New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy

Arterial hypertension (HTN) is a class effect of anti-vascular endothelial growth factor (VEGF) therapies, including the monoclonal antibody bevacizumab. Data are conflicting regarding the role of the renin-angiotensin system on angiogenesis and recent data suggest that the use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) is associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with VEGF targeted therapies. The aim of this review is to discuss the available treatment options for mRCC and associated incidence of hypertension as well as summarize the known data about ASIs use and mRCC. Additionally, given that the optimal management of HTN remains unclear, we will focus on prevention strategies and propose potential therapeutic approaches.

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New treatment strategy for metastatic renal cell carcinoma

Nature Clinical Practice Urology ◽

10.1038/ncpuro0262 ◽

2005 ◽

Vol 2 (9) ◽

pp. 406-407

Author(s):

Tamsin Osborne

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Treatment Strategy ◽

Renal Cell ◽

New Treatment

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Comparative effectiveness research in renal cell carcinoma: Lenvatinib with everolimus as a potential new treatment option.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.7_suppl.27 ◽

2016 ◽

Vol 34 (7_suppl) ◽

pp. 27-27 ◽

Cited By ~ 1

Author(s):

Gabriel Tremblay ◽

Corey Pelletier ◽

Unnati Majethia ◽

Anna Forsythe

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Comparative Effectiveness ◽

Treatment Options ◽

Progression Free Survival ◽

Treatment Comparison ◽

Hazard Ratios ◽

New Treatment ◽

Comparative Effectiveness Analysis

27 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer and represents about 90% of all kidney cancers. As comprehensive comparison of the efficacy associated with mRCC treatments is not available, the goal of this research was to provide a comparative effectiveness analysis including overall survival (OS) and progression free survival (PFS) for first and second line treatments. Methods: Systematic literature review yielded the following randomized active-controlled studies: lenvatinib + everolimus (LEN+EVE) versus everolimus (EVE), axinitib (AXI) versus sorafenib (SOR), cabozantinib (CAB) versus EVE, nivolumab (NIV) versus EVE, and pazopanib (PAZ) versus sunitinib (SUN). In addition, placebo-controlled studies were identified for EVE, PAZ, and SOR. An indirect treatment comparison (ITC) was performed on OS and PFS hazard ratios (HR). Results: Scenario A presents the HR and confidence intervals (95% CI) generated with ITC of all treatments against EVE. In scenario B, the HR of LEN + EVE are compared to all treatment options. Only LEN + EVE and CAB demonstrated significance against EVE for both OS and PFS. LEN + EVE proved to be significant against EVE, PAZ, SOR, SUN, AXI and NIV for PFS and against EVE, SOR and AXI for OS. The use of crossover trials in the network for the treatment compared to placebo remains a potential bias in the results. Conclusions: Even if limitations exist regarding the use of ITC, the option of LEN+EVE demonstrated a strong comparative effectiveness profile for both OS and PFS. [Table: see text]

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A phase Ib study targeting PIM1 and CDK4/6 kinases in metastatic renal cell carcinoma (PICKRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.tps771 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. TPS771-TPS771

Author(s):

Sheldon L. Holder ◽

Joshua Warrick ◽

Junjia Zhu ◽

Joseph J. Drabick ◽

Monika Joshi

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitor ◽

Treatment Options ◽

Dose Escalation Study ◽

Phase Ib ◽

Pim1 Kinase ◽

Potential Biomarker

TPS771 Background: Over the last few years there has been a rapid increase in the clinically relevant agents available to treat metastatic renal cell carcinoma (mRCC). We note, however, that the vast majority of new agents available for mRCC do not exploit new clinical targets or pathways. We believe that the identification of new, clinically relevant targets in RCC will propel the field even further forward, expand treatment options, and lead to improved survival for mRCC patients. SGI-1776, a selective PIM1 kinase inhibitor, has previously been shown to induce reduction in tumor size as monotherapy and in combination with sunitinib in mouse pre-clinical studies of RCC. In our tissue microarray studies a subset of ~26% of RCC showed high staining for PIM1 kinase while only 1% of normal adjacent tissue showed similar high staining. Wildtype PIM1 is constitutively active, thus these data suggest that PIM1 activity is increased in a subset of RCC. Abemaciclib is a potent CDK4/6 inhibitor with an IC50 of 2 and 10 nM, respectively. It is also a potent PIM1 inhibitor with an IC50 of 50 nM. We have shown that abemaciclib decreases cell viability and increases apoptosis in RCC cell lines, and does so at greatest effect in combination with sunitinib. We have also shown that abemaciclib induces regression of RCC tumors in a mouse model of RCC, with the most rapid responses observed when abemaciclib is combined with sunitinib. Based on these data we have opened a phase Ib dose escalation study to determine the safety and tolerability of abemaciclib in combination with sunitinib in patients with mRCC. The study includes an expansion cohort at the recommended phase II dose to evaluate for a signal for efficacy. Pattern and intensity of PIM1 staining in tumor tissue will be evaluated as a potential biomarker of response. We are also collecting blood and urine to evaluate additional potential biomarkers of response. Methods: Clinical trial information: NCT03905889 .[Table: see text]

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New systemic treatment options for metastatic renal-cell carcinoma in the era of targeted therapies

Asia-Pacific Journal of Clinical Oncology ◽

10.1111/j.1743-7563.2010.01277.x ◽

2010 ◽

Vol 6 (1) ◽

pp. 5-18 ◽

Cited By ~ 5

Author(s):

Thean Hsiang TAN ◽

Ganesalingam PRANAVAN ◽

Hodo Z HAXHIMOLLA ◽

Desmond YIP

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Targeted Therapies ◽

Renal Cell ◽

Systemic Treatment ◽

Treatment Options

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Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s1590 ◽

2010 ◽

Vol 4 ◽

pp. CMO.S1590 ◽

Cited By ~ 8

Author(s):

Sumanta Kumar Pal ◽

Robert A. Figlin

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Treatment Options ◽

Mammalian Target Of Rapamycin ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Mtor Inhibitors ◽

Phase Iii

The agents currently approved for use in metastatic renal cell carcinoma (mRCC) can be divided broadly into two categories: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.

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