Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma

Herrmann, Edwin; Marschner, Norbert; Grimm, Marc‐Oliver; Ohlmann, Carsten-Henning; Hutzschenreuter, Ulrich; Overkamp, Friedrich; Groschek, Matthias; Blumenstengel, K.; Pühse, G.; Steiner, Thomas

doi:10.1007/s00345-011-0673-4

Cited by 25 publications

(11 citation statements)

References 10 publications

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“…In a phase 3 study of sorafenib in pretreated (mostly with cytokines) mRCC patients, the ORR was low (2% by independent radiologic review) with no CRs [2]. 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).…”

Section: Discussionmentioning

confidence: 99%

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Bhatia¹,

Curti²,

Ernstoff³

et al. 2014

j. immunotherapy cancer

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BackgroundDespite 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.MethodsIn 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.ResultsIn 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.ConclusionIL-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.Trial registrationClinicalTrials.gov Identifier: NCT00389285

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Section: Discussionmentioning

confidence: 99%

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Bhatia¹,

Curti²,

Ernstoff³

et al. 2014

j. immunotherapy cancer

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“…Herrmann et al [17] reported 54 patients in So-Su and 33 patients in Su-So group. The median PFS were 12.1 vs 15.4 months and the median OS were 28.8 vs 28.9 months.…”

Section: Resultsmentioning

confidence: 99%

“…Parts of recent retrospective studies have suggested that sorafenib followed by sunitinib (So-Su) was optimal to sunitinib followed by sorafenib (Su-So) in progression-free survival and overall survival [8–12]. Nevertheless, a recent randomized controlled trial SWITCH [13] and several retrospective studies [14–17] argued that So-Su and Su-So offer similar clinical efficacy in mRCC, with no statistically differences.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of sequential therapies with sorafenib-sunitinib versus sunitinib-sorafenib in metastatic renal cell carcinoma: A systematic review and meta-analysis

et al. 2017

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The most efficient sequence of targeted agents for metastatic renal cell carcinoma patients has yet to be identified. Whether the sequence of sorafenib and sunitinib really matters is controversial and not answered clearly until now. This meta-analysis aims to estimate the efficacy of receptor tyrosine kinase inhibitors sorafenib-sunitinib and sunitinib-sorafenib for metastatic renal cell carcinoma, on the outcome of first-line progression-free survival, second-line progression-free survival, total progression-free survival and overall survival.We searched PubMed, Embase, Cochrane Library and ClinicalTrails.gov for eligible studies. Data were analyzed using random or fixed effects model depending on the heterogeneity of the eligible studies. Heterogeneity across studies were analyzed using Q and I2 statistics.Of 902 identified studies, ten were qualified in our analysis (N = 1732 patients). Sorafenib-sunitinib yielded no statistically significant benefit in first-line progression-free survival (fixed effects; HR = 0.95; 95%CI 0.75-1.21; p = 0.702), total progression-free survival (random effects; HR = 0.92; 95%CI 0.71-1.19; p = 0.531) and overall survival (fixed effects; HR = 0.89; 95%CI 0.72-1.09; p = 0.257), compared with sunitinib-sorafenib. Second-line progression-free survival was longer for sorafenib-sunitinib than sunitinib-sorafenib (fixed effects; HR = 0.55; 95%CI 0.44-0.68; p = 0.000).Sequential therapies with sorafenib and sunitinib is well tolerated and efficient in mRCC. However, there are no evidence supported that sorafenib–sunitinib has the superiority to sunitinib-sorafenib in sequence. The ideal sequence of targeted agents requires further elucidation.

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“…Wie demgegenüber unter Berücksichtigung retrospektiver Serien unter Einschluss von >700 Patienten offensichtlich wird, entfalten Sorafenib und Sunitinib auch in der Zweitlinie nach Therapieversagen gegenüber einer TKIbasierten Erstlinienbehandlung Wirksamkeit [9,10,11,12,13].…”

Section: Systemtherapie In Der Zweitlinie Sequenzund Kombinationstheunclassified

Systemische und operative Therapie des metastasierten Nierenzellkarzinoms

Kramer

Merseburger

Peters

et al. 2011

Urologe

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Several targeted therapies have become available for first-line (sunitinib, bevacizumab, pazopanib, temsirolimus) and second-line (sorafenib, pazopanib, everolimus) use in recent years. The superior outcomes achieved with these targeted agents have led to replacement of the formerly administered cytokines. New developments have raised the question of whether patients benefit from sequential therapies with tyrosine kinase inhibitors and/or whether combination regimes can improve clinical outcomes. This review gives an overview of the current therapeutic options for first- and second-line treatment in metastatic RCC as well as sequential and combination therapies. Adjuvant and neoadjuvant treatment options are being discussed. Furthermore, this review addresses surgical alternatives in the treatment of RCC.

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Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma

Abstract: This study endorses the notion of a clinical benefit of the sequential use of sorafenib and sunitinib and supports observations from previous studies. In terms of the optimal succession of the two TKIs, the study does not allow a definite answer.

Cited by 25 publications

References 10 publications

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Efficacy of sequential therapies with sorafenib-sunitinib versus sunitinib-sorafenib in metastatic renal cell carcinoma: A systematic review and meta-analysis

Systemische und operative Therapie des metastasierten Nierenzellkarzinoms

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