Sequential therapy with sorafenib and sunitinib in renal cell carcinoma

Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Cancer (Impact Factor: 4.89). 01/2009; 115(1):61-7.
Source: PubMed


Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.
Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first-line therapy with either sunitinib or sorafenib and subsequently receiving second-line therapy with the other TKI agent.
Twenty-nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P=.016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P=.061).
The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation.

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    • "Similarly, in various studies of sorafenib in patients who had previously received VEGF-targeted therapies, response rates have been low (0%–9.6%) with a modest median PFS or time-to-progression (around 4 months) [37,39-43]. Although it is not possible to discern the relative contributions of IL-21 and sorafenib to the overall antitumor activity in this single-arm study, it is plausible that IL-21 contributed to the activity of the combination, given the modest ORR and PFS generally seen with sorafenib monotherapy in mRCC patients who have previously been treated (especially with VEGF-targeted therapies). "
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    ABSTRACT: Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10-50 mcg/kg) on days 1-5 and 15-19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. Identifier: NCT00389285.
    01/2014; 2(1):2. DOI:10.1186/2051-1426-2-2
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    • "Similar data also exist for sunitinib after sorafenib failure. Dudek et al. [50] revealed that patients who received sorafenib followed by sunitinib had a median duration of stable disease of 20 weeks (median OS, 102 weeks; 59% clinical benefit). Subsequently, it was also reported that secondline sunitinib showed efficacy in patients with an initial failure from bevacizumab [51]. "
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    ABSTRACT: The treatment of metastatic renal cell carcinoma (mRCC) has recently evolved from being predominantly cytokine-based treatment to the use of targeted agents, which include sorafenib, sunitinib, bevacizumab (plus interferon alpha [IFN-α]), temsirolimus, everolimus, pazopanib, and most recently, axitinib. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies for treating the disease. In Korea, it has been 5 years since targeted therapy became available for mRCC. Thus, we now have broader and better therapeutic options at hand, leading to a significantly improved prognosis for patients with mRCC. However, the treatment of mRCC remains a challenge and a major health problem. Many questions remain on the efficacy of combination treatments and on the best methods for achieving complete remission. Additional studies are needed to optimize the use of these agents by identifying those patients who would most benefit and by elucidating the best means of delivering these agents, either in combination or as sequential single agents. Furthermore, numerous ongoing research activities aim at improving the benefits of the new compounds in the metastatic situation or their application in the early phase of the disease. This review introduces what is currently known regarding the fundamental biology that underlies clear cell RCC, summarizes the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in pivotal clinical trials, and outlines future research directions.
    Korean journal of urology 04/2012; 53(4):217-28. DOI:10.4111/kju.2012.53.4.217
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    • "This retrospective study suggested the benefit of utilizing sorafenib as first line may improve duration of disease control if a subsequent agent is used and certainly warrants further investigation. (Dudek et al, 2009) The SWITCH trial is a prospective phase III trial which will randomize patients to upfront sunitinib and switching to sorafenib on progression versus switching from sorafenib to sunitinib on progression. The primary end point is the PFS and hopefully this trial will show further insight into which anti-VEGF treatment sequence will confer better clinical outcome in patients with metastatic RCC. "

    Emerging Research and Treatments in Renal Cell Carcinoma, 02/2012; , ISBN: 978-953-51-0022-5
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