Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Including the patient voice in the development and implementation of patient-reported outcomes in cancer clinical trials.

CONTEXT: Patient-reported outcomes (PROs) are used in parallel with clinical evidence to inform decisions made by industry, clinicians, regulators, health technology assessment bodies and other health-care decision-makers. In addition, PRO data can also guide shared decision making and individual patient choice. Yet, the quality of many PROs in cancer clinical trials is suboptimal and requires improvement to add value to health care and policy decision making. OBJECTIVE: To show how the integration of the patient and/or patient advocate at all stages of PRO development can help to realize the full potential of PROs. METHODS: We examined the literature to show that the patient voice is often absent from the planning and implementation of PROs in cancer clinical trials. Good practice examples from the literature were combined with guideline recommendations, training or educational resources, and our own experience to create detailed practical steps for the inclusion of patients and/or patient advocates throughout PRO development. RESULTS: Patient or patient advocates can play an active role in shaping PROs that are meaningful to the patient. They can contribute to content, choice of medium and implementation in a way that may support PRO completion and minimize missing data. Patients and their advocates can work to ensure PRO findings are disseminated appropriately in a way that is accessible to patients. CONCLUSION: This practical guidance aims to optimize PRO development and implementation in clinical trials, resulting in robust, relevant data that reflect the patient experience and that support decisions made by all stakeholders involved in research and health care.

The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER?

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.

Patient value: Perspectives from the advocacy community.

All health-care systems are under financial pressure and many have therefore developed value frameworks to assist decision making regarding access to treatment. Unfortunately, many frameworks simply reflect the clinically focused values held by health-care professionals rather than outcomes that also matter to patients. It is difficult to define one single homogeneous set of patient values as these are shaped by social, religious and cultural factors, and health-care environment, as well as many factors such as age, gender, education, family and friends and personal finances. Instead of focusing on an aggregated set of values, frameworks should attempt to incorporate the broader range of outcomes that patients may regard as more relevant. Patient advocates are well placed to advise assessment bodies on how particular therapies will impact the patient population under consideration and should be closely involved in developing value frameworks. In this paper, a group of patient advocates explore the varying definitions of patient value and make positive recommendations for working together to strengthen the patient voice in this area. The authors call on framework developers, the patient advocacy and research communities, the health-care industry and decision-makers to undertake specific actions to ensure patient value is included in current and future value frameworks. This is justified on compassionate and economic grounds: better health outcomes result when patients receive treatment tailored to individual needs. Paying attention to the patient perspective also results in better use of resources-a goal that should appeal to all stakeholders.

Evolving Role of Adjuvant Systemic Therapy for Kidney and Urothelial Cancers.

The role of adjuvant therapy in renal cell carcinoma and urothelial carcinoma is rapidly evolving. To date, the U.S. Food and Drug Administration has approved sunitinib and pembrolizumab in the adjuvant setting for renal cell carcinoma and nivolumab for urothelial carcinoma based on disease-free survival benefit. The U.S. Food and Drug Administration held a joint workshop with the National Cancer Institute and the Society of Urologic Oncology in 2017 to harmonize design elements, including eligibility and radiologic assessments across adjuvant trials in renal cell carcinoma and urothelial carcinoma. Considerations from the discussion at these workshops led the U.S. Food and Drug Administration to draft guidances to help inform subsequent adjuvant trial design for renal cell carcinoma and urothelial carcinoma. Patient-centered decision-making is crucial when determining therapeutic choices in the adjuvant setting; utility functions can be used to help quantify each patient's goals, values, and risk/benefit trade-offs to ensure that the decision regarding adjuvant therapy is informed by their preferences and the evolving outcomes data.

Patient-reported Experience of Diagnosis, Management, and Burden of Renal Cell Carcinomas: Results from a Global Patient Survey in 43 Countries.

The International Kidney Cancer Coalition (IKCC) is a federation of 46 affiliated patient organisations representing 1.2 million patients worldwide that is committed to reducing the global burden of kidney cancer. A large-scale global survey of patients with renal cell carcinoma (RCC) to capture real-world experiences has never been undertaken. The 35-question survey was designed to identify geographic variations in patient education, experience, awareness, access to care, best practices, quality of life, and unmet psychosocial needs. A total of 1983 responses were recorded from 43 countries in 14 languages. Analysis revealed key findings. (1) At diagnosis, 43% of all respondents had no understanding of their RCC subtype. (2) Shared decision-making remains aspirational: globally, 29% of all patients reported no involvement in their treatment decision, responding "My doctor decided for me". (3) While 96% of respondents reported psychosocial impacts, surprisingly, only 50% disclosed them to their health care team. (4) Lastly, 70% of patients were not asked to participate in a clinical trial, although 90% indicated they would be interested. The survey reflects patient perspectives from diverse clinical scenarios in which different treatment options are available. The data point to actionable deficits in the fields of clinical trials, psychosocial support, and shared decision-making. PATIENT SUMMARY: In this brief report, we highlight the key results from the first large-scale global survey of patients with kidney cancer to capture real-world experiences. This survey reflects patient perspectives from diverse clinical scenarios in which different treatment options are available. We conclude that there is a need for improvement in the fields of clinical trials, psychosocial support, and shared decision-making.

Recommendations for the Management of Rare Kidney Cancers.

CONTEXT: The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non-clear-cell renal cell carcinomas (RCCs), which showed a substantial lack of evidence for management recommendations. OBJECTIVE: To improve the outcomes of patients with rare kidney cancers (RKCs), we performed a subsequent unstructured review to determine current treatment strategies and druggable pathways, involving key stakeholders with a global perspective to generate recommendations. EVIDENCE ACQUISITION: Based on the systematic review, literature was queried in Pubmed, Medline, and abstracts from proceedings of European Society for Medical Oncology and American Society of Clinical Oncology, in addition to consulting key opinion leaders and stakeholders. A conventional narrative review strategy was adopted to summarize the data. EVIDENCE SYNTHESIS: The systematic review showed an absence of evidence for treating RKCs, with data only supporting sunitinib or MET inhibitors for some specific subtypes. However, a growing body of evidence implicates druggable pathways in specific RKC subtypes. To test hypotheses, the small patient numbers in each subtype require coordinated multicenter efforts. Many RKC patients are currently excluded from studies or are not analyzed using subtype-specific parameters, despite their unmet medical need. CONCLUSIONS: We recognize the need for additional multicenter studies and subtype-specific analyses; however, we present management recommendations based on the data available. Web-based tools facilitating subtype-specific global registries and shared translational research resources will help generate sufficient data to formulate evidence-based recommendations for guidelines. PATIENT SUMMARY: Patients confronted with rare kidney cancers are often treated the same way as clear-cell renal cell carcinoma patients, despite little evidence from randomized trials. Molecular characterization of tumors to stratify patients may improve outcomes. Availability of potential agents and trials remain a problem. Collaboration among medical centers is important to pool scarce data.

Kidney cancer survivorship survey of urologists and survivors: The gap in perceptions of care, but agreement on needs.

INTRODUCTION: There is lack of evidence-based literature addressing comprehensive long-term care for kidney cancer (KC) survivors. Additionally, it is unclear if the concerns of KC patients/caregivers are being adequately addressed. Therefore, Kidney Cancer Canada, a patient-led support organization for Canadians with KC, commissioned this first recorded survivorship survey specific to KC patients/caregivers. METHODS: We conducted a cross-sectional online survey of Canadian patients/caregivers diagnosed with localized KC, and a separate parallel survey of Canadian urologists. The primary objectives were to assess patient/caregivers' and urologists' perceptions of information provided, as well as the physical/psychological/emotional impact of KC treatment. RESULTS: Urologists recalled providing information about surgical complications (90%) and their management (63%), while patients/caregiver recalled much less (33% and 35%). Of the urologists, 93% recalled providing information on cancer recurrence, but only 42% of patients/caregivers remembered receiving this information. Concerns identified by patients/caregivers and urologists were similar: fear of recurrence, concerns about cancer, fatigue, and anxiety. Importantly, all agreed that survivorship information was paramount. Education of both patients/caregivers and physicians and the development of guidelines were factors identified to ensure optimal KC survivorship. Study limitations include potential biases in recall and selection of participants. CONCLUSION: There was some discordance between urologists' and patients/caregivers' rates of recall of information provided. Patients/caregivers would have desired more information about their cancer, long-term follow-up, and potential complications. A survivorship care plan (SCP) tailored to KC may be an effective measure to address these needs. The impact of this SCP on survivor outcomes should be rigorously assessed.