Publications by authors named "Martin Richardet"

5 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

Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial.

Cancer 2020 Sep 16;126(18):4156-4167. Epub 2020 Jul 16.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus.

Methods: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL).

Results: Eight hundred twenty-one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus.

Conclusions: The superior efficacy of nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of nivolumab monotherapy in patients with previously treated aRCC.

Lay Summary: CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.
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September 2020

Treatment Beyond Progression in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab in CheckMate 025.

Eur Urol 2017 09 12;72(3):368-376. Epub 2017 Apr 12.

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

Background: Response patterns to nivolumab differ from those seen with other approved targeted therapies.

Objective: To investigate the efficacy of nivolumab in previously treated patients with advanced renal cell carcinoma who were treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression.

Design, Setting, And Participants: This was a subgroup analysis of patients treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to tolerate therapy and exhibiting investigator-assessed clinical benefit were eligible to be treated beyond RECIST progression (TBP) and received therapy for ≥4 wk after first progression; patients not treated beyond RECIST progression (NTBP) received 0 wk to <4 wk of therapy after progression.

Interventions: Nivolumab 3mg/kg intravenously every 2 wk.

Results And Limitations: Of 406 nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response rate (95% confidence interval) was 20% (14-28) and 14% (9-21) in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at first progression between patients TBP versus NTBP included better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all patients TBP (20/153) had ≥30% tumor burden reduction including patients with preprogression and postprogression tumor measurements (n=142) and complete/partial response (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as their best response before being TBP. Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression. Limitations included potential bias from the nonrandomized nature of the analysis.

Conclusions: A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy. Identifier: NCT01668784.

Patient Summary: A subset of patients with advanced renal cell carcinoma and disease progression may continue to benefit from nivolumab treatment beyond progression as evidenced by tumor reduction postprogression and an acceptable safety profile.
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September 2017

Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism.

Invest New Drugs 2003 Nov;21(4):435-43

Medical Oncology Service, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.

Purpose: Inherited variations in drug metabolizing enzymes may influence drug efficacy. This phase II study assesses the impact of second-line weekly irinotecan (CPT-11)/docetaxel in non-small cell lung cancer (NSCLC) patients, and gauges the uridine diphosphate glucuronosyl transferase (UGT1A1) polymorphism influence in toxicity and antitumor activity.

Experimental Design: Fifty-one patients with NSCLC treated with at least one prior chemotherapy regimen were enrolled. Patients received irinotecan 70 mg/m(2) followed by docetaxel 25 mg/m(2). Both drugs were given on days 1, 8, and 15 every 28 days. UGT1A1 polymorphism were analyzed in blood samples of 47 patients. The UGT1A1 polymorphism are classified according to the number of TA repeats in the promoter region of this gene.

Results: Three patients (6%) achieved a partial response and nineteen patients (37%) had stable disease. Median survival was 8 months (95% CI: 4.8-11.2) and 1-year survival 30%. Grade 3-4 hematologic toxicity was low (less than 10% of patients); 15% of patients had grade 3 asthenia and 25% of patients had grade 3/4 diarrhea. The frequency of UGT1A1 genotypes was as follows: 6/6 49%, 6/7 36%, and 7/7 15%. No differences in toxicity were observed according to UGT1A1 polymorphism. A nonsignificant improvement in time to progression (4 vs. 3 months) and median survival (11 vs. 8 months) was detected in patients with the variant alleles (6/7 and 7/7).

Conclusions: This weekly irinotecan/docetaxel regimen has shown an acceptable toxicity profile while encouraging median and 1-year survival in heavily pretreated NSCLC patients. The tendency to better prognosis in patients carrying the variant genotypes 6/7 and 7/7 of UGT1A1 gene requires further validation.
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November 2003

Phase II non-randomized study of three different sequences of docetaxel and vinorelbine in patients with advanced non-small cell lung cancer.

Lung Cancer 2002 Dec;38(3):309-15

Medical Oncology Service, Hospital Germans Trias i Pujol, Ctra Canyet s/n, 08916 Badalona, Barcelona, Spain.

Docetaxel and vinorelbine as single agents and in combination with cisplatin have shown significant activity in advanced non-small cell lung cancer (NSCLC). Significant neutropenia has been observed with the combination of docetaxel/vinorelbine. To gain insight into the potential synergism of this combination, we examined three different sequences of docetaxel 75 and vinorelbine 20 mg/m(2), every 3 weeks, in locally advanced and metastatic NSCLC patients. About 14 patients were evaluable in each schedule: schedule A, docetaxel day 1, vinorelbine days 1 and 6; schedule B, docetaxel day 6, vinorelbine days 1 and 6; schedule C, docetaxel day 1, vinorelbine days 6 and 15. Response rates were: 42.8, 7.1 and 21.4% for schedules A, B and C, respectively (P=0.01, schedule A vs. B). Median survival time was 16, 6.5 and 10.6 months for schedules A, B and C, respectively (P=0.04, schedule A vs. B). Neutropenia was the commonest toxicity; 43% of patients in schedule A and 57% of patients in schedule B had a febrile neutropenia episode. Prophylactic granulocyte-colony stimulating factor (G-CSF) was prescribed in schedule C after the first episode of febrile neutropenia. Non-hematologic toxicities were mild in all three schedules. For future studies, schedule A with lower doses is recommended.
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December 2002