OBJECTIVE: The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations.
METHODS: A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate.
RESULTS: Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated.
CONCLUSIONS: ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

With the recent approval of the combinations of axitinib with the immune checkpoint inhibitor (ICI) pembrolizumab or avelumab for first-line treatment of advanced renal cell carcinoma, guidance on how to distinguish between immune-related adverse events (AEs) caused by ICI versus axitinib-related AEs is necessary to optimise therapy with axitinib-ICI combinations. The recommendations here are based on (1) systematic review of published evidence, (2) discussion among experts in the field and (3) a survey to obtain expert consensus on specific measures for therapy management with the combinations axitinib/avelumab and axitinib/pembrolizumab. The experts identified areas of AEs requiring unique management during treatment with axitinib-ICI combinations that were not covered by current recommendations. Diarrhoea, hepatic toxicity, fatigue and cardiovascular AEs were found to be applicable to such specialised management. Triage between immune-suppressive and supportive measures is a key component in therapy management. Clinical monitoring and experience with both classes of agents are necessary to manage this novel therapeutic approach. We focused on AEs with an overlap between axitinib and ICI therapy. Our recommendations address AE management of axitinib-ICI combinations with the aim to improve the safety of these therapies.

Recent randomised trials have demonstrated a survival benefit for a front-line ipilimumab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies. PATIENT SUMMARY: Pembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naïve). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.

A method based on micellar liquid chromatography to quantify the tyrosine kinase inhibitors axitinib, lapatinib and afatinib in plasma is reported. The sample pretreatment was a simple 1/5-dilution in a pure micellar solution, filtration and direct injection, without requiring extraction or purification steps. The three drugs were resolved from the matrix in 17min, using an aqueous solution of 0.07M sodium dodecyl sulfate - 6.0% 1-pentanol, buffered at pH7 with 0.01M phosphate salt as mobile phase, running under isocratic mode at 1mL/min through a C18 column. The detection was performed by absorbance at 260nm. An accurate mathematical relationship was established between the retention factor of each drug and the surfactant/organic solvent concentration in the mobile phase, achieved with a limited number of experiments, in order to optimize these factors. A binding behavior of the analytes face to the micelles was found out. The method was successfully validated by the guidelines of the European Medicines Agency in terms of: selectivity, linearity (r2>0.9995), calibration range (0.5 to 10mg/L), limit of detection (0.2mg/L), carry-over effect, accuracy (-8.1 to +6.9%), precision (<13.8%), dilution integrity, matrix effect, stability and robustness. The procedure was found reliable, practical, economic, accessible, short-time, easy-to-handle, inexpensive, environmental-friendly, safe, useful for the analysis of many samples per day. Finally, the method was applied to the analysis of incurred, using quality control samples in the same analytical run, with adequate results. Therefore, it can be implementable for routine analysis in clinical laboratories.

BACKGROUND: Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making.
METHODS: Eleven international experts were asked to provide their treatment strategies for second-line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach.
RESULTS: The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria.
CONCLUSIONS: In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred.

BACKGROUND: The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy of metastatic renal cell carcinoma (mRCC).
METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.
RESULTS: Six international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Association for Urology (2013), the European Society of Medical Oncology (2012), the National Institute of Health and Clinical Excellence (2011), the Canadian Kidney Cancer Forum (2013) and the Asian Oncology Summit (2012). Recommendations on the first-, second- and third-line treatment for mRCC were developed.
CONCLUSIONS: These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of mRCC.