Systemic therapy in metastatic renal cell carcinoma

Abstract

PurposeCurrent systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).MethodsA panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.ResultsSunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.ConclusionsDespite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI–TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.

Epidemiology and screening for renal cancer

“…Early detection of smaller tumours may allow increasing use of minimally invasive techniques such as robotic or laparoscopic partial nephrectomy and tumour ablation, reducing rates of open surgery with associated high morbidity and hospital stay [21–24]. Modern systemic therapies used in the treatment of metastatic RCC, such as sunitinib, pazopanib, axitinib and nivolumab, are highly expensive and the median cost of anticancer drugs is rising, as is patient life expectancy, and therefore, duration of treatment [25, 26]. It has been postulated that screening for RCC may be a cost-effective strategy through downstaging the disease, reducing the prevalence of metastatic tumours and associated expenditure relating to systemic therapies.…”

Genomics and clinical correlates of renal cell carcinoma

“…Targeted immunotherapy, for instance, in the form of programmed death 1 (PD-1) checkpoint inhibition or cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) inhibition is being increasingly used in both first- and second-line therapies [45]. Prediction of favourable response has not been correlated with PD-1 ligand biomarker expression [46].…”

Use of targeted therapies for advanced renal cell carcinoma in the Veterans Health Administration

“…Despite the approval of multiple targeted therapies for the treatment of metastatic renal cell carcinoma (RCC), including a vascular endothelial growth factor‐antibody (VEGF‐mAb), multitargeted VEGF tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and immune checkpoint inhibitors, the optimal sequencing of these agents is unknown, especially beyond second‐line therapy . Additionally, the degree to which clinical trial results (eg, duration of therapy, overall survival) match real‐world outcomes remains uncertain …”