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Purpose: The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC., Methods: Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non-clear-cell subtype, papillary, and chromophobe carcinomas., Results: Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non-clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC., Conclusion: The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non-clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC., Competing Interests: Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported. Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported.

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., (Copyright © 2021. Published by Elsevier Inc.)

Background: 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., Methods/design: 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)., 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, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Purpose: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence., Patients and Methods: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo., Results: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib., Conclusion: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART., Competing Interests: Cancer Research UK and Bayer had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Staff funded by the Medical Research Council and University College London contributed to study design, data collection, data analysis, data interpretation, and writing of this report.