks (RECIST). Other endpoints included the response rate and time dependent efficacy measures. The trial also assessed the efficacy of L-carnitine to prevent Plitidepsin-related toxicity. The two regimes given as 24 hour infusion every two weeks showed hints of antitumoral activity. Disease control at 12 weeks was 15.8% in Arm A (5mg/m2, no L-carnitine) and 11,1% in Arm B (7 mg/m2 with L-carnitine). Two partial responses were observed in Arm A (19 patients), none in Arm B (20 patients). Both schedules had the same progression-free interval (2.1 months). The median overall survival was 7.0 and 7.6 months. The safety profile was similar in both arms of the trial and adverse events were mainly mild to moderate (NCI CTC version 2.0). Increasing the dose to 7 mg/m2 did not increase the treatment efficacy but the incidence of transaminase and CPK elevations and serious AEs. Coadministration of L-carnitine did not prevent muscular toxicity or CPK-elevation associated with Plitidepsin.