Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma—Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study

Oudard, Stéphane; Geoffrois, Lionnel; Guillot, Aline; Chevreau, Christine; Deville, Jean‐Laurent; Falkowski, Sabrina; Boyle, Helen; Baciuchka, Marjorie; Gimel, P.; Laguerre, Brigitte; Laramas, Mathieu; Pfister, Christian; Topart, Delphine; Rolland, Frédéric; Legouffe, Eric; Dénéchère, Gwénaël; Amela, Eric Yaovi; Abadie‐Lacourtoisie, Sophie; Gross‐Goupil, Marine

doi:10.1016/j.ejca.2016.04.003

Cited by 34 publications

(26 citation statements)

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“…The above articles all concluded that sunitinib rechallenge is an effective and safe treatment choice for patients who relapsed after sunitinib and subsequent TKIs and/or mTOR inhibitors. The treatment type between the two sunitinib exposures seemed to be indifferent regarding the efficacy of rechallenged sunitinib; however, only our report and two other authors presented cases when TKIs (other than sunitinib) were applied [ 9 , 10 ]. The above statement is strengthened by the above-mentioned prospective study [ 15 ] the preliminary results of which were very similar to that of other retrospective studies (Table 3 ).…”

Section: Discussionmentioning

confidence: 83%

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Sunitinib Rechallenge After Other Targeted Therapies in Metastatic Renal Cell Carcinoma Patients: A Single-Center, Retrospective Study

et al. 2019

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Background Sunitinib is still one of the standard therapies in metastatic renal cell carcinoma (mRCC). Despite the benefit of sunitinib resistance will develop in the majority of patients. Most of them receive multiple sequential therapies during the course of disease. Objectives To retrospectively investigate the efficacy and safety of rechallenged sunitinib in third or later line settings. Patients and Methods Twenty-one mRCC patients were identified who received rechallenged sunitinib between March 2010 and April 2018. Patients received sunitinib in first or second line, then other tyrosine kinase and/or mTOR inhibitors were applied, then sunitinib was rechallenged. Patients’ characteristics, tolerability, treatment modalities, and treatment outcomes were recorded. The primary end-point was progression-free survival (PFS) of rechallenged sunitinib. Results Median age of patients was 62 years at the start of sunitinib rechallenge. Sixty-seven percent of patients were male. All patients had prior nephrectomy. Upon rechallenge 4 patients achieved partial response and 12 stable disease. The median PFS of first sunitinib treatment was 22 (95% CI 17–26) months and for rechallenged sunitinib 14 (95% CI 6–20) months. No increased severity of prior toxicity or new adverse events was reported during rechallenged sunitinib. The median overall survival (OS) from the start of first sunitinib was 67 (95% CI 46–76) months. Multivariate Cox regression analysis revealed that younger age (< 57 years) at start of first sunitinib (HR = 0.24; 95% CI 0.07–0.79; p = 0.019) and longer (> 2 years) first sunitinib treatment (HR = 0.28; 95% CI 0.09–0.93; p = 0.038) were independent markers of longer OS. Conclusion Sunitinib rechallenge is a feasible and tolerable option with clinical benefit in selected mRCC patients.

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Section: Discussionmentioning

confidence: 83%

“…Oudard et al [ 9 ] reported significantly longer PFS of rechallenged sunitinib for patients having longer PFS for the first sunitinib. Compared to our study (29%) they had many more patients (78%) receiving both mTOR and TKI between sunitinib treatments.…”

Section: Discussionmentioning

confidence: 99%

Sunitinib Rechallenge After Other Targeted Therapies in Metastatic Renal Cell Carcinoma Patients: A Single-Center, Retrospective Study

et al. 2019

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“…The mechanisms of sunitinib resistance can be roughly divided into the following: activation of the angiogenic signalling pathway, changes in the tumour microenvironment, increase in tumour invasion and metastasis, and the role of microRNAs and lncRNAs in the activation of other signal bypasses 43. Pro-angiogenic factors, such as Ang2, FGF, and PDGF, are upregulated in most cases of sunitinib resistance 44, 45. In fact, anti-angiogenic-induced hypoxia activates the mTOR pathway and induces HIF production, which activates the transcription HRE-containing genes such as VEGF, PDGF, TGF-α, EPO, MMP-1, EGFR, HGFR/cMET, cyclin D1, and SDF1 and its receptor CXCR4 46.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation-regulated QPCT promotes sunitinib resistance by increasing HRAS stability in renal cell carcinoma

et al. 2019

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Rationale: Although sunitinib has been shown to improve the survival rate of advanced renal cell carcinoma (RCC) patients, poor drug response is a major challenge that reduces patient benefit. It is important to elucidate the underlying mechanism so that the therapeutic response to sunitinib can be restored.Methods: We used an Illumina HumanMethylation 850K microarray to find methylation-differentiated CpG sites between sunitinib-nonresponsive and -responsive RCC tissues and Sequenom MassARRAY methylation analysis to verify the methylation chip results. We verified glutaminyl peptide cyclotransferase (QPCT) expression in sunitinib-nonresponsive and -responsive RCC tissues via qRT-PCR, western blot and immunohistochemical assays. Then, cell counting kit 8 (CCK-8), plate colony formation and flow cytometric assays were used to verify the function of QPCT in RCC sunitinib resistance after QPCT intervention or overexpression. Chromatin immunoprecipitation (ChIP) was performed to clarify the upstream regulatory mechanism of QPCT. A human proteome microarray assay was used to identify downstream proteins that interact with QPCT, and co-immunoprecipitation (co-IP) and confocal laser microscopy were used to verify the protein chip results.Results: We found that the degree of methylation in the QPCT promoter region was significantly different between sunitinib-nonresponsive and -responsive RCC tissues. In the sunitinib-nonresponsive tissues, the degree of methylation in the QPCT promoter region was significantly reduced, and the expression of QPCT was upregulated, which correlated with a clinically poor response to sunitinib. A knockdown of QPCT conferred sunitinib sensitivity traits to RCC cells, whereas an overexpression of QPCT restored sunitinib resistance in RCC cells. Mechanistically, reducing the methylation degree of the QPCT promoter region by 5-aza-2'-deoxycytidine (decitabine) in RCC cells could increase the expression of QPCT and NF-κB (p65) bound to the QPCT promoter region, positively regulating its expression, while the hypermethylation in the QPCT promoter region could inhibit the binding of NF-κB (p65). QPCT could bind to HRAS and attenuate the ubiquitination of HRAS, thus increasing its stability and leading to the activation of the ERK pathway in RCC cells.Conclusion: QPCT may be a novel predictor of the response to sunitinib therapy in RCC patients and a potential therapeutic target.

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“…The mixed retrospective and prospective REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study has evaluated the efficacy, as measured by PFS, and safety of sunitinib rechallenge in mRCC patients who received first-line sunitinib, then one or more lines of different targeted treatments, followed by further sunitinib. 57 A total of 28 patients (54% of 52 patients eveluated) had a complete ( n = 1) or partial response (PR) with first-line sunitinib, and 8 patients (15%) achieved a PR upon sunitinib rechallenge. Median PFS with first-line sunitinib was 18.4 months (95% CI: 12.5–23.7) and 7.9 months (95% CI: 5.4–13.2) with sunitinib rechallenge.…”

Section: Sunitinib Rechallengementioning

confidence: 99%

Sunitinib in the treatment of renal cell carcinoma: an update on recent evidence

Rizzo

Porta

2017

Therapeutic Advances in Urology

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Sunitinib is a multitarget tyrosine kinase inhibitor endowed mainly by antiangiogenic effects, although an indirect inhibitory effect on tumor growth and, more recently, a complex activity on antitumor immune response has been described. From approval by the US Food and Drug Administration (FDA) in January 2006, sunitinib represents a key molecule in the treatment of metastatic renal cell carcinoma (mRCC) due to the peculiar molecular pathogenesis of this neoplasm. Over the past 10 years, clinical trials and real-world experiences helped clinicians to understand how, when and for how long to use sunitinib. Although a huge amount of data evidenced the relationship existing between sunitinib dose intensity and improved clinical outcome, the management of sunitinib-induced adverse events is often complex; thus, alternative schedules have been proposed over time which allow increased tolerability, without decreased daily sunitinib exposure, leading to improved clinical outcomes. To date, combinations of sunitinib with other approved targeted agents did not demonstrate any significant benefit over its single-agent use, mainly due to tolerability issues. Sunitinib has also been tested in the adjuvant setting, within the ASSURE and S-TRAC trials, with opposite results; indeed, equivocal risk-stratification criteria, as well as immature overall survival (OS) data prevent any definitive conclusion on this important issue. Despite being on the market for a long time, sunitinib still plays a role as the 'comparator arm' of a number of trials in the field of mRCC. Combinations with immune checkpoint inhibitors and vaccines look promising; once again, sunitinib can help us to optimize mRCC management.

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Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma—Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study

Cited by 34 publications

References 21 publications

Sunitinib Rechallenge After Other Targeted Therapies in Metastatic Renal Cell Carcinoma Patients: A Single-Center, Retrospective Study

Sunitinib Rechallenge After Other Targeted Therapies in Metastatic Renal Cell Carcinoma Patients: A Single-Center, Retrospective Study

DNA methylation-regulated QPCT promotes sunitinib resistance by increasing HRAS stability in renal cell carcinoma

Sunitinib in the treatment of renal cell carcinoma: an update on recent evidence

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