First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis

Quhal, Fahad; Mori, Keiichiro; Bruchbacher, Andreas; Resch, Irene; Mostafaei, Hadi; Pradère, Benjamin; Schuettfort, Victor M.; Laukhtina, Ekaterina; Egawa, Shin; Fajković, Harun; Remzi, Mesut; Shariat, Shahrokh F.; Schmidinger, Manuela

doi:10.1016/j.euo.2021.03.001

Cited by 119 publications

(94 citation statements)

References 30 publications

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“… 10–13 However, patients with ≥1% PD-L1 expression seem to benefit particularly from intensified immunotherapy with nivolumab plus ipilimumab. 3 In our multicenter RCC-ICB Cohort, CTLA4 promoter hypomethylation outperformed PD-L1 CPS, which had no significant predictive value in our cohort. Thus, it remains to be prospectively elucidated whether the predictive potential of CTLA4 promoter methylation status will lead to an improved stratification for rational upfront treatment decisions for either ICB+TKI or ICB+ICB.…”

Section: Discussionmentioning

confidence: 59%

CTLA4promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma

Klümper

Ralser²,

Zarbl³

et al. 2021

J Immunother Cancer

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BackgroundIn metastatic clear cell renal cell carcinoma (ccRCC), different combination therapies, each including anti-PD-1 immune checkpoint blockade (ICB), are applied as first-line treatment. Robust predictive biomarkers for rational upfront therapy decisions are lacking, although they are urgently needed. Recently, we showed that CTLA4 promoter methylation predicts response to ICB in melanoma. Here, we aimed to investigate CTLA4 methylation in ccRCC and its utility to serve as a predictive biomarker for anti-PD-1 based ICB in metastatic ccRCC.MethodsCTLA4 methylation was analyzed with regard to transcriptional gene activity (mRNA expression), intratumoral immune cell composition, and clinical course in two ccRCC cohorts obtained from The Cancer Genome Atlas (TCGA cohort, n=533) and the University Hospital Bonn (UHB Non-ICB Cohort, n=116). In addition, CTLA4 methylation as well as CD8+ T cell infiltrates and PD-L1 expression were evaluated in pre-treatment samples from a multicenter cohort (RCC-ICB Cohort, n=71). Patients included in the RCC-ICB Cohort were treated with either first line anti-PD-1 based combination therapy (n=25) or monotherapy post–tyrosine kinase inhibition in second line or later. Analyses were performed with regard to treatment response according to RECIST, progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) following treatment initiation.ResultsCTLA4 promoter hypomethylation was significantly correlated with CTLA4 mRNA expression, lymphocyte infiltration, and poor OS in both primary ccRCC cohorts (TCGA: HR 0.30 (95% CI 0.18 to 0.49), p<0.001; UHB Non-ICB: HR 0.35 (95% CI 0.16 to 0.75), p=0.007). In contrast, CTLA4 promoter hypomethylation predicted response and, accordingly, favorable outcomes (PFS and OS) in patients with ICB-treated ccRCC, overcompensating the negative prognostic value of CTLA4 hypomethylation at initial diagnosis. Moreover, in multivariable Cox regression, CTLA4 promoter hypomethylation remained an independent predictor of improved outcome in ICB-treated ccRCC after co-adjustment of the International Metastatic Renal Cell Carcinoma Database Consortium score (HR 3.00 (95% CI 1.47 to 6.28), p=0.003).ConclusionsOur study suggests CTLA4 methylation as a powerful predictive biomarker for immunotherapy response in metastatic RCC.

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Section: Discussionmentioning

confidence: 59%

CTLA4promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma

Klümper

Ralser²,

Zarbl³

et al. 2021

J Immunother Cancer

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“…A previous meta-analysis, with similar objectives, strengths and limitations, was recently published by other authors. 13 We believe that the true usefulness of such a type of work is considering the efficacy end point together with the safety/tolerability of the treatment, trying to provide a ‘combined’ recommendation, taking into account both elements jointly. For this reason, we combined the rankings for both OS and toxicity, reporting the global ranking in graphical form (see Figure 2(g) ).…”

Section: Discussionmentioning

confidence: 99%

Is there a preferred first-line therapy for metastatic renal cell carcinoma? A network meta-analysis

Cattrini

Messina

Airoldi

et al. 2021

Therapeutic Advances in Urology

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Background: In recent years, new therapeutic combinations based on immunotherapy provided significant benefits as a first-line treatment for patients with advanced renal cell carcinoma (mRCC). Objective: This work aims to address the lack of head-to-head comparisons and the uncertainty of the benefit from immunotherapy-based combinations in all the International Metastatic RCC Database Consortium (IMDC) subgroups. Design, setting, and participants: A systematic review and a network meta-analysis were performed. Overall survival (OS) in the intention-to-treat (ITT) population was the primary endpoint. OS according to IMDC subgroups (favorable, intermediate, poor), PD-L1 expression, and grade ⩾3 adverse events (AEs) were secondary endpoints. A SUCRA analysis was performed. Results and limitations: Six randomized phase III trials with 5121 patients were included. There was a high likelihood (82%) that nivolumab-cabozantinib was the preferred treatment in OS. The benefit of ICI-based combinations over sunitinib was unclear in the favorable-risk subgroup. Nivolumab-ipilimumab had the best risk/benefit ratio among all the ICI-based combinations. The limitations were the lack of individual patient data; the heterogeneity of patients’ characteristics, trial designs, and follow-up times; and a limited number of studies for indirect comparisons. Conclusions: A customized approach for the first-line treatment of patients with mRCC should consider the risk/benefit profile of each treatment option, especially considering the likeliness of long-term survival finally reached in this setting.

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“…Currently, there is no widely accepted strategy in selecting immunotherapy combinations or immunotherapy‐VEGFR inhibitors combinations. The recent meta‐analysis 21 revealed that immunotherapy‐VEGFR inhibitors combinations provide superior PFS, ORR, and OS to immunotherapy combinations. However, immunotherapy combination provided the highest likelihood of OS and PFS improvement in patients with high PD‐L1 expression.…”

Section: Discussionmentioning

confidence: 99%

A case of clear cell renal cell carcinoma with vena cava thrombus responding to presurgical avelumab, and axitinib

et al. 2021

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Introduction We report a case of renal cell carcinoma with vena cava thrombus showing a marked reduction with presurgical avelumab plus axitinib, facilitating nephrectomy with thrombectomy. Case presentation A 50‐year‐old man was taken to emergent care unit due to spontaneous renal rupture and was diagnosed to have left‐sided renal cell carcinoma with level IV tumor thrombus. After hemostasis was obtained via transcatheter arterial embolization, avelumab plus axitinib was introduced because upfront surgery was deemed unfeasible due to poor performance status and possible retroperitoneal tumor dissemination. After four treatment cycles, thrombus was reduced to level II, and nephrectomy with thrombectomy was performed. Histological analyses revealed massive CD8+ T cell infiltration in the thrombus, suggesting immunotherapy efficacy. He has remained recurrence‐free without any additional treatment for eight months. Conclusion For locally advanced renal cell carcinoma with vena cava thrombus, presurgical combination therapy with avelumab plus axitinib could be an option to facilitate curative surgery.

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First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis

Cited by 119 publications

References 30 publications

CTLA4promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma

CTLA4promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma

Is there a preferred first-line therapy for metastatic renal cell carcinoma? A network meta-analysis

A case of clear cell renal cell carcinoma with vena cava thrombus responding to presurgical avelumab, and axitinib

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