Monday, September 25, 2023
| Predictors of Short Survival1,62,* | MSKCC Risk Criteria10 |
|---|---|
| LDH > 1.5 times upper limit of normal | LDH > 1.5 times upper limit of normal |
| Hemoglobin < lower limit of normal | Hemoglobin < lower limit of normal |
| Corrected serum calcium > 10 mg/dL | Corrected serum calcium > 10 mg/dL |
| < 1 y between diagnosis and start of first systemic therapy | < 1 y between diagnosis and start of first systemic therapy |
| Karnofsky performance status ≤ 70 | Karnofsky performance status < 80% |
| ≥ 2 sites of organ metastasis |
Prognostic Models for Patients With Renal Cell Carcinoma
Favorable = 0 risk factors; intermediate = 1–2 risk factors; poor = 3–5 risk factors.
Abbreviations: LDH, lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center.
*Patients were required to have 3 of these poor risk factors to be eligible for the phase III clinical trial of temsirolimus,
interferon, or both.
| Toxicities/Agents | Hand-Foot Skin Reaction | Hypertension | Cytopenia | Proteinuria | Gastrointestinal Toxicity | Hyperlipidemia |
|---|---|---|---|---|---|---|
| Sunitinib | Yes | Yes | Yes | Yes | Yes | No |
| Sorafenib | Yes | Yes | Yes | Yes | Yes | No |
| Pazopanib | No | Yes | No | Yes | Yes | No |
| Bevacizumab | No | Yes | No | Yes | Yes | No |
| Temsirolimus | No | No | Yes | No | Yes | Yes |
| Everolimus | No | No | Yes | No | Yes | Yes |
Common Toxicities Associated With Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factor Receptor,
and Mammalian Target of Rapamycin Inhibitors
Adapted from Hudes GR, Carducci MA, Choueiri TK, et al. NCCN Task Force Report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. J Natl Compr Cancer Netw 2011;9:S14, with permission.
| VEGFR Inhibitor | VEGF Inhibitor | mTOR Inhibitor | Dose/Toxicity | Reference |
|---|---|---|---|---|
| Sunitinib | – | Temsirolimus | Sunitinib: 25 mg (“4 + 2”) Temsirolimus: 15 mg/wk Intolerable |
Patel et al.55 (2009) |
| Sunitinib | – | Everolimus | Sunitinib: 37.5 mg (“4 + 2”) Everolimus: 30 mg/wk |
Molina et al.54 (2011) |
| Sunitinib | Bevacizumab | – | Intolerable | Feldman et al.53 (2009) |
| – | Bevacizumab | Temsirolimus | Bevacizumab: 10 mg Temsirolimus: 25 mg |
Merchan et al.63 (2009) Escudier et al.56 (2010) |
| – | Bevacizumab | Everolimus | Bevacizumab: 10 mg Everolimus: 10 mg |
Hainsworth et al.64 (2010) |
| Sorafenib | Bevacizumab | – | Sorafenib: 200 mg Bevacizumab: 5 mg |
Sosman et al.65 (2008) |
| Sorafenib | – | Temsirolimus | Sorafenib: 200 mg Temsirolimus: 25 mg |
Patnaik et al.66 (2007) (all solid tumors) |
| Sorafenib | – | Everolimus | Sorafenib: 400 mg Everolimus: 5 mg |
Cen et al.67 (2009) |
Phase I/II Studies Using Various Combinations of Therapy
Abbreviations: mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial
growth factor receptor.
Modified from Hudes GR, Carducci MA, Choueiri TK, et al. NCCN Task Force Report: optimizing treatment of advanced renal cell
carcinoma with molecular targeted therapy. J Natl Compr Cancer Netw 2011;9:S10, with permission.
| Class | Target/ Mechanism of Action | Agent | Phase | Trial/Comment |
|---|---|---|---|---|
| Angiogenesis inhibitors |
VEGFR | Axitinib | III | Phase III trial in sunitinib-refractory RCC; head-to-head comparison with sorafenib |
| AZD2171 | II | Phase II single agent in refractory RCC | ||
| AV-951 | III | Phase III randomized, controlled study of AV-951 versus sorafenib in patients with advanced RCC |
||
| IMC-1121B | II | Phase II in patients treated with prior TKI | ||
| VEGFR, FGFR | Dovitinib | III | Phase III randomized, controlled study of dovitinib versus sorafenib in patients treated with a prior TKI and mTOR inhibitor |
|
| VEGF/PLGF | VEGF Trap (AVE0005) | II | Phase II in patients treated with a prior TKI and mTOR inhibitor |
|
| ANG 1/2 | AMG836 | II | Combination studies planned in first-line setting | |
| Signal transduction inhibitors |
AKT/PKB | Perifosine | II | Two single-agent trials are ongoing in patients experiencing TKI failure |
| RX-0201 | II | Planned single-agent study | ||
| Cell cycle | Ispinesib | II | Single-agent study in patients receiving second-line therapy |
|
| HDAC | Panobinostat Vorinostat Entinostat |
I/II | Studies of single-agent and combination chemotherapy are planned in first-line setting or in patients experiencing TKI failure |
|
| HGF/c-MET | GSK1363089 | II | A phase II study of single agent in papillary RCC | |
| AMG102 | II | Single-agent trial in patients unable to receive or previously treated with VEGF/VEGFR agents |
||
| Immune checkpoint inhibitors |
PDL-1/PD-1 | MDX-1105/1106 | I | Single-agent studies |
Emerging Agents in Clinical Trials for Treatment of Renal Cell Carcinomas
Abbreviations: ANG, angiopoietin; FGFR, fibroblast growth factor receptor; HDAC, histone deacetylase; HGF, hepatocyte growth
factor; mTOR, mammalian target of rapamycin; PD-1, programmed death-1; PDL-1, programmed death-ligand 1; PLGF, placental growth
factor; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular
endothelial growth factor receptor.
From Hudes GR, Carducci MA, Choueiri TK, et al. NCCN Task Force Report: optimizing treatment of advanced renal cell carcinoma
with molecular targeted therapy. J Natl Compr Cancer Netw 2011;9:S22, with permission.
This activity is intended for primary care clinicians, internists, nephrologists, oncologists, and other healthcare practitioners caring for patients with RCC.
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Advanced renal cell carcinoma (RCC) is a heterogeneous disease with variable histology, biology, and response to treatment. In the past 5 years, 6 new agents have been approved for the treatment of RCC, and many more are in clinical development. With an ever-increasing number of treatment options, selecting among them for a particular patient can be a daunting task for clinicians. This article describes how treatment choice can be guided by the disease setting and histology, as well as patient characteristics, comorbidities, and preference within the context of available data. Results from clinical trials are combined with practical considerations to make recommendations for first-line and subsequent treatment of patients with clear cell and non–clear cell RCC. These recommendations should supplement the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of advanced RCC. (JNCCN 2011;9:997–1007)
In the past 5 years, 6 new agents were approved for the treatment of renal cell carcinoma (RCC). These can be broadly categorized into 2 groups: vascular endothelial growth factor (VEGF)–directed therapies (sorafenib, sunitinib, pazopanib, and bevacizumab) and mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus). With such a large number of treatment options, selecting among them for a particular patient can be daunting for clinicians. This article describes how treatment choices can be guided by the disease setting, histology, patient characteristics and comorbidities, and patient preference.
