Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial
Jazyk angličtina Země Velká Británie, Anglie Médium print-electronic
Typ dokumentu klinické zkoušky, fáze III, srovnávací studie, časopisecké články, multicentrická studie, randomizované kontrolované studie, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
P30 CA008748
NCI NIH HHS - United States
P30 CA016672
NCI NIH HHS - United States
PubMed
31427204
PubMed Central
PMC7497870
DOI
10.1016/s1470-2045(19)30413-9
PII: S1470-2045(19)30413-9
Knihovny.cz E-zdroje
- MeSH
- alanintransaminasa krev MeSH
- amylasy krev MeSH
- analýza podle původního léčebného záměru MeSH
- doba přežití bez progrese choroby MeSH
- hypertenze chemicky indukované MeSH
- ipilimumab aplikace a dávkování MeSH
- karcinom z renálních buněk farmakoterapie MeSH
- lidé MeSH
- lipasa krev MeSH
- míra přežití MeSH
- nádory ledvin farmakoterapie MeSH
- následné studie MeSH
- nivolumab aplikace a dávkování MeSH
- parestezie chemicky indukované MeSH
- protinádorové látky škodlivé účinky terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- sunitinib škodlivé účinky terapeutické užití MeSH
- únava chemicky indukované MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Research Support, N.I.H., Extramural MeSH
- srovnávací studie MeSH
- Názvy látek
- alanintransaminasa MeSH
- amylasy MeSH
- ipilimumab MeSH
- lipasa MeSH
- nivolumab MeSH
- protinádorové látky MeSH
- sunitinib MeSH
BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.
Bristol Myers Squibb Princeton NJ USA
Department of Cancer Services Oncology Mount Vernon Cancer Centre Northwood Middlesex UK
Department of Hematology and Oncology Fox Chase Cancer Center Philadelphia PA USA
Department of Medical Oncology Centro de Invetigación Clínica Bradford Hill Santiago Chile
Department of Medical Oncology Fundación Arturo López Pérez Santiago Chile
Department of Medical Oncology Gustave Roussy Villejuif France
Department of Medical Oncology Hôpitaux Universitaires de Strasbourg Strasbourg France
Department of Medical Oncology Hospital Universitario Marques de Valdecilla IDIVAL Santander Spain
Department of Medical Oncology IRCCS San Matteo University Hospital Foundation Pavia Italy
Department of Medical Oncology Westmead Hospital and Macquarie University Sydney NSW Australia
Department of Medicine British Columbia Cancer Agency Vancouver BC Canada
Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA
Department of Medicine Roswell Park Cancer Institute Buffalo NY USA
Department of Oncology Aarhus University Hospital Aarhus Denmark
Department of Oncology Monash Health Melbourne VIC Australia
Department of Oncology Palacky University and University Hospital Olomouc Olomouc Czech Republic
Department of Oncology Tom Baker Cancer Center University of Calgary Calgary AB Canada
Department of Oncology University Hospitals Leuven Leuven Belgium
Department of Urology Jena University Hospital Jena Germany
Department of Urology Niigata University Niigata Japan
Division of Medical Oncology Duke Cancer Institute Durham NC USA
Zobrazit více v PubMed
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378: 1277–90. PubMed PMC
OPDIVO (nivolumab) [package insert]. Bristol-Myers Squibb Company, Princeton, NJ, USA; 2018.
YERVOY (ipilimumab) [package insert]. Bristol-Myers Squibb Company, Princeton, NJ, USA; 2018.
Jonasch E Updates to the management of kidney cancer. J Natl Compr Canc Netw 2018; 16: 639–41. PubMed
European Medicines Agency. European Public Assessment Report (EPAR), Opdivo https://www.ema.europa.eu/en/medicines/human/EPAR/opdivo (accessed March 20, 2019), 2019.
Cella D, Grünwald V, Escudier B, et al. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol 2019; 20: 297–310. PubMed PMC
Anagnostou V, Yarchoan M, Hansen AR, et al. Immuno-oncology trial endpoints: Capturing clinically meaningful activity. Clin Cancer Res 2017; 23: 4959–69. PubMed PMC
Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009; 27: 5794–9. PubMed
McDermott DF, Rini BI, Motzer RJ, et al. Treatment-free survival (TFS) after discontinuation of first-line nivolumab (NIVO) plus ipilimumab (IPI) or sunitinib (SUN) in intention-to-treat (ITT) and IMDC favorable-risk patients (pts) with advanced renal cell carcinoma (aRCC) from CheckMate 214. Presented at: 2019 Genitourinary Cancers Symposium, February 14–16, 2019; San Francisco, CA, USA Abstract.
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 (accessed September 25, 2017).
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–81.
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002; 20: 289–96. PubMed
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934; 26: 404–13.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–88. PubMed
Atkins MB, Tannir NM. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev 2018; 70: 127–37. PubMed
Lalani AA, Xie W, Martini DJ, et al. Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunother Cancer 2018; 6: 5. doi: 10.1186/s40425-018-0315-0. PubMed DOI PMC
Zahoor H, Barata PC, Jia X, et al. Patterns, predictors and subsequent outcomes of disease progression in metastatic renal cell carcinoma patients treated with nivolumab. J Immunother Cancer 2018; 6: 107. PubMed PMC
McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 2018; 24: 749–57. PubMed PMC
Tannir NM, Motzer RJ, Plimack ER, et al. Outcomes in patients (pts) with advanced renal cell carcinoma (aRCC) who discontinued (DC) first-line nivolumab + ipilimumab (N+I) or sunitinib (S) due to treatment-related adverse events (TRAEs) in CheckMate 214. Presented at: 2019 Genitourinary Cancers Symposium, February 14–16, 2019; San Francisco, CA, USA Abstract.
Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019; 380: 1103–15. PubMed PMC
Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019. PubMed
Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: Efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Presented at: European Society of Medical Oncology 2017, September 8–12, 2017; Madrid, Spain Oral presentation LBA5.
Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC) Presented at: 2018 Genitourinary Cancers Symposium, February 8–10, 2018; San Francisco, CA, USA Poster 578.
McDermott DF, Motzer RJ, Rini BI, et al. CheckMate 214 retrospective analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features. Presented at: 17th International Kidney Cancer Symposium, November 2–3, 2018; Miami, FL, USA Poster.
The Evolving Landscape of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma
ClinicalTrials.gov
NCT02231749