Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study.

BACKGROUND: Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor. METHODS: We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811. FINDINGS: Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2). INTERPRETATION: Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting. FUNDING: Pfizer.

Response to post-axitinib treatment in patients with metastatic renal cell carcinoma.

BACKGROUND: Axitinib is a potent inhibitor of the vascular endothelial growth factor (VEGF) receptor family with clinical activity in patients with metastatic renal cell carcinoma (mRCC). Given this biochemical potency, the clinical activity of subsequent treatment with targeted therapies in patients progressing on axitinib is of interest. METHODS: Patients with advanced renal cell carcinoma of any pathologic subtype treated with at least one cycle (four weeks) of axitinib followed by at least one subsequent targeted therapy were investigated in a retrospective analysis. Patient characteristics, duration of treatment and clinical outcomes were analyzed for axitinib and each subsequent line of therapy by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Twenty-five mRCC patients who received at least one approved targeted agent following axitinib were identified. Eight percent of patients achieved a partial response (one patient each to sunitinib and pazopanib) and 42 % had a best response of stable disease to the first therapy after axitinib. The estimated median duration of therapy was 4.4 months (range, 0.2-27.5+). Twelve patients received a second post-axitinib targeted therapy. Six out of 11 evaluable patients (55 %) had a best response of SD. The estimated median duration of treatment was 4.8 months (range, 0.7-19.1+). CONCLUSION: Objective responses and stable disease is observed to post-axitinib targeted therapies and prospective studies are needed for validating role of predictive biomarkers.

A Phase II Study of Pazopanib in Patients with Localized Renal Cell Carcinoma to Optimize Preservation of Renal Parenchyma.

PURPOSE: Preservation of renal function is prioritized during surgical management of localized renal cell carcinoma. VEGF targeted agents can downsize tumors in metastatic renal cell carcinoma and may do the same in localized renal cell carcinoma, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy. MATERIALS AND METHODS: Localized clear cell renal cell carcinoma patients meeting 1 or both of the following criteria were enrolled in a prospective phase II trial, including radical or partial nephrectomy likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m(2), or partial nephrectomy high risk due to high complexity (R.E.N.A.L. 10 to 12) or tumor adjacent to hilar vessels. Pazopanib (800 mg once daily) was administered for 8 to 16 weeks with repeat imaging at completion of therapy, followed by surgery. RESULTS: A total of 25 patients enrolled with a median tumor size of 7.3 cm and a median R.E.N.A.L. score of 11. Of index lesions 80% were high complexity and 56% of patients had a solitary kidney. Patients received a median of 8 weeks of pazopanib. The median interval from treatment start to surgery was 10.6 weeks. R.E.N.A.L. score decreased in 71% of tumors and 92% of patients experienced a reduction in tumor volume. Six of 13 patients for whom partial nephrectomy was not possible at baseline were able to undergo partial nephrectomy after treatment. The mean parenchymal volume that could be saved with surgery increased from an estimated 107 to 173 cc (p = 0.0015). In 5 patients a urine leak developed, which was managed conservatively, and 7 received a transfusion, of whom 1 required embolization. CONCLUSIONS: Neoadjuvant pazopanib resulted in downsizing localized renal cell carcinoma, allowing for improved preservation of renal parenchyma and enabling partial nephrectomy in a select subset of patients who would otherwise require radical nephrectomy.

A phase 2, single-arm study of ramucirumab in patients with metastatic renal cell carcinoma with disease progression on or intolerance to tyrosine kinase inhibitor therapy.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) have antitumor activity in metastatic renal cell carcinoma (mRCC). Resistance to these agents develops frequently, and their use is often limited by intolerance. Ramucirumab is a recombinant human monoclonal antibody directed against human vascular endothelial growth factor receptor-2. For this study, the authors investigated the clinical efficacy and safety of ramucirumab in patients with TKI-resistant/intolerant mRCC. METHODS: In this single-arm phase 2 trial, patients received ramucirumab 8 mg/kg every 2 weeks until they developed disease progression or intolerable toxicity. The primary endpoint was the best objective response rate (ORR); additional endpoints included the disease control rate (DCR), progression-free survival (PFS), the median duration of overall response, and safety. RESULTS: Thirty-nine patients with RCC received ramucirumab monotherapy. Prior TKI therapy included sunitinib (59% of patients), sunitinib and sorafenib (30.8% of patients), and sorafenib (10.3% of patients). The ORR was 5.1% (95% confidence interval [CI], 0.6%-17.3%). The 12-week DCR was 64.1% (95% CI, 47.2%-78.8%). The median PFS was 7.1 months (95% CI, 4.1-9.7 months), and the median overall survival was 24.8 months (95% CI, 18.9-32.6 months). Grade 3 or higher adverse events that occurred in ≥5% of patients included grade 3 hypertension (7.7%) and proteinuria (5.1%). There was 1 on-study death from multiorgan failure. CONCLUSIONS: Although the study did not meet its primary endpoint of ≥15% ORR, ramucirumab was associated with evidence of antitumor activity in patients with TKI-resistant/intolerant mRCC. Ramucirumab was safe and well tolerated.

The Role of Nurses in the Management of Adverse Events in Patients Receiving First-Line Axitinib Plus Immuno-Oncology Agents for Advanced Renal Cell Carcinoma.

OBJECTIVES: The recent approval of first-line tyrosine kinase inhibitor plus immuno-oncology agent combination therapy for the treatment of advanced renal cell carcinoma offers substantially improved response rates and survival compared with the previous standard of care. This expansion of treatment options has also led to a greater range and complexity of potential treatment-related adverse events related to overlapping toxicities. The aim of this article is to discuss the management of common treatment-emergent adverse events (AEs) associated with axitinib plus immuno-oncology therapy, highlight the specific roles of oncology nurses in managing these events, and provide AE management resources to aid oncology nurses in their care of patients with advanced renal cell carcinoma. DATA SOURCES: Author experience, journal articles, and treatment guidelines were used. CONCLUSION: The use of oncology nurses and nurse-led innovations to monitor and assess treatments can have a positive impact on the management of AEs in cancer patients by identifying those who are most at risk, providing regular assessment, appropriate patient education, and supporting the monitoring of patient safety. IMPLICATIONS FOR NURSING PRACTICE: Skilled oncology nurses should be a key part of a team that addresses the supportive care needs and management of AEs that are associated with novel cancer treatments. Early and ongoing communication between the patient and oncology nurses regarding the development of adverse events is a critical component of maximizing treatment outcomes and quality of life.

Avelumab First-Line Maintenance Therapy: Managing Patients With Advanced Urothelial Carcinoma.

BACKGROUND: The phase 3 of JAVELIN Bladder 100 trial demonstrated that avelumab first-line (1L) maintenance in addition to best supportive care significantly prolonged overall survival compared to best supportive care alone. It is now the standard of care for platinum-eligible patients with locally advanced or metastatic urothelial carcinoma that has not progressed with 1L platinum-containing chemotherapy. OBJECTIVES: This article provides considerations for oncology nurses to effectively implement avelumab 1L maintenance treatment in the clinical setting. METHODS: This article reviews clinical evidence and implications for oncology nurses caring for patients receiving avelumab 1L maintenance treatment. FINDINGS: Oncology nurses can provide comprehensive care for patients with advanced urothelial carcinoma and ensure the safe and appropriate use of avelumab 1L maintenance treatment by educating patients and caregivers, ensuring correct administration, and promptly recognizing and managing immune-related adverse events.

Cessation of vascular endothelial growth factor-targeted therapy in patients with metastatic renal cell carcinoma: feasibility and clinical outcome.

BACKGROUND: The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)-targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time. METHODS: A retrospective study of patients with mRCC who initiated VEGF-targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave-Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)-defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression-free survival (PFS), measured as the time from discontinuation of therapy to RECIST-defined PD. RESULTS: Forty patients were identified. After a median follow-up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4-27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19-5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model. CONCLUSIONS: A select subset of mRCC patients achieving stable disease or better on VEGF-targeted therapy can be observed off all therapy. Further prospective investigation is warranted.

Avelumab First-Line Maintenance Treatment in Advanced Bladder Cancer: Practical Implementation Steps for Infusion Nurses.

Immune checkpoint inhibitors, such as programmed cell death ligand 1 inhibitors pembrolizumab, nivolumab, atezolizumab, and avelumab, are used to treat patients with advanced urothelial carcinoma (UC). Based on data from the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance is now considered the standard-of-care treatment for patients with locally advanced or metastatic UC who responded or experienced disease stabilization after 1L platinum-containing chemotherapy, and it is the only category 1 preferred checkpoint inhibitor maintenance option in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for patients with cisplatin-eligible and cisplatin-ineligible locally advanced or metastatic UC. This article reviews key considerations related to avelumab 1L maintenance therapy that infusion nurses should be familiar with, including dosing, administration, and immune-related adverse event recognition and management, to ensure safe and appropriate use of this important and impactful therapy.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Laboratory Reference Ranges and Testing Intervals Work Group.

PURPOSE: In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population. EXPERIMENTAL DESIGN: Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures. The working group evaluated current eligibility criteria across different clinical trial phases and performed a literature review to evaluate the impact of and justification for laboratory test eligibility requirements and testing intervals in clinical trials. Recommendations were developed on the basis of the goals of promoting safety and optimizing the evidence generated, while also expanding eligibility and applicability, and minimizing excess burden of trial participation. RESULTS: In general, we found little variation over time and trial phase in laboratory test requirements, suggesting that these eligibility criteria are not refined according to ongoing clinical experience. We propose recommendations to optimize the use of laboratory tests when considering eligibility criteria. CONCLUSIONS: Tailoring the use of laboratory test requirements and testing intervals may increase the number and diversity of patients in clinical trials and provide clinical data that more closely represent the general practice populations.See related commentary by Giantonio, p. 2369.

Association of percentage of tumour burden removed with debulking nephrectomy and progression-free survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy.

OBJECTIVE: To determine if the fractional percentage of tumour volume (FPTV) removed with debulking nephrectomy was associated with progression-free survival (PFS) after subsequent targeted therapy, as a debulking nephrectomy is the standard of care in metastatic renal cell carcinoma (mRCC), but there are few data. PATIENTS AND METHODS: The Cleveland Clinic Taussig Cancer Institute Urologic Oncology database was retrospectively reviewed from 2005 to 2008 to identify patients with mRCC who had undergone debulking nephrectomy followed by vascular endothelial growth factor (VEGF)-targeted therapy, defined as sunitinib-, sorafenib- or bevacizumab-based therapy. FPTV was calculated as the largest diameter of the primary tumour divided by the total tumour burden (as per the Response Evaluation Criteria in Solid Tumors, RECIST) through investigator re-review of imaging. PFS was defined from the start date of systemic therapy to disease progression per RECIST criteria. RESULTS: Forty-six patients were identified (80% men, median age 61 years, all clear cell histology and 67% with an Eastern Cooperative Oncology Group performance status of 0). Patients received treatment with bevacizumab ± interleukin-2 (18), sunitinib (14), sorafenib (11) or sunitinib + bevacizumab (three). The median diameter of the primary tumour was 10.0 cm. The median (range) FPTV removed was 95 (80-99)%. In univariable analysis, the FPTV removed (P = 0.002) and normal haemoglobin level (P = 0.04) were associated with improved PFS. In multivariable analysis, the FPTV removed (P < 0.001), male gender (P = 0.001) and corrected calcium (P = 0.05) were independent predictors of PFS. CONCLUSION: A greater percentage of tumour burden removed at debulking nephrectomy is significantly associated with improved PFS on subsequent VEGF-targeted systemic therapy.

New therapeutic strategies for renal cell carcinoma.

Treatment options for renal cell carcinoma have changed dramatically since 2005 when the U.S. Food and Drug Administration approved six new therapies. These agents inhibit pathways relevant in the pathogenesis of renal cell carcinoma, interfering with tumor angiogenesis, cell progression, and metastasis. Understanding the pharmacology of these agents is necessary for clinicians to provide appropriate patient education, assure adherence with the treatment plan, and facilitate early identification and intervention for side effects. These activities will provide positive clinical outcomes.

The Critical Role of the Oncology Nurse as a Partner in the Management of Patients With Advanced Kidney Cancer: Toxicity Management, Symptom Control, and Palliative Care.

The treatment of advanced renal cell carcinoma has changed dramatically since 2005 with the approval of 12 regimens including oral, intravenous, and combination strategies. These approvals have changed the treatment paradigm for these patients and developed new challenges and a critical role for oncology nurses to ensure that the treatment plan and adverse events are managed effectively. The majority of these regimens include an oral anticancer drug, which requires patients and their caregivers to understand the medication, the potential adverse events, the importance of medicine adherence, and the importance of early and ongoing education with the oncology team to maximize clinical outcomes. The evolution of the role of the nurse in meeting this need and its critical contribution to the comprehensive care of the kidney cancer patient will be reviewed.

Toxicity Management of Front-Line Pembrolizumab Combined With Axitinib in Clear Cell Metastatic Renal Cell Carcinoma: A Case Study Approach.

Immune checkpoint inhibitors have improved clinical outcomes in many malignancies, including renal cell carcinoma (RCC). Awareness of potential adverse events and effective management of these toxicities is critical to maximizing clinical outcomes. Pembrolizumab plus axitinib is approved as front-line treatment of advanced renal cell carcinoma (aRCC), making it the first checkpoint inhibitor and tyrosine kinase inhibitor combination approved for any malignancy. Given overlapping toxicities with this combination, the toxicity profile of each drug must be considered when assessing and managing toxicities in patients treated with pembrolizumab and axitinib. Use of online resources, including published guidelines from ASCO, the Immuno-Oncology Essentials Web site, and other organizations, can assist oncology and nononcology health care professionals to more effectively manage toxicities, maximize clinical outcomes, and improve quality of life for patients with aRCC. Herein, we describe a case of a patient with aRCC treated with pembrolizumab and axitinib, highlighting a systematic approach to toxicity management.

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Ipilimumab plus nivolumab has been approved for intermediate- and poor-risk metastatic renal cell carcinoma (RCC). However, the activity in non-clear cell RCC (nccRCC) is unknown. PATIENTS AND METHODS: Patients from Cleveland Clinic and the University of Texas Southwestern who had received ipilimumab plus nivolumab for metastatic nccRCC from October 2017 to May 2019 were retrospectively identified. Ipilimumab plus nivolumab was administered in accordance with the CHECKMATE 214 trial. Imaging was obtained at baseline and every 12 weeks. The baseline patient characteristics, objective response per Response Evaluation Criteria in Solid Tumors, version 1.1, and treatment-related adverse events (TRAEs) per Common Terminology Criteria for Adverse Events, version 5.0, were analyzed. RESULTS: Eighteen patients were identified. The median age was 59 years (range, 32-81 years), 77.8% were men, and the Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (50%). The median treatment duration was 2.4 months (range, 0.7-12.3 months). The non-clear cell histologic types included 6 papillary, 5 chromophobe, 3 unclassified, 2 adenocarcinoma of renal origin, 1 translocation, and 1 medullary. Most had an intermediate (66%) or poor (22%) International Metastatic Database Consortium risk. The best objective response included 6 partial responses (PRs; 33.3%) and 3 with stable disease (16.7%). Of the patients with a PR, the median time to the best response was 3.0 months, and median duration of the PR was 4.3 months. The median progression-free survival was 7.1 months. All-grade TRAEs were noted in 11 patients (61.1%) and included colitis (22%), hepatotoxicity (16%), rash (11%), and fatigue (11%). Eleven patients (61%) had TRAEs requiring high-dose glucocorticoids (> 40 mg of prednisone equivalent daily). CONCLUSIONS: Ipilimumab plus nivolumab demonstrated objective responses and notable toxicity in patients with nccRCC.

Search for evidence-based approaches for the prevention and palliation of hand-foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs).

BACKGROUND: The anticancer multikinase inhibitors (MKIs) are associated with cutaneous adverse events, including hand-foot skin reaction (HFSR), a condition affecting 20%-40% of patients. Symptoms are usually mild, but can evolve into a painful condition that limits function and impacts quality of life (QoL), resulting in shortened cancer treatment duration or intensity. The goal of this study was to systematically review the literature on the prevention and palliation of MKI-associated HFSR, to identify areas for further clinical study, and to provide a foundation for evidence-based guidelines for HFSR management. METHODS: Systematic searches of the National Library of Medicine's PubMed database, Cochrane Reviews, BIOSIS, CancerLit, and the American Society of Clinical Oncology website were conducted using search terms for cutaneous toxicities associated with chemotherapeutic agents. Articles were categorized (C) based on type of agent and cutaneous reaction as: C1 (MKI and HFSR); C2 (MKI and other cutaneous toxicity); C3 (other antineoplastic agents and HFSR); and C4, other. RESULTS: Of the 2,069 abstracts screened, 350 (17%) met the criteria for C1-C4, with 56 (16%) coded as C1 with details of HFSR histology, pathogenesis, clinical outcome, QoL impact, and/or prevention and treatment approaches in MKI-treated patients. No randomized, controlled trials (RCTs) on prevention/palliation of HFSR were identified. Anecdotal evidence or expert opinion advocated protective measures, preventive and therapeutic skin care, systemic analgesics for pain, vitamin B(6), and MKI dose modification. CONCLUSION: No articles containing evidence from RCTs on preventive/palliative approaches to MKI-associated HFSR have been published. Systematic study of optimal treatment strategies for HFSR is needed to advance development of evidence-based treatment guidelines.

Immune-Related Adverse Events From Immunotherapy: Incorporating Care Step Pathways to Improve Management Across Tumor Types.

Immune checkpoint inhibitor (ICI) therapy provides a valuable treatment option for many cancer patients but is associated with immune-related adverse events (irAEs) that can involve any organ system. Managing irAEs can be a challenge, as these AEs differ from those associated with conventional chemotherapy in both appearance and care. Prompt and successful irAE management is important for patient health and the maintenance of effective therapy. A group of advanced practice providers has developed Care Step Pathways (CSPs) to improve the management of irAEs (see Appendix and aimwithimmunotherapy.org). These CSPs, which combine established guidelines with practical experience, provide information on assessing, grading, and managing irAEs. Proactive strategies, implementation tactics, patient education points, and "red flags" are also featured. This article provides a brief summary of ICI therapies currently used in oncology and an overview of irAEs that may occur during treatment. The importance of medication reconciliation and a thorough baseline assessment is stressed, and detailed information on baseline clinical and laboratory tests is provided. Specific CSPs for several irAEs, such as gastrointestinal toxicity, adrenal insufficiency, nephritis, and neuropathy, are reviewed in detail. As these CSPs illustrate, advanced practice providers are well positioned to play a key role in collaborative care for oncology patients, particularly with respect to providing in-depth patient education and "owning" AE management.

Immune Checkpoint Inhibitor Therapy: Key Principles When Educating Patients.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is a fast-developing field within the spectrum of cancer care. ICIs are associated with distinctive immune-related adverse events (irAEs), reflecting their unique mechanisms of action. OBJECTIVES: Effective management of irAEs requires early recognition and prompt reporting of their signs and symptoms; appropriate patient education is critical to maximizing this opportunity. METHODS: A comprehensive literature search was conducted in the public domain concerning awareness, assessment, and management of irAEs associated with ICIs. FINDINGS: Educational resources should provide timely, consistent, and personalized information, using a variety of teaching strategies that consider individual patient needs. Patient education should be developed with interprofessional team input and regularly reviewed in response to emerging guidance. Key messages include timing of therapeutic response and corresponding irAEs, early identification of irAEs, and the unique ability of ICIs to influence immune responses after treatment discontinuation.

A phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior anti-angiogenic therapy.

BACKGROUND: Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. METHODS: Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. RESULTS: Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16-53) off therapy. No patients developed RECIST PD while off therapy. CONCLUSIONS: This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. TRIAL REGISTRATION: NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331 ).

Myalgia and Arthralgia Immune-related Adverse Events (irAEs) in Patients With Genitourinary Malignancies Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Myalgia and arthralgia immune-related adverse events (irAEs) in patients treated with checkpoint inhibitors (CPIs) present a clinical challenge. We describe the clinical characteristics and treatment of myalgia and arthralgia irAEs in CPI-treated patients with genitourinary (GU) malignancies. PATIENTS AND METHODS: Patients with GU malignancies who were treated with CPIs and developed myalgia and arthralgia irAEs that resulted in interruption or discontinuation of CPI therapy were reviewed. Patient-, disease-, and irAE-related data were collected and analyzed. RESULTS: Twenty-one patients were identified. Eighteen (86%) had renal cell carcinoma; 3 (14%) had urothelial carcinoma. The majority (71%) were male; the median age at diagnosis was 56 years (range, 36-78 years). CPI therapy included anti-programmed death-ligand 1 (29%), anti-programmed cell death protein 1 (48%), and combined programmed cell death protein 1/cytotoxic T-lymphocyte-associated protein 4 antibodies (24%). The median time from CPI initiation to myalgia and arthralgia irAE was 5.1 months (range, 0.23-50.5 months). All patients were treated with prednisone with a median initial dose of 40 mg/d (range, 10-90 mg/d) for a median duration of 64 weeks (range, 3-242 weeks). Treatment with methotrexate (14%), infliximab (14%), tocilizumab (10%), gabapentin (10%), and etanercept (5%) was also required in some patients. Six (29%) patients restarted CPI therapy following symptom improvement, 3 (15%) switched to a subsequent therapy, and 12 (55%) patients had an ongoing sustained response to therapy (median, 14.5 months; range, 3-55 months) despite no subsequent anti-cancer therapy. CONCLUSION: Myalgia and arthralgia irAEs in CPI-treated patients with GU malignancies vary in timing of presentation, severity, and treatment. Multidisciplinary teams that include a rheumatologist are critical for optimal management. Durable response to CPIs can be maintained even after therapy discontinuation.

The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC).

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.