Publications by authors named "Rubén Kowalyszyn"

7 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

Efficacy and Safety of Nivolumab in Previously Treated Patients With Non-Small-cell Lung Cancer: Real World Experience in Argentina.

Clin Lung Cancer 2020 09 26;21(5):e380-e387. Epub 2020 Feb 26.

Clinical Oncology Unit, Hospital Universitario Austral, Argentina.

Background: Nivolumab was the first anti-programmed cell death 1 drug approved in Argentina for non-small-cell lung cancer treatment in the second-line setting.

Materials And Methods: The present study was a multicenter, observational, retrospective study of patients with progression to stage IV NSCLC during platinum-based chemotherapy who had received nivolumab monotherapy in a drug-expanded access program in Argentina.

Results: The data from 109 patients were assessed retrospectively for safety and clinical outcomes. The follow-up period was 8.83 months (interquartile range, 3.4-12.67); 57.8% were men, 29.4% were current smokers, and 78.0% had a diagnosis of nonsquamous cell cancer. The median number of chemotherapy lines before nivolumab was 2 (range, 1-4). Also, 59.6% had received radiotherapy and 89% had received platinum-based chemotherapy. The drug-related toxicity rate was 78.9%, the grade 2-3 toxicity rate was 28.4%, and 33.9% of patients had required corticosteroids. The treatment response was evaluated in 104 patients. The best response was a complete response in 2 (2%), partial response in 28 (27%), stable disease in 33 (32%), and progressive disease in 41 (39%). Univariate analysis revealed that the absence of corticosteroid use (P = .034), toxicity grade 1-3 (P = .0025), and performance status of ≤ 1 (P = .049) were associated with longer disease-free survival, performance status of ≤ 1 (P < .001), and toxicity grade 1-3 (P = .001) were associated with longer overall survival. On multivariate Cox regression analysis, toxicity grade 1-3 (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.81; P = .008) and age ≤ 50 years (HR, 0.28; 95% CI, 0.13-0.61; P = .001) were associated with longer progression-free survival and corticosteroid use was associated with shorter progression-free survival (HR, 2.06; 95% CI, 1.22-3.48; P = .007).

Conclusions: The use of nivolumab in the real world setting in patients with heavily pretreated NSCLC was well tolerated and showed promising clinical efficacy. The performance status, use of corticosteroids, and immune-mediated toxicity seem to be the conditions that can affect the clinical outcomes.
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September 2020

Efficacy and Safety of Ramucirumab With Docetaxel Versus Placebo With Docetaxel as Second-Line Treatment of Advanced Non-Small-Cell Lung Cancer: A Subgroup Analysis According to Patient Age in the REVEL Trial.

Clin Lung Cancer 2018 05 21;19(3):270-279.e3. Epub 2017 Dec 21.

David Geffen School of Medicine at UCLA/TRIO-US Network, Los Angeles, CA.

Introduction: Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2), was evaluated as second-line treatment in combination with docetaxel in patients with non-small-cell lung cancer in the REVEL trial (NCT01168973). Ramucirumab significantly improved overall survival (OS) and progression-free survival (PFS). We report age subgroup analysis results primarily on the basis of a 65-year cutoff.

Patients And Methods: Patients were randomized 1:1 to ramucirumab with docetaxel or placebo with docetaxel (n = 1253). Of these, 798 were younger than 65 years (ramucirumab, n = 391; control, n = 407) and 455 were 65 years or older (ramucirumab, n = 237; control, n = 218). Treatment comprised 21-day cycles of 75 mg/m docetaxel with 10 mg/kg ramucirumab or placebo. Prespecified age subgroup analyses were performed, including OS, PFS, and objective response rate. Quintiles age analysis was conducted to establish a relationship between efficacy and age. The Lung Cancer Symptom Scale (LCSS) measured quality of life outcomes. Safety was assessed according to adverse events (AEs).

Results: Patients younger than 65 years showed favorable OS outcomes with ramucirumab treatment (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.62-0.87; P < .001) and PFS (HR, 0.68; 95% CI, 0.59-0.79; P < .001). In patients 65 years or older, benefits of ramucirumab were not as evident; after model adjustment for prognostic factors, OS and PFS HRs were 0.96 (95% CI, 0.77-1.21; P = .04) and 0.87 (95% CI, 0.71-1.05; P = .03), respectively. Age analysis according to quintiles showed HRs favoring ramucirumab for all age groupings. LCSS scores and AEs did not considerably differ between age groups.

Conclusion: In this subgroup analysis, true treatment effect differences on the basis of age have not been established, and treatment should not be deterred solely because of age.
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May 2018

Treatment outcomes by histology in REVEL: A randomized phase III trial of Ramucirumab plus docetaxel for advanced non-small cell lung cancer.

Lung Cancer 2017 10 3;112:126-133. Epub 2017 Jun 3.

David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA.

Objectives: Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody inhibiting vascular endothelial growth factor receptor-2, increased overall survival (OS) combined with docetaxel versus docetaxel alone in non-small cell lung cancer (NSCLC) in the REVEL trial. Pre-specified exploratory analysis examined efficacy and safety by histology.

Materials And Methods: 1253 patients with NSCLC were randomized to receive ramucirumab (10mg/kg; n=628) plus docetaxel (75mg/m) or placebo plus docetaxel (n=625) after disease progression on or after platinum-based therapy, with or without bevacizumab or maintenance therapy. OS was analyzed using Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Primary quality-of-life analysis was time to deterioration (TtD) of the Lung Cancer Symptom Scale (LCSS) scores using the Kaplan-Meier method and Cox regression.

Results: Median OS for adenocarcinoma was 11.2 months for ramucirumab-docetaxel (n = 377) and 9.8 months for placebo-docetaxel (n=348); HR=0.83 (95% CI: 0.69-0.99). In squamous disease, median OS was 9.5 months for ramucirumab-docetaxel (n=157) versus 8.2 months for placebo-docetaxel (n=171); HR 0.88 (95% CI: 0.69-1.13). Median OS for other nonsquamous was 10.8 months for ramucirumab-docetaxel (n=74) and 9.3 months for placebo-docetaxel (n=78); HR=0.86 (95% CI: 0.59-1.26). Treatment-emergent adverse events were comparable between treatment arms across histologic subgroups. TtD for LCSS scores was similar between treatment arms in the nonsquamous and squamous subgroups.

Conclusion: REVEL demonstrated similar favorable efficacy and manageable safety for ramucirumab-docetaxel across histologic subgroups of NSCLC.
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October 2017

An Open-Label, Multicenter, Randomized, Phase II Study of Cisplatin and Pemetrexed With or Without Cixutumumab (IMC-A12) as a First-Line Therapy in Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer.

J Thorac Oncol 2017 02 25;12(2):383-389. Epub 2016 Jul 25.

Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research, Grosshansdorf, Germany.

Introduction: Type 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting.

Methods: In this open-label, phase II study, patients with stage IV nonsquamous NSCLC and a performance status of 0 to 1 were randomized (1:1) to receive 20 mg/kg cixutumumab, 500 mg/m pemetrexed, and 75 mg/m cisplatin (cixutumumab [n = 87]) or pemetrexed and cisplatin (control [n = 85]). Eligible patients received pemetrexed-based maintenance therapy with cixutumumab (cixutumumab arm) or without it (control arm). The primary end point was progression-free survival. Secondary end points assessed overall survival, objective response rate, and safety. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model. Exploratory correlative analyses were also performed.

Results: The mean age of the intent-to-treat population (n = 172) was 59 years (range 32-83). Median progression-free survival was 5.45 months with cixutumumab versus 5.22 months in the control (hazard ratio = 1.15, 95% confidence interval: 0.81-1.61; p = 0.44). Median overall survival was 11.33 months with cixutumumab versus 10.38 months in the control (hazard ratio = 0.93, 95% confidence interval: 0.64-1.36). Objective response rate did not differ between treatments (p = 0.338). Grade 3 or 4 hyperglycemia occurred at a higher rate with cixutumumab than in the control (9.4% versus 1.2%). One death possibly related to cixutumumab occurred.

Conclusions: Efficacy was not improved in patients with nonsquamous NSCLC when cixutumumab was added to pemetrexed/cisplatin. Combination therapy was well tolerated and no new safety concerns were reported.
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February 2017

Quality of life results from the phase 3 REVEL randomized clinical trial of ramucirumab-plus-docetaxel versus placebo-plus-docetaxel in advanced/metastatic non-small cell lung cancer patients with progression after platinum-based chemotherapy.

Lung Cancer 2016 Mar 19;93:95-103. Epub 2016 Jan 19.

David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA. Electronic address:

Objectives: REVEL demonstrated that ramucirumab+docetaxel (RAM+DTX) improved overall survival, progression-free survival, and objective response rate in patients with advanced/metastatic non-small cell lung cancer with progression after platinum-based chemotherapy. This analysis examined quality of life (QoL) as assessed by the Lung Cancer Symptom Scale (LCSS) and clinician-reported functional status.

Materials And Methods: The LCSS includes 6 symptom and 3 global items measured on a 0-100-mm scale; higher scores represent greater symptom burden. LCSS and ECOG PS data were collected at baseline, every 3-week cycle, the summary visit, and at the 30-day follow-up. LCSS total score and Average Symptom Burden Index (ASBI) were calculated. The primary analysis compared time to deterioration (TtD) between treatment arms for all individual items and summary scores, defined as increase from baseline by ≥ 15 mm using the Kaplan-Meier method and Cox regression. TtD to ECOG PS ≥ 2 was analyzed.

Results: There were 1253 patients randomized to receive RAM+DTX or placebo+docetaxel (PL+DTX). Across all assessments, LCSS compliance was approximately 75% and balanced across arms. The mean (SD) baseline LCSS total score was 27.3mm (17.08 mm) on RAM+DTX and 29.6mm (17.59 mm) on PL+DTX. At 30-day follow-up, mean (SD) LCSS total score was 32.0 (19.03) on RAM+DTX and 32.5 (19.87) on PL+DTX. The TtD for all LCSS scores was similar between treatment arms. Stratified HRs (95% CI) for LCSS total score and ASBI were HR=0.99 (0.81, 1.22), p=0.932 and HR=0.93 (0.75, 1.15), p=0.514 with approximately 70% of patients censored. TtD to PS ≥ 2 was similar between treatment arms (HR=1.03 [95% CI: 0.85, 1.26], p=0.743) with approximately two-thirds of the patients censored.

Conclusion: In addition to improvement of clinical efficacy outcomes demonstrated in REVEL, these results suggest that adding ramucirumab to docetaxel did not impair patient QoL, symptoms, or functioning.
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March 2016

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.

Lancet 2014 Aug 2;384(9944):665-73. Epub 2014 Jun 2.

Léon-Bérard Cancer Centre, Lyon, France.

Background: Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy.

Methods: In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with, number NCT01168973.

Findings: Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care.

Interpretation: Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC.

Funding: Eli Lilly.
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August 2014