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With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC—sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC. [ABSTRACT FROM PUBLISHER]

Abstract: This review summarises available data and describes planned clinical trials designed to evaluate the potential of targeted agents as adjuvant therapy for renal cell carcinoma (RCC). Advanced RCC is refractory to standard cytotoxic chemotherapy, and clinical trials of adjuvant cytokine therapy in this therapeutic setting have not yet demonstrated clear evidence of clinical benefit. However, molecularly targeted therapies may offer a new approach for adjuvant therapy of this disease. Sorafenib (Nexavar®; Bayer Healthcare, West Haven, CT, USA) and sunitinib (Sutent®; Pfizer Inc, New York, NY, USA) are candidates for adjuvant therapy, because they are efficacious in the treatment of metastatic RCC and have side-effect profiles that can usually be well managed during long-term administration. The clinical benefit and tolerability of these agents as adjuvant therapies are being investigated in three ongoing phase 3 trials: ASSURE (adjuvant sorafenib or sunitinib in unfavourable renal cell carcinoma; Eastern Cooperative Oncology Group 2805), STAR (sunitinib trial in adjuvant renal cancer) and SORCE (a phase 3, randomised, double-blind, controlled study comparing sorafenib with placebo in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse). The results of these studies will address important clinical and translational questions, the answers to which may help define future treatment strategies and guide treatments towards the most appropriate patients. [Copyright &y& Elsevier]

Abstract: Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but a need exists to develop more effective systemic therapies. Angiogenesis has a key role in the pathophysiology of renal cell carcinoma and vascular endothelial growth factor (VEGF) is an important mediator of this process. Sunitinib, sorafenib and axitinib are new agents which belong to a class of drugs called kinase inhibitors and inhibit the VEGF, platelet-derived growth factor (PDGF) and c-KIT receptor tyrosine kinases. Temsirolimus inhibits the mammalian target of rapamycin (mTOR). All these agents have shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients generally pretreated with immunotherapy, whilst prolonged progression-free survival in a phase 3 study has been reported with sorafenib in comparison with placebo. Further phase 3 trials are recruiting and the combination of kinase inhibitors with other therapies is under investigation. [Copyright &y& Elsevier]

To present our results on managing loco-regional recurrence of renal cell carcinoma (RCC) with surgical excision, as local recurrence at the site of a previous nephrectomy is resistant to both systemic therapy and radiotherapy.In all, 16 patients were operated on between 1994 and 2003 for local recurrence of RCC. The median (mean, range) age at the time of local recurrence was 57.9 (57.4, 28.9–71.7) years, and the median interval from primary surgery 2.22 (3.88, 0.27–14.46) years. Before surgery eight patients had been given systemic immunotherapy, with no response of their local recurrence.Two patients were deemed inoperable because of direct invasion of the great vessels and the liver by tumour. The remaining 14 patients had recurrence in residual adrenal tissue (two), para-aortic nodes (three), para-caval nodes (two), retrocaval nodes (one), renal bed (six), liver, spleen and stomach (one each), and diaphragm (two). Although complete macroscopic en-bloc clearance was achieved in these patients, only eight had tumour-free margins on histological examination. The histology was consistent with RCC recurrence in all cases. All of the patients were followed with computed tomography at regular intervals. At a median follow-up of 1.0 (1.65, 0.25–6.5) years, five patients remain disease-free, four have local and distant relapse, and five developed distant metastasis only. The presence of tumour at the resection margin was a significant factor in predicting local and distant disease-free survival (P < 0.05).En bloc excision of isolated locally recurrent RCC is possible, and complete surgical extirpation can lead to prolonged disease-free survival. [ABSTRACT FROM AUTHOR]

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib. [ABSTRACT FROM AUTHOR]

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532 , EUDRACT #: 2017–002329-39. CTA #: 20363/0380/001–0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC_UU_12023/25.. RAMPART Protocol version 5.0. [ABSTRACT FROM AUTHOR]

20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART). ISRCTN #: ISRCTN53348826, NCT #: NCT03288532 , EUDRACT #: 2017–002329-39, CTA #: 20363/0380/001–0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532 , RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0. • RAMPART is the first international, academically led adjuvant trial to assess both single and combination immune checkpoint inhibitors in patients with RCC at intermediate and high risk of recurrence after nephrectomy. • RAMPART is a three arm adaptive MAMS platform trial upon which at least one new research arm can be added over the coming years. • The target population is participants with histologically proven RCC (clear cell and non-clear cell), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). • Patients with synchronous ipsilateral adrenal metastases, resected at the time of nephrectomy are included in RAMPART. • Significant changes have been made to the RAMPART protocol during the COVID-19 pandemic to optimise safety for participants including the option for remote patient consent and clinical assessment. • TransRAMPART is a unique scientific collaboration linked to RAMPART that will provide an opportunity to address pertinent unanswered issues for patients with RCC. • The RAMPART protocol can be found at https://www.rampart-trial.org/. [ABSTRACT FROM AUTHOR]