First-Line Immune-Oncology Combinations for Metastatic Clear Cell Renal Cell Carcinoma (mRCC): A Systematic Review of Phase III Clinical Trials

BACKGROUND: The introduction of immune checkpoint inhibitors rapidly changed treatment for patients with metastatic clear cell renal cell carcinoma (mRCC). First-line treatment now includes multiple immuno-oncology (IO) combinations that were approved over a short time period and were not directly compared in randomized clinical trials. Thus, clinicians face a challenge in individualizing first-line treatment to optimize clinical outcomes. OBJECTIVE: We sought to systematically review clinical outcomes for first-line IO combinations for patients with mRCC. METHODS: Literature reporting outcomes from phase III clinical trials that evaluated first-line IO combination therapies was identified through a search of the PubMed electronic database following PRISMA guidelines. Abstracts were screened to identify manuscripts that fit the search criteria, and then, a descriptive review was performed. RESULTS: Our literature search identified 2,229 abstracts that met the initial search criteria, and then, it was narrowed to 431 abstracts using filters for “clinical trial” and a “ten year” time window. After review of the abstracts, six manuscripts were selected for data extraction and subsequent review. CONCLUSION: When compared to sunitinib, four IO combinations improved overall survival as first-line treatment, and five improved progression free survival for patients with mRCC. These IO combination therapies have unique characteristics, so clinicians should take into account patient and cancer factors to individualize treatment recommendations.

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Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

International Journal of Oncology ◽

10.3892/ijo.2019.4830 ◽

2019 ◽

Cited By ~ 1

Author(s):

Piotr Wierzbicki ◽

Jakub Klacz ◽

Anna Kotulak‑Chrzaszcz ◽

Agata Wronska ◽

Marcin Stanislawowski ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Prognostic Significance ◽

Line Treatment ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

P53 Expression ◽

First Line Treatment

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Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma

Cancer Treatment Reviews ◽

10.1016/j.ctrv.2018.07.009 ◽

2018 ◽

Vol 70 ◽

pp. 127-137 ◽

Cited By ~ 63

Author(s):

Michael B. Atkins ◽

Nizar M. Tannir

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Line Treatment ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

Emerging Therapies ◽

First Line Treatment

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Algorithms in the First‐Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma—Analysis Using Diagnostic Nodes

The Oncologist ◽

10.1634/theoncologist.2015-0145 ◽

2015 ◽

Vol 20 (9) ◽

pp. 1028-1035 ◽

Cited By ~ 16

Author(s):

Christian Rothermundt ◽

Alexandra Bailey ◽

Linda Cerbone ◽

Tim Eisen ◽

Bernard Escudier ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Line Treatment ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

Diagnostic Nodes ◽

First Line Treatment

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PDL-1 and PDL1 expressions in clear cell renal cell carcinoma (ccRCC) of metastatic patients with sunitinib first-line treatment.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.e14002 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. e14002-e14002 ◽

Cited By ~ 3

Author(s):

Angélique Brunot ◽

Jean-Christophe Bernhard ◽

Mokrane Yacoub ◽

Julien Edeline ◽

Gregory Verhoest ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Line Treatment ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

First Line Treatment

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A Prospective Observational Study for Assessment and Outcome Association of Circulating Endothelial Cells in Clear Cell Renal Cell Carcinoma Patients Who Show Initial Benefit from First-line Treatment. The CIRCLES (CIRCuLating Endothelial cellS) Study (SOGUG-CEC-2011-01)

European Urology Focus ◽

10.1016/j.euf.2016.09.004 ◽

2017 ◽

Vol 3 (4-5) ◽

pp. 430-436 ◽

Cited By ~ 2

Author(s):

Jesús García-Donas ◽

Luis Angel Leon ◽

Emilio. Esteban ◽

Maria Jose Vidal-Mendez ◽

Jose Angel Arranz ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Endothelial Cells ◽

Observational Study ◽

Prospective Observational Study ◽

Clear Cell ◽

Circulating Endothelial Cells ◽

Line Treatment ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

First Line Treatment

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Five-year survival analysis of interferon-a plus sorafenib versus sorafenib monotherapy as first-line treatment for metastatic clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.486 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 486-486

Author(s):

Ye Ding-Wei ◽

Zhang Hai-Lang

Keyword(s):

Renal Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Line Treatment ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

Group A ◽

Group B ◽

First Line Treatment

486 Background: We compared the short- and long-term efficacy and safety of interferon-a plus sorafenib with sorafenib monotherapy as first-line treatment in metastatic clear cell renal cell carcinoma (mRCC) patients. Methods: mRCC patients who had not received systemic treatment were administered either interferon-a (300 MIU IM every other day) plus sorafenib (400 mg bid n=24, Group A) or sorafenib monotherapy (400 mg bid; n=24, Group B). Objective responses (OR; RECIST criterion ver 1.0) and differences in OR, progression-free survival (PFS), overall survival (OS) and toxicity were compared. Results: Sixty eight percent males were present in both the groups with comparable baseline demographic characteristics. After a median follow-up of 68 months, the OR was comparable (p=0.726) in Group A vs B; complete remission (1 vs 0 cases), partial remission (6 vs 7 cases), stable disease (14 vs 15 cases), and progressive disease (3 vs 3 cases). No significant difference was observed in the median PFS (p=0.965) and median OS (p=0.223) between both groups [9.4 months (95% CI: 5.8-17.4), Group A vs 14.0 months (95% CI: 9.9-18.0), Group B] and [32.9 months (95% CI: 8.2-87.1), Group A vs 20.4 months (95% CI: 16.2-24.6), Group B], respectively. The 5-year survival rate was higher in Group A vs B (46% vs 25%). Toxicity symptoms like fever (13 vs 3 cases), fatigue (15 vs 9 cases) and neutropenia (6 vs 1 cases) were more pronounced in Group A vs B. The incidence of hand and foot skin reactions, alopecia, rash, hypertension, liver dysfunction, hypophosphatemia, anemia, and other toxicities was similar in both groups. There were 14 (58.3%) and 8 (33.3%) cases of dosage reduction or suspension in Groups A and B, respectively. Conclusions: Short-term effect of interferon-a plus sorafenib as first-line treatment for mRCC was comparable to sorafenib monotherapy in terms of OR and PFS. Although higher toxicity was reported for interferon-a plus sorafenib, the combination holds promise for improving long-term OS.

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Analysis of Efficacy and Toxicity Profile of First-Line Sunitinib or Pazopanib in Metastatic Clear Cell Renal Cell Carcinoma in the Brazilian Population

Journal of Global Oncology ◽

10.1200/jgo.18.00073 ◽

2018 ◽

pp. JGO.18.00073

Author(s):

Pedro Isaacsson Velho ◽

Mirella Nardo ◽

Manoel Carlos Leonardi de Azevedo Souza ◽

Renata R.C. Colombo Bonadio ◽

Guilherme Nader Marta ◽

...

Keyword(s):

Public Health ◽

Renal Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cancer Center ◽

Line Treatment ◽

First Line ◽

Cell Renal Cell Carcinoma ◽

Discontinuation Of Treatment ◽

First Line Treatment

Purpose Sunitinib and pazopanib are multitargeted tyrosine kinase inhibitors (TKIs) that act against vascular endothelial growth factor receptors and are standard first-line treatment options for metastatic clear cell renal cell carcinoma (ccRCC). The Brazilian public health system diverges from the randomized clinical trials in the availability of first and subsequent lines of treatment and in clinical and demographic characteristics of patients. Therefore, it is essential to describe the history of advanced ccRCC during and after TKI treatment in this population. Methods We performed a retrospective analysis of patients with advanced ccRCC treated with a first-line TKI (either sunitinib or pazopanib) between February 2009 and March 2017 in a single academic Brazilian cancer center (Instituto do Câncer do Estado de São Paulo). Results Of the 222 patients, 109 were treated with sunitinib and 113 with pazopanib. The median duration of treatment and overall survival (OS) were 6.4 and 15.2 months for sunitinib and 6.7 and 14.2 months for pazopanib, respectively. Discontinuation of treatment occurred secondarily to progressive disease or death in 64.2% of patients using sunitinib and in 54.8% of patients using pazopanib. Adverse events were responsible for discontinuation of treatment in 28.4% of patients in the sunitinib group and in 22.1% in the pazopanib group. According to Memorial Sloan-Kettering Cancer Center risk categories, the OS was 32.9 months, 15.9 months, and 8.1 months for low risk, intermediate risk, and poor risk, respectively (hazard ratio, 1.72; 95% CI, 1.13 to 2.26; P < .001). Conclusion The use of TKI inhibitors as first-line treatment of metastatic RCC is effective and feasible in the Brazilian public health. However, the median OS of our population is considerably lower compared with the prospective trials that evaluated the same drugs.

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