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Open accessJournal ArticleDOI: 10.1056/NEJMOA2026982

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

04 Mar 2021-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 384, Iss: 9, pp 829-841
Abstract: 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. ...

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Topics: Sunitinib (58%), Nivolumab (58%), Cabozantinib (58%)
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151 results found


Journal ArticleDOI: 10.1056/NEJMOA2106391
Toni K. Choueiri1, Piotr Tomczak1, Se Hoon Park1, Balaji Venugopal1  +29 moreInstitutions (2)
Abstract: Background Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. Me...

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Topics: Nephrectomy (64%), Adjuvant therapy (62%), Renal cell carcinoma (59%) ... read more

15 Citations


Journal ArticleDOI: 10.1016/J.EURURO.2021.04.042
Jens Bedke1, Laurence Albiges2, Umberto Capitanio3, Rachel H. Giles  +15 moreInstitutions (16)
01 Oct 2021-European Urology
Abstract: The recent randomized controlled phase III CLEAR trial results are the last to complement immune checkpoint inhibitor (ICI)-based doublet combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma. The CLEAR trial demonstrated an improved progression-free survival (PFS), overall survival (OS), and an objective response rate (ORR) benefit for the combination of lenvatinib plus pembrolizumab over sunitinib. The CheckMate-9ER trial update demonstrated an ongoing PFS, OS, and quality-of-life benefit for cabozantinib plus nivolumab over sunitinib as did the update of Keynote-426 for axitinib plus pembrolizumab in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups. In the IMDC intermediate- and poor-risk groups, the CheckMate-214 trial of ipilimumab plus nivolumab confirmed the OS benefit with a PFS plateauing after 30 months. The RCC Guidelines Panel recommends three tyrosine kinase inhibitors + ICI combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all IMDC risk groups in advanced first-line RCC, and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate- and poor-risk groups. Patient summary New data from combination trials with immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit for lenvatinib plus pembrolizumab, cabozantinib plus nivolumab (with improved quality-of-life), axitinib plus pembrolizumab, and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.

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Topics: Nivolumab (65%), Pembrolizumab (61%), Ipilimumab (58%) ... read more

10 Citations



Journal ArticleDOI: 10.1016/S1470-2045(21)00241-2
Chung-Han Lee1, Amishi Yogesh Shah2, Drew W. Rasco, Arpit Rao3  +24 moreInstitutions (12)
01 Jul 2021-Lancet Oncology
Abstract: Summary Background Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. Methods We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0–1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov ( NCT02501096 ) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. Findings Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3–28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8–89·3) of 22 treatment-naive patients, seven (41·2%, 18·4–67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7–65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). Interpretation Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. Funding Eisai and Merck Sharp & Dohme.

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Topics: Lenvatinib (60%), Pembrolizumab (56%), Sudden death (53%) ... read more

5 Citations


Open accessJournal ArticleDOI: 10.3390/CANCERS13112741
Pavlos Msaouel1, Juhee Lee2, Peter F. Thall1Institutions (2)
01 Jun 2021-Cancers
Abstract: We argue that well-informed patient-specific decision-making may be carried out as three consecutive tasks: (1) estimating key parameters of a statistical model, (2) using prognostic information to convert these parameters into clinically interpretable values, and (3) specifying joint utility functions to quantify risk-benefit trade-offs between clinical outcomes. Using the management of metastatic clear cell renal cell carcinoma as our motivating example, we explain the role of prognostic covariates that characterize between-patient heterogeneity in clinical outcomes. We show that explicitly specifying the joint utility of clinical outcomes provides a coherent basis for patient-specific decision-making.

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4 Citations


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34 results found


Open accessJournal ArticleDOI: 10.1056/NEJMOA1510665
Robert J. Motzer1, Bernard Escudier2, David F. McDermott3, Saby George4  +23 moreInstitutions (19)
Abstract: BackgroundNivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. MethodsA total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. ResultsThe median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The haz...

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Topics: Nivolumab (58%), Everolimus (57%)

3,838 Citations



Journal ArticleDOI: 10.2307/2530245
Peter C. O'Brien1, Thomas R. Fleming1Institutions (1)
01 Sep 1979-Biometrics
Abstract: A multiple testing procedure is proposed for comparing two treatments when response to treatment is both dichotomous (i.e., success or failure) and immediate. The proposed test statistic for each test is the usual (Pearson) chi-square statistic based on all data collected to that point. The maximum number (N) of tests and the number (m1 + m2) of observations collected between successive tests is fixed in advance. The overall size of the procedure is shown to be controlled with virtually the same accuracy as the single sample chi-square test based on N(m1 + m2) observations. The power is also found to be virtually the same. However, by affording the opportunity to terminate early when one treatment performs markedly better than the other, the multiple testing procedure may eliminate the ethical dilemmas that often accompany clinical trials.

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Topics: Test statistic (56%), Statistic (51%), Pocock boundary (51%)

2,778 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA1712126
Abstract: Background Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. Methods We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. Results A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follo...

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Topics: Nivolumab (60%), Ipilimumab (59%), Sunitinib (52%)

1,944 Citations


Journal ArticleDOI: 10.1093/BIOMET/70.3.659
01 Dec 1983-Biometrika
Abstract: SUMMARY Pocock (1977), O'Brien & Fleming (1979) and Slud & Wei (1982) have proposed different methods to construct discrete sequential boundaries for clinical trials. These methods require that the total number of decision times be specified in advance. In the present paper, we propose a more flexible way to construct discrete sequential boundaries. The method is based on the choice of a function, a*(t), which characterizes the rate at which the error level ac is spent. The boundary at a decision time is determined by a*(t), and by past and current decision times, but does not depend on the future decision times or the total number of decision times.

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1,840 Citations


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