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

Motzer, Robert J.; Rini, Brian I.; McDermott, David F.; Frontera, Osvaldo Arén; Hammers, Hans J.; Carducci, Michael A.; Salman, Pamela; Escudier, Bernard; Beuselinck, Benoît; Amin, Asim; Porta, Camillo; George, Saby; Neiman, Victoria; Bracarda, Sergio; Tykodi, Scott S.; Barthélémy, Philippe; Leibowitz-Amit, Raya; Plimack, Elizabeth R.; Oosting, Sjoukje F.; Redman, Bruce G.; Melichar, Bohuslav; Powles, Thomas; Nathan, Paul; Oudard, Stéphane; Pook, David; Choueiri, Toni K.; Donskov, Frede; Grimm, Marc‐Oliver; Gurney, Howard; Heng, Daniel Y.C.; Kollmannsberger, Christian; Harrison, Michael R.; Tomita, Yoshihiko; Durán, Ignacio; Grünwald, Viktor; McHenry, M. Brent; Mekan, Sabeen; Tannir, Nizar M.; Investigators, CheckMate

doi:10.1016/s1470-2045(19)30413-9

Cited by 620 publications

(582 citation statements)

References 20 publications

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“…In a registrational trial of patients with treatmentnaïve mRCC randomised to ipilimumabnivolumab versus sunitinib, the combination immunotherapy improved median overall survival (OS; not reached vs 26.6 months, p<0.0001) and objective response rates (42% vs 27%, p<0.0001), with a remarkable complete response (CR) rate of 10% in patients with intermediate-risk and poor-risk disease. 6 The combination of ipilimumabnivolumab has therefore changed first-line Open access treatment of patients with intermediate-risk to high-risk mRCC. 7 However, although there is now the possibility of robust responses with ICIs, the majority of patients do not achieve objective responses.…”

Section: Introductionmentioning

confidence: 99%

Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

Labriola

Zhu

Gupta

et al. 2020

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC.MethodsTumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1 criteria.ResultsPatients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03).ConclusionsOverall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.

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Section: Introductionmentioning

confidence: 99%

Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

Labriola

Zhu

Gupta

et al. 2020

J Immunother Cancer

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“…No differences were observed in terms of PFS. A recent update showed an interesting increase in OS after 30 months of follow-up in favor of nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) combination (60% vs. 47%; HR: 0.66 ; CI 0.54 to 0.80 ; p < 0.0001) [43].…”

Section: First-line Treatmentmentioning

confidence: 99%

Immunotherapy in Renal Cell Carcinoma: The Future Is Now

Deleuze

Saout

Dugay

et al. 2020

IJMS

141

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Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose.

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“…The extended follow-up data for ipilimumab 1 nivolumab continues to support its use compared with sunitinib for intermediate-or poor-risk patients, showing an improved OS at 30 months (60% vs 47%) and ORR (42% for ipilimumab 1 nivolumab; 95% CI, 37-47, vs 29% for sunitinib; 95% CI, 25-34; P5.0001). 34 Given the significant improvement in PFS and the OS benefit for intermediate-or poor-risk patients compared with sunitinib, the panel listed ipilimumab 1 nivolumab and axitinib 1 pembrolizumab as category 1 preferred treatment options. The open-label phase II CABOSUN trial included intermediate-and poor-risk patients based on IMDC criteria with advanced RCC who received first-line therapy with either cabozantinib or sunitinib.…”

Section: Changing Treatment Landscapementioning

confidence: 99%

NCCN Guidelines Insights: Kidney Cancer, Version 2.2020

Motzer

Jonasch

Michaelson

et al. 2019

Journal of the National Comprehensive Cancer Network

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197

163

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The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non–clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

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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

Cited by 620 publications

References 20 publications

Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

Immunotherapy in Renal Cell Carcinoma: The Future Is Now

NCCN Guidelines Insights: Kidney Cancer, Version 2.2020

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