The most common AEs are manageable hypertension and hoarseness

On By msisig

The most common AEs are manageable hypertension and hoarseness. of the fastest increasing cancers in the past decades.2 Males are more frequently affected than females and the peak incidence is at 60C80 years. The most frequently diagnosed histological subtype is clear cell RCC (80%) followed by papillary (10C15%) and chromofobe (5C10%) RCC. Due to its location, RCC initially goes often unnoticed, and as a result, most patients present with either locally advanced or metastatic disease. About one-third of patients presenting with RCC have metastatic disease (metastatic renal cell RKI-1313 carcinoma (mRCC)) at their time of diagnosis.3 In contrast to the situation of locally advanced disease, where a radical nephrectomy is a potentially curative option, performing a nephrectomy in case of metastatic disease does not seem to be the golden standard anymore.4 Before considering a systemic treatment for mRCC, it is crucial to consider that in many patients mRCC can have a very indolent course, meriting close observation as a viable and rational first-line treatment option. As a general finding, mRCC is insensitive to either hormonal and cytotoxic therapies, but blocking the intracellular signalling activity of vascular endothelial growth factors receptors (VEGFR) through tyrosinekinase inhibitors (TKI) and thereby inhibiting angiogenesis has been shown to be an effective standard of care.5 Inhibiting the mammalian target of rapamycin (mTOR), a kinase protein which is important in signal transduction of factors associated with angiogenesis and proliferation, has for years been considered another rational target for treatment, but nowadays this paradigm is rapidly losing terrain. The standard of care in advanced or mRCC in essence depends on the risk stratification according to the Memorial Sloan Kettering Cancer Center and/or International Metastatic RCC Database consortium criteria.6,7 Until recently, first-line therapy in patients with good or intermediate prognosis mRCC usually consisted of a VEGFR targeting TKI such as pazopanib or sunitinib or alternatively the combination of bevacizumab with IF8N-.C11 For patients with poor prognosis mRCC, first-line treatment with the mTOR inhibitor temsirolimus was recommended, even though sunitinib, sorafenib, and pazopanib were frequently used alternatives.12 Recently, a large randomized phase III study, however, has unequivocally shown that the combination of nivolumab and ipilimumab was superior to sunitinib with regard to the primary end point overall survival in patients with intermediate- and poor-risk mRCC, but not in good-risk patients.13 Based on this study, the updated ESMO 2019 guidelines prefer this combination as first-line treatment in patients with intermediate- and poor-risk mRCC.14 Whether the recent publications of the combination of either pembrolizumab or avelumab with the TKI axitinib will again change the current (and seemingly ever-moving) landscape of first-line treatment of mRCC remains to be established.15, 16Second-line treatment in patients with progressive disease either during or after first-line treatment depends on a variety of factors. For patients with disease progression during or after first-line cytokine treatment, second-line therapy usually consists of single-agent TKI treatment, where sorafenib, tivozanib, or axitinib can be considered.11,14,17C19 In case of disease progression during or after first-line TKI treatment, a variety of treatment options is available, whereby either nivolumab or cabozantinib have compelling data regarding effects on overall survival.20,21 If these options cannot be considered, lenvatinib combined with everolimus could be an option, albeit that their effect on the primary end point progression-free survival CDC25A is based upon randomized phase II clinical data.18,22 There is no standard recommendation for third-line treatment; hence, these patients should preferably be enrolled into clinical trials to create more evidence for TKI or immunotherapy in third or fourth line.23C25 Even though the prognosis for patients with advanced or mRCC has significantly improved over the last one to two decades following the introduction of the above-mentioned treatment options, there still remains a need for more effective and (better) tolerable treatment options in the various lines of treatment. Tivozanib In August 2017, the European Medicines Agency (EMA) approved tivozanib, a highly selective VEGFR TKI for treatment of mRCC patients who were previously untreated or in whom the disease progression occurred after.In the USA, a large randomized phase III study comparing tivozanib to sorafenib in patients with refractory mRCC has been closed for accrual and first results are expected to become available in the next couple of months. to its location, RCC initially goes often unnoticed, and as a result, most patients present with either locally advanced or metastatic disease. About one-third of patients presenting with RCC have metastatic disease (metastatic renal cell carcinoma (mRCC)) at their time of diagnosis.3 In contrast RKI-1313 to the situation of locally advanced disease, where a radical nephrectomy is a potentially curative option, performing a nephrectomy in case of metastatic disease does not seem to be the golden standard anymore.4 Before considering a systemic treatment for mRCC, it is crucial to consider that in many patients mRCC can have a very indolent course, meriting close observation as a viable and rational first-line treatment option. As a general finding, mRCC is insensitive to either hormonal and cytotoxic therapies, but blocking the intracellular signalling activity of vascular endothelial growth factors receptors (VEGFR) through tyrosinekinase inhibitors (TKI) and thereby inhibiting angiogenesis has been shown to be an effective standard of care.5 Inhibiting the mammalian target of rapamycin (mTOR), a kinase protein which is important in signal transduction of factors associated with angiogenesis and proliferation, has for years been considered another rational target for treatment, but nowadays this paradigm is rapidly losing terrain. The standard of care in advanced or mRCC in essence depends on the risk stratification according to the Memorial Sloan Kettering Cancer Center and/or International Metastatic RCC Database consortium criteria.6,7 Until recently, first-line therapy in patients with good or intermediate prognosis mRCC usually consisted of a VEGFR targeting TKI such as pazopanib or sunitinib or alternatively the combination of bevacizumab with IF8N-.C11 For patients with poor prognosis mRCC, first-line treatment with the mTOR inhibitor temsirolimus was recommended, even though sunitinib, sorafenib, and pazopanib were frequently used alternatives.12 Recently, a large randomized phase III study, however, has unequivocally shown that the combination of nivolumab and ipilimumab was superior to sunitinib with regard to the primary end point overall survival in patients with intermediate- and poor-risk mRCC, but not in good-risk patients.13 Based on this study, the updated ESMO 2019 guidelines prefer this combination as first-line treatment in patients with intermediate- and poor-risk mRCC.14 Whether the recent publications of the combination of either pembrolizumab or avelumab with the TKI axitinib will again change the current (and seemingly ever-moving) landscape of first-line treatment of mRCC remains to be established.15, 16Second-line treatment in patients with progressive disease either during or after first-line treatment depends on a variety of factors. For patients with disease progression during or after first-line cytokine treatment, second-line therapy usually consists of single-agent TKI treatment, where sorafenib, tivozanib, or axitinib can be considered.11,14,17C19 In case of disease progression during or after first-line TKI treatment, a variety of treatment options is available, whereby either nivolumab or cabozantinib have compelling data regarding effects on overall survival.20,21 If these options cannot be considered, lenvatinib combined with everolimus could be an option, albeit that their effect on the primary end point progression-free survival is based upon randomized phase II clinical data.18,22 There is no standard recommendation for third-line treatment; hence, these patients should preferably be enrolled into clinical trials to create RKI-1313 more evidence for TKI or immunotherapy in third or fourth line.23C25 Even though the prognosis for patients with advanced or mRCC has significantly improved over the last one to two decades following the introduction of the above-mentioned treatment options, there still remains.