Publications by authors named "Jakub Żołnierek"

10 Publications

  • Page 1 of 1

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2021 03;384(9):829-841

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER number, NCT03141177.).
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March 2021

Real-world Experience of Cabozantinib as Second- or Subsequent Line Treatment in Patients With Metastatic Renal Cell Carcinoma: Data From the Polish Managed Access Program.

Clin Genitourin Cancer 2019 06 20;17(3):e556-e564. Epub 2019 Feb 20.

Clinical Hospital Number 1 of Poznan University of Medical Sciences, Poznan, Poland.

Background: Cabozantinib is an approved treatment for metastatic renal cell carcinoma (mRCC). This report presents an analysis of the safety profile and efficacy of cabozantinib in an unselected population from Poland.

Patients And Methods: Patients with mRCC, who had been treated with at least 1 previous agent targeting the vascular endothelial growth factor pathway, were eligible to receive cabozantinib at a once-daily dose of 60 mg orally, according to the Managed Access Program (MAP). Data were collected in 4 Polish centers. Patients who had received ≥ 1 dose of cabozantinib were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.

Results: A total of 115 patients were enrolled between October 2016 and March 2018, including 50% with bone metastases, 10% with brain metastases and 4.3% with non-clear-cell RCC; 76% had received ≥ 2 lines of therapy. The median time of follow-up was 12.6 months (95% confidence interval [CI], 11.5-14.1 months). The most common grade 3 and 4 AEs were fatigue (23%), hand-foot syndrome (12%), and diarrhea (10%). Only 4% of patients discontinued treatment owing to AEs, and there were no treatment-related deaths. Partial response was observed in 19% of patients, whereas 56% had stable disease. The median progression-free survival was 12.5 months (95% CI, 9.2-14.2 months), with a 12-month overall survival rate of 70.4% (95% CI, 60.2%-78.5%).

Conclusions: Cabozantinib demonstrated acceptable tolerability and activity in a large unselected population of patients with mRCC under clinical conditions.
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June 2019

Capecitabine and temozolomide combination for treatment of high-grade, well-differentiated neuroendocrine tumour and poorly-differentiated neuroendocrine carcinoma - retrospective analysis.

Endokrynol Pol 2019 7;70(4):313-317. Epub 2019 Mar 7.

Medical University of Silesia, Katowice, Poland.

Introduction: Many retrospective studies have confirmed that capecitabine combined with temozolomide is effective in neuroendocrine neoplasms. Most of the studies focused on grade 1 and grade 2 neuroendocrine tumours, mainly of pancreatic origin. There are limited data regarding the efficacy capecitabine with temozolomide in grade 3 neuroendocrine tumours. The new World Health Organisation 2017 classification distinguished well-differentiated grade 3 neuroendocrine tumours from poorly differentiated grade 3 neuroendocrine carcinomas. Treatment options for grade 3 neuroendocrine neoplasms are limited, and the overall prognosis is better in the subgroup of patients with grade 3 neuroendocrine tumours.

Material And Methods: It was a retrospective study in the population of patients with diagnosed grade 3 neuroendocrine neoplasms of different origin treated with capecitabine and temozolomide. Data on clinical and demographic characteristics of the population were collected from four Polish clinical centres. This study aimed to evaluate response and survival parameters and compare outcomes of treatment of neuroendocrine tumours and carcinomas.

Results: The study included 32 patients with grade 3 neuroendocrine tumours treated with capecitabine and temozolomide. The disease control rate was twice as high in the group of patient with neuroendocrine tumours in comparison to carcinomas (70 vs. 30%). The progression-free survival for patients with neuroendocrine tumours was 15.3 months (95% CI: 3.9-30.4), and for patients with neuroendocrine carcinomas it was 3.3 months (95% CI: 2.5-7.1). Median overall survival was 22 months (95% CI: 11.8-22.0) and 4.6 months (95% CI: 2.2-5.9) for patients with tumours and carcinomas, respectively. The treatment regimen was generally well tolerated.

Conclusions: The combination of capecitabine and temozolomide is an effective treatment for patients with grade 3 neuroendocrine tumours with Ki-67 index ranging between 20 and 54%. The treatment did not overcome the aggressive character of neuroendocrine carcinomas and resulted in low response and survival outcomes in comparison to those achieved in tumour therapy.
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February 2020

External validation of the systemic immune-inflammation index as a prognostic factor in metastatic renal cell carcinoma and its implementation within the international metastatic renal cell carcinoma database consortium model.

Int J Clin Oncol 2019 May 2;24(5):526-532. Epub 2019 Jan 2.

Department of Oncology, Military Institute of Medicine, Szaserow 128st, PO Box 04141, 04141, Warsaw, Poland.

Background: We conducted a study to validate the influence of the systemic immune-inflammation index (SII) on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) and to verify whether the implementation of the SII in place of neutrophil and platelet counts within the International Metastatic Renal Cell Carcinoma Consortium (IMDC) model might increase its prognostic accuracy.

Patients And Methods: We retrospectively analyzed consecutive patients with mRCC, who were treated with first-line tyrosine kinase inhibitors from 2008 to 2016 in two major oncology centres in Poland. We stratified patients into low SII (< 730) and high SII (≥ 730) groups according to a recent literature report. We used multivariable Cox proportional hazards regressions (CPHRs) to assess the impact of the SII on OS and concordance, global 'goodness-of-fit', calibration and reclassification measures to quantify a potential prognostic benefit from the modification of the IMDC model.

Results: Overall, 502 patients (294 with low and 208 with high SII) were included. Median OS was 36.7 months [95% confidence interval (CI) 30.4-41.5 months] and 17.0 months (95% CI 12.5-19.6 months) in the low and high SII groups, respectively. The SII status was significant in CPHRs with the hazard ratio ranging from 1.38 to 1.68. All prognostic accuracy measures favored the SII-modified-IMDC model over the original IMDC model.

Conclusions: Using an external dataset, we showed that high SII was an independent factor for poor OS. The addition of the SII to the IMDC model in place of neutrophil and platelet counts increased the model's prognostic performance.
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May 2019

Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.

Lancet Oncol 2015 Nov 22;16(15):1473-1482. Epub 2015 Oct 22.

Royal Marsden Hospital NHS Foundation Trust, London, UK.

Background: Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma.

Methods: We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with, number NCT01136733.

Findings: Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib.

Interpretation: Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma.

Funding: Eisai Inc.
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November 2015

Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial.

Lancet Oncol 2014 Mar 17;15(3):286-96. Epub 2014 Feb 17.

Institut Gustave Roussy, Villejuif, France.

Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma.

Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with, number NCT01223027.

Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9-14·6). Median PFS was 3·7 months (95% CI 3·5-3·9) in the dovitinib group and 3·6 months (3·5-3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72-1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively).

Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting.

Funding: Novartis Pharmaceuticals Corporation.
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March 2014

New therapeutic options in systemic treatment of advanced cutaneous melanoma.

Expert Opin Investig Drugs 2013 Feb 8;22(2):181-90. Epub 2012 Dec 8.

University of Medical Sciences, Department of Dermatology, Poznan, Poland.

Introduction: For many years systemic treatment of advanced/metastatic melanoma has been based on chemotherapy or immunotherapy. However, even very toxic regimens (e.g., polychemotherapy, bio-chemotherapy or immunotherapy with HD-IL-2) despite increased response rates as compared with standard dacarbazine monotherapy have not improved patients' outcomes. Over the last two decades, a huge effort, made in order to determine the molecular and immunological mechanisms responsible for biology of melanoma led to development of novel targeted agents.

Areas Covered: The aim of this article is to summarize data on novel targeted agents used for treatment of metastatic melanoma. The authors searched PubMed, EMBASE and abstracts from ASCO, ESMO, AACR congresses for Phase II/III clinical studies evaluating novel immunomodulating agents and kinase inhibitors in melanoma patients.

Expert Opinion: Elucidation of the crucial role of MAPK pathway and BRAF kinase mutations in particular has led to development of specific small molecule kinase inhibitors (vemurafenib, dabrafenib, trametinib), and new insight into molecular mechanisms responsible for immune response and tolerance resulted in development of immunomodulatory agents (ipilimumab, anti-PD1, anti-PD-L1). The introduction of novel drugs has changed the natural history of melanoma. However, it has also generated new clinical challenges that have to be resolved as soon as possible.
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February 2013

Cardiovascular comorbidities for prediction of progression-free survival in patients with metastatic renal cell carcinoma treated with sorafenib.

Kidney Blood Press Res 2012 6;35(6):468-76. Epub 2012 Jun 6.

Department of Oncology, Military Institute of Medicine, Warsaw, Poland. s.szmit @

Background/aims: The purpose of the present study was to determine the relationship between iatrogenic arterial hypertension or baseline cardiovascular comorbidities and outcomes in metastatic renal cell cancer (mRCC) patients treated with sorafenib.

Methods: The study included 148 mRCC patients treated with sorafenib, 63 patients (43%) had preexisting hypertension, 18 patients (12%) coronary artery disease, and 15 patients (10%) mild heart failure. Resting blood pressure (BP) was monitored by clinic and home measurements. Sorafenib-induced hypertension was defined as systolic BP ≥140 and/or diastolic BP ≥90 mm Hg during the first month of treatment.

Results: Preexisting cardiovascular comorbidities were not associated with worsening prognosis of patients with mRCC treated with sorafenib. During the first month of treatment, sorafenib-induced hypertension was diagnosed in 76 patients (51.4%), and these patients had a significantly longer PFS (p < 0.00001) and a significantly lower overall mortality risk (p = 0.038). Patients with preexisting and sorafenib-induced hypertension had the longest PFS (p < 0.00001).

Conclusions: Sorafenib-induced hypertension is a positive predictive factor in mRCC patients treated with sorafenib, especially in patients with a history of hypertension.
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October 2013

Efficacy of targeted therapy in patients with renal cell carcinoma with pre-existing or new bone metastases.

J Cancer Res Clin Oncol 2010 Mar 27;136(3):371-8. Epub 2009 Aug 27.

Oncology Clinic, CSK MON WIM, Warsaw, Poland.

Introduction: This single-centre retrospective analysis of data from three randomised studies and two expanded-access studies compared the effect of interferon (IFN)-alfa, sunitinib, and sorafenib on the occurrence and progression of metastatic bone lesions in patients with renal cell carcinoma (RCC).

Methods: The analysis included 292 patients: 107 received sunitinib 50 mg/day in 6-week cycles (Schedule 4/2), 147 received sorafenib 800 mg/day, and 38 received placebo or IFN-alfa 9 MU t.i.w.

Results: Pre-existing metastatic bone lesions were reported in 82 patients, of which 30 experienced progression. Twenty-three of 210 patients developed new bone lesions. Overall, sunitinib appeared slightly more effective than sorafenib or IFN-alfa at extending mean time to progression of pre-existing bone lesions (P = 0.057). Compared with sorafenib, sunitinib significantly decreased formation (P = 0.034) and prolonged time to occurrence of new bone lesions (P = 0.047).

Conclusion: Further evaluation of the effect of these therapies on bone metastases in RCC is warranted.
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March 2010

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma.

Cancer 2009 Jan;115(1):61-7

Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Background: 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.

Methods: 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.

Results: 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).

Conclusions: The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation.
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January 2009