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

Nagyiványi, Krisztián; Budai, Barna; Gyergyay, Fruzsina; Küronya, Zsófia; Bíró, Krisztina; Gergely, Lajos

doi:10.1007/s40261-019-00778-5

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…First, median PFS on Sunitinib rechallenge is higher than usually observed with the same agent in large phase III studies conducted in the first-line setting, that is, between 8.3 and 11.1 months; 28 –33 even longer as compared to what was expected is the overall survival of our case series. Of course, it is clear that our patient population was highly biased, having shown particular sensibility to VEGFR inhibition (patients, by protocol, had to have had a disease control of at least 10 months in first line) and having survived enough to reach a third-line (or even more) treatment still in good conditions.…”

Section: Discussioncontrasting

confidence: 44%

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Prospective phase II study of sunitinib rechallenge in metastatic renal cell carcinoma: The “retry” study from the Italian Group of Onco-Nephrology (G.I.O.N.)

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Ferrari

Zucali³

et al. 2022

Journal of Onco-Nephrology

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Background: Sunitinib is still a recommended treatment option for metastatic renal cell carcinoma (RCC) patients; lack of cross-resistance to sequential antiangiogenic drugs has been postulated. Objective: The possibility of a successful rechallenge with sunitinib was tested in this prospective phase II trial. Methods: Main inclusion criteria were: histologically proven RCC with clear cell component, previous first-line sunitinib with a Disease Control Rate lasting ⩾10 months, and second-line everolimus. The primary end-point was 6-months progression-free survival (PFS). A Simon’s 2-stage design was used; after testing sunitinib on 12 patients, the trial would have been terminated if ⩽5 had a PFS <6 months. Otherwise, the trial would have proceeded enrolling a total of 38 patients. If the total number of patients free of progression at 6 months would have been ⩽18, sunitinib would have been rejected. Results: A total of 39 patients (30 males, 9 females) were enrolled. The study reached the second stage, and ultimately succeeded; indeed, 6-months PFS was 64.1%, median PFS being 14.9 months (95% confidence interval: 9.06–20.91). Treatment-related grade 3–4 adverse events observed in ⩾5% of the patients were: hand-foot skin reaction, fatigue, nausea, hypertriglyceridemia, hypophosphatemia, hypocalcemia, hyperglycemia, and neutropenia. One case each of myocardial infarction, atrial flutter, and spontaneous pneumothorax, were also reported. Conclusions: Despite an ineluctable time-lead-bias, median PFS on sunitinib rechallenge was high, clearly showing that many patients may become sensitive again to antiangiogenic treatment. In countries where treatment options are still limited, sunitinib rechallenge could represent an option. EudraCT number: 2012-000473-23.

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Section: Discussioncontrasting

confidence: 44%

“…Indeed, most data on sunitinib re-challenge came from retrospective studies, small case series, or even single case reports, 14,[19][20][21][22][23][24][25] constantly showing activity, efficacy, as well as tolerability. Of note, in few patients, PFS was longer following re-challenge than with initial treatment.…”

Section: Discussionmentioning

confidence: 99%

Prospective phase II study of sunitinib rechallenge in metastatic renal cell carcinoma: The “retry” study from the Italian Group of Onco-Nephrology (G.I.O.N.)

Porta

Ferrari

Zucali³

et al. 2022

Journal of Onco-Nephrology

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“…Combination therapies, sunitinib re-challenge, and sequential therapy have been investigated to overcome resistance to sunitinib [ 2 , 36 , 37 , 38 ]. We further tested an optimized multidrug combination consisting of four tyrosine kinase inhibitors, AZD4547, osimertinib, AZD8055 and pictilisib [ 37 ], to reveal whether acquired resistance to sunitinib can be overcome.…”

Section: Introductionmentioning

confidence: 99%

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

Rausch

Rutz

Allard

et al. 2021

IJMS

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Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of N-desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.

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“…Previous results obtained from experiments in mice had already suggested that RCC tumours could still re‐gain sensitivity to sunitinib or sorafenib after failed response or resistance to the same drugs [37,38]. In this sense, re‐introduction of sunitinib as second‐, third‐ or subsequent lines of therapy after RCC progression has proven efficacy [39–43]. All these results suggested that changes in the tumour microenvironment or temporal breaks between treatments could favour the re‐gain of tumour sensitivity to targeted therapy.…”

Section: Discussionmentioning

confidence: 96%

Outcomes of systemic targeted therapy in recurrent renal cell carcinoma treated with adjuvant sunitinib

et al. 2021

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To assess the efficacy and tolerability of rechallenge with sunitinib and other targeted therapies (TTs) in patitents with relapsed recurrent renal cell carcinoma (RCC) in the advanced setting. MethodsIn this multi-institutional retrospective study, patients with relapsed RCC were rechallenged with sunitinib or other systemic TTs as a first-line therapeutic approach after failed adjuvant sunitinib treatment. Patient characteristics, treatments and clinical outcomes were recorded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR) and overall survival (OS). ResultsA total of 34 patients with relapses were recorded, and 25 of these (73.5%) were men. Twenty-five patients were treated with systemic TT: 65% of patients received TT against the vascular endothelial growth factor pathway (including sunitinib), 21.7% received mammalian target of rapamycin inhibitors and 13% received immunotherapy. The median (interquartile range) time to relapse was 20.3 (5.2-20.4) months from diagnosis, and 7.5 months (1.0-8.5) from the end of adjuvant suntinib treatment. At a median follow-up of 23.5 months, 24 of the 25 patients had progressed on first-line systemic therapy. The median PFS was 12.0 months (95% confidence interval [CI] 5.78-18.2). There were no statistical differences in PFS between different treatments or sunitinib rechallenge. PFS was not statistically different in patients relapsing on or after adjuvant suntinib treatment (≤ 6 or >6 months after adjuvant suntinib ending). The ORR was 20.5%. The median OS was 29.1 months (95% CI 16.4-41.8). ConclusionsRechallenge with sunitinib or other systemic therapies is still a feasible therapeutic option that provides patients with advanced or metastastic RCC with additional clinical benefits with regard to PFS and OS after failed response to adjuvant sunitinib.

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

Cited by 6 publications

References 23 publications

Prospective phase II study of sunitinib rechallenge in metastatic renal cell carcinoma: The “retry” study from the Italian Group of Onco-Nephrology (G.I.O.N.)

Prospective phase II study of sunitinib rechallenge in metastatic renal cell carcinoma: The “retry” study from the Italian Group of Onco-Nephrology (G.I.O.N.)

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

Outcomes of systemic targeted therapy in recurrent renal cell carcinoma treated with adjuvant sunitinib

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