This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. © 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada. Key Words Competing Interests Article Information Renal cell carcinoma, treatment-related adverse events, vascular endothelial growth factor receptor tyrosine kinase inhibitors, mTOR inhibitors, immune checkpoint inhibitors None declared. Received on August 1, 2022 Accepted on September 21, 2022 This article has been peer reviewed. Soc Int Urol J. 2022;3(6):485–499 DOI: 10.48083/SYAB9165 2022 WUOF/SIU International Consultation on Urological Diseases: Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma Kate Young,1 Andreas M. Schmitt,1,2 Deborah Mukherji,3 Lavinia Spain,4 Manuela Schmidinger,5 Lisa M. Pickering1 1 Renal and Skin Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom 2 Department of Clinical Research, University Hospital Basel, Basel, Switzerland. 3 Department of Medical Oncology, American University of Beirut, Lebanon; Department of Medical Oncology, Clemenceau Medical Center Dubai, United Arab Emirates 4 Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Medical Oncology, Eastern Health, Melbourne, Australia; Eastern Health Clinical School, Monash University, Melbourne, Australia 5 Department of Urology, Medical University of Vienna, Vienna, Austria Abstract Standard approved systemic treatment options for the management of renal cancer have entirely transformed in the last 15 years and now comprise molecularly targeted therapies against the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR) as well as immune checkpoint inhibitors. These agents may be used alone as monotherapies but increasingly are used in various combinations. The associated important improvements in cancer control and survival have therefore been accompanied by a range of new toxicities. Good management of these toxicities is important for patient safety and quality of life, and also to optimize patients’ opportunity to continue with and therefore benefit from these therapies. The most common toxicities associated with VEGFR tyrosine kinase inhibitors are fatigue, skin rashes, gastrointestinal, stomatitis, hypertension and other cardiovascular toxicities, and hematological and endocrine dysfunction. Common side effects of mTOR inhibitors include asthenia, stomatitis, skin rashes, pneumonitis, metabolic changes and infections. Checkpoint inhibitors can lead to toxicities of any organ system with those seen most frequently including dermatologic, gastrointestinal and hepatic, endocrine, musculoskeletal, and pulmonary, whilst renal, hematological, ophthalmic, cardiac and neurological toxicities are seen less often. In general terms, toxicity management should start preemptively with patient education and may also include a combination of supportive approaches, dose reduction, schedule alteration, treatment interruption and occasionally treatment cessation. Treatment of individual toxicities is dependent on the likely causative agent and is guided by its grade or severity. Specific recommendations for management are discussed in this chapter. Introduction Since the mid-2000s, the introduction of new systemic therapies has transformed the management of renal cell carcinoma (RCC). Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), mammalian target of rapamycin (mTOR) inhibitors (mTORIs), and most recently immune checkpoint inhibitors (CPIs) have led to dramatically improved outcomes in advanced disease. In the past 5 years, several studies have demonstrated improved survival for the combination of CPIs and TKIs or the combination of the 2 CPI agents nivolumab and ipilimumab compared to first-line therapy with single-agent TKIs, and these combinations are now established as standard of care[1–4]. The CPI pembrolizumab is also now approved as adjuvant therapy following 484SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES https://orcid.org/0000-0002-9500-2046 https://orcid.org/0000-0002-9568-8164 https://orcid.org/0000-0002-0192-5828 https://orcid.org/0000-0002-2567-2749 https://orcid.org/0000-0002-7579-340X http://SIUJ.org resection of high-risk localized disease, or following nephrectomy and full resection of all metastatic lesions[5]. However, alongside their beneficial effects, these agents can cause a range of toxicities. Optimal management of such side effects is required to ensure safe treatment, manageable quality of life, and optimal drug delivery. General Principles of RCC Toxicity Management Prior to initiating systemic therapy for RCC, the patient’s current fitness, medical history and comorbidities, and concurrent medications should be considered. This allows for identification of patients at greater risk for toxicity and can trigger targeted pretreatment investigations, such as evaluation of cardiac, endocrine, gastrointestinal, or respiratory status. It may also highlight use of cy tochrome P450 3A4 (CYP3A4) enzyme inducers or inhibitors that will interact with the planned RCC treatment[6]. When toxicities arise, they should be graded accord- ing to the Common Terminology Criteria for Adverse Events (CTCAE)[7] in conjunction with guidelines for immune-related adverse events (irAEs) to help select optimal management strategies. These include treat- ment interruption, dose or schedule modification, or occasionally treatment cessation, each of which has a role to play according to the severity or “grade” of the toxicity. Early recognition and intervention aids opti- mal management of treatment-related adverse events (TRAEs). Support and education for patients, general physicians, and oncologists therefore minimizes the risks associated with these treatments. This is particu- larly important in the first few months after treatment initiation, but ongoing vigilance is required throughout, especially for CPI-induced toxicities, which can emerge late into, or even after, treatment. Toxicity of VEGFR TKIs VEGFR TK Is including a x it inib, caboza nt inib, lenvatinib, pazopanib, sorafenib, sunitinib, and tivozanib are highly effective treatments for advanced RCC, with approvals by the United States Food and Drug Administration (FDA) both as single agents and in combination with CPIs or mTOR inhibitors. Collectively, these agents have led to a marked improvement in sur vival compared with the “pre-TKI” era[8–14]. VEGFR TKIs have varying potency and selectivity for VEGFRs and other tyrosine kinase receptors including platelet-derived growth factor receptor (PDGF), MET, and c-KIT, which contributes to differences in their toxicity and clinical profiles. Most patients experience some side effects, with TRAE rates for all-grade toxicity > 98% in the registration clinical trials and grade ≥3 toxicity in 10% to 15% of patients. Dose interruptions were reported in 19% to 40% of patients, dose reductions in 14% to 46%, and treatment discontinuation in 4% to 21%. The most common TRAEs reported in registration trials are skin, gastrointestinal, stomatitis, hypertension, hematological abnormalities, fatigue, and endocrine dysfunction (Table 1). Management of VEGFR TKI–Associated Toxicities General principles of managing VEGFR TKI–induced toxicities involve supportive interventions, treatment interruption, dose reduction and, particularly with sunitinib, schedule modification, with occasional treatment discontinuation. Grade 1 and 2 toxicities can often be managed with supportive approaches in the first instance but may benefit from temporary treatment interruption. For treatment-related toxicities grade ≥ 3, treatment interruption is usually required, other than for some laboratory abnormalities. Subsequent dose reduction or schedule modification may be needed. Most VEGFR TKIs are administered on a continu- ous dosing schedule. Sunitinib, however, is routinely administered on a dosing schedule that incorporates treatment-free periods: its approved starting dose and schedule is 50 mg daily for 4 weeks followed by a 2-week treatment break (4/2). Several nonrandomized studies[15–17] and the prospective SURF study[18] have shown that the alternate schedule of 2 weeks continu- ous dosing followed by a 1-week treatment break (2/1) reduces toxicity with no apparent compromise to effi- cacy. This schedule is not recommended at initiation of sunitinib but can be a useful switch option for ther- apy management. In selected cases in clinical practice, similar dosing regimens or "drug holidays” can be used for the management of toxicity associated with other VEGFR TKIs[19,20]. Recognized guidelines for VEGFR TKI–driven toxic- ities should be followed where available. However, unlike Abbreviations CPI immune checkpoint inhibitor CTCAE Common Terminology Criteria for Adverse Event CTLA-4cytotoxic T-lymphocyte antigen 4 irAE immune-related adverse event mRCC metastatic renal cell carcinoma mTOR mammalian target of rapamycin mTORI mammalian target of rapamycin inhibitor PD-1 programmed cell death 1 receptor RCC renal cell carcinoma TRAE treatment-related adverse event VEGFR vascular endothelial growth factor receptor 485 SIUJ • Volume 3, Number 6 • November 2022 SIUJ.ORG 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES http://SIUJ.org TABLE 1. Safety outcomes reported in pivotal clinical trials of vascular endothelial growth factor receptor tyrosine kinase inhibitors in metastatic renal cell carcinoma Sunitinib first line NCT00083889 n = 375 17215529[13] Pazopanib first or second line, NCT00334282 n = 290 20100962[11] Tivozanib first or second line NCT01030783 n = 260 24019545[12] Cabozantinib first line NCT01835158 n = 78 28199818[10] Axitinib first line NCT00835978 n = 192 NCT00920816[19] Lenvatinib second line NCT01136733 n = 52 26482279[9] TRAE leading to discontinuation in % 8 NR 4 21 4 Death due to TRAE — n (%) NR 4 (1) NR 3 (4) None Adverse event in % All Grade 3/4 All Grade 3/4 All Grade 3/4 All Grade 3/4 All Grade 3/4 All Grade 3/4 Diarrhea 53 5 52 4 23 2 72 10 50 9 71 12 Fatigue 51 7 19 2 19 5 86 6 33 5 50 8 Nausea 44 3 26 < 1 12 < 1 32 3 20 1 62 8 Stomatitis 25 1 – – 11 < 1 36 5 – – 25 2 Hypertension 24 8 40 4 44 27 81 28 49 13 48 17 Vomiting 24 4 21 2 – – – – – – 38 4 Hand-foot syndrome 20 5 – – 14 2 42 8 26 7 15 0 Anorexia – – 22 2 18 3 47 5 – – 48 6 Back pain – – – – 14 3 – – 21 0 Decreased appetite – – – – 10 < 1 – – 29 2 58 4 Lower respiratory tract infection – – – – – – – – – – 8 8 Laboratory abnormality Neutropenia 72 11 34 1 11 2 15 0 – – – – Thrombocytopenia 65 8 32 1 18 < 1 40 1 – – – – Lymphopenia 60 12 31 4 – – – – – – – – Leukopenia 60 5 0 0 – – 12 0 – – – – AST increase 52 2 53 8 37 2 62 3 – – – – Increased lipase 52 13 – – 46 11 – – – – – – ALT increase 46 3 53 12 28 1 55 5 – – – – Hyponatremia – – 31 5 – – – – – – – Proteinuria 3 – – – 72 3 – – – – 31 19 Hypothyroidism – – – – – – – – – – 37 2 All adverse events grade 3 or worse that occurred in at least 5% of patients in one of the trials are reported. ALT: alanine transaminase; AST: aspartate transaminase; NR: not reported in cited publication; TRAE: treatment-related adverse event. 486SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma http://SIUJ.org for toxicities associated with immune CPIs, there are no regularly updated consensus guidelines, and recom- mendations are primarily derived from clinical exper- tise. Practical recommendations for common VEGFR TKI–associated toxicities are summarized in Table 2. A related and important point concerns hypertension as a potential biomarker for efficacy, best demonstrated with axitinib. It has been shown that blood pressure rise is somewhat correlated with axitinib serum concentra- tion and that correct axitinib dose titration, including dose increase according to its approval, is associated with improved response to treatment[19]. Toxicity of mTOR Inhibitors The mTORIs temsirolimus and everolimus are usually well tolerated, with low rates of grade 3 and 4 adverse events[21–24]. Common side effects include asthenia, stomatitis, skin rashes, pulmonary toxicity, metabolic changes particularly hyperglycemia and hyperlipidemia, TABLE 2. Management recommendations for key toxicities associated with VEGFR tyrosine kinase inhibitors Toxicity Management recommendations Hypertension Almost all patients commencing these medications experience a dose-dependent elevation in blood pressure. Pretreatment evaluation and treatment of blood pressure and cardiovascular risk essential as treatment-related reduction in LVEF correlates with baseline risk. Blood pressure should be monitored regularly with initiation of antihypertensive therapy ≥140/90 mmHg according to clinical practice guidelines. Nondihydropyridine calcium-channel blockers that inhibit CPY3A4 (verapamil, diltiazem) should be avoided[25]. Fatigue Fatigue is common and often multifactorial. Monitoring for and treatment of anemia, hypothyroidism, cardiac dysfunction, diarrhea, hypophosphatemia, and low testosterone levels in males can be of help. Dose reduction may be required if fatigue persists despite correcting these factors. Aerobic exercise reduces fatigue in fit patients. Diarrhea Dietary adjustment (BRAT diet: bananas rice, applesauce, toast) and increase in fluid intake. Loperamide or pancreatic enzyme supplementation can also be considered in specific cases. Diarrhea / Emerging data Probiotics have been shown to reduce the severity of chemotherapy-induced diarrhea; however; have not specifically been evaluated in TKI-induced diarrhea[25]. Fecal microbiota transplantation has recently shown promising results for the treatment of TKI-induced diarrhea[27]. Hand-foot syndrome Preventative advice includes avoiding unnecessary friction/removing hyperkeratosis prior to treatment and avoiding excessively hot water. For erythema (grade 1), recommend self-care plus moisturizing creams and 20% to 40% urea creams. Pain (grade 2) requires dose interruption/modification with addition of clobetasol 0.05% ointment/topical or systemic analgesia as required[28]. Other dermatologic effects including skin and hair color changes are relatively common, thus patients should be counseled accordingly. Stomatitis Stomatitis may result in a significant reduction in food intake and QOL. Good oral hygiene. Oral rinses (saline, sodium bicarbonate, or nonalcoholic mouthwash) can be used for mucosal erythema (grade 1). For grade ≥ 2 mucositis requiring dose interruption/modification; topical anesthetics, mucosal coating agents, and/or benzydamine HCl may be administered as needed for pain[29] Hypothyroidism TSH should be measured at baseline and monitored during treatment at least every 3 cycles. Replacement with thyroxine should be considered for patients with TSH above 10 IU/mL[30] LVEF: left ventricular ejection fraction; QOL: quality of life; TSH: thyroxine stimulating hormone; VEGFR: vascular endothelial growth factor receptor. 487 SIUJ • Volume 3, Number 6 • November 2022 SIUJ.ORG 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES http://SIUJ.org and infections[31]. As for VEGFR TKI–related toxicities, the general principles of managing the side effects from mTORIs are to consider treatment interruption, dose reduction, and use of supportive therapies, as well as treatment cessation for grade 3 and 4 toxicities[32]. Key recommendations are summarized in Table 3. Toxicity of Immune Checkpoint Inhibitors Immune CPIs are a well-established component of treatment for advanced renal cell carcinoma and now are also approved in the adjuvant setting[2,5,33,34]. While CPIs are well tolerated by many patients, immune checkpoint blockade is associated with a unique collection of irAEs. These irAEs behave differently than the more predictable toxicities oncologists are accustomed to managing with chemotherapy or targeted therapies, occurring any time between initiation of treatment to many months after treatment cessation. Mechanism, Spectrum, and Frequency of CPI-Associated Toxicities Mechanisms of Immune-Related Adverse Events The exact mechanisms responsible for the development of irAEs are not fully understood. The immune checkpoint proteins cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) play important roles in immune homeostasis and self- tolerance, acting to suppress T-cell function. CTLA-4 signaling reduces T-cell proliferation early in the immune response, and PD-1 signaling inhibits activated TABLE 3. Management recommendations for key toxicities of mTOR inhibitors Toxicity Management recommendations Stomatitis One of the most common TRAEs, presenting with an aphthous stomatitis different from cytotoxic induced mucositis[35,36]. Grade 1: Modified diet and alcohol-free mouthwash may alleviate symptoms. Grade ≥ 2: Treatment should be interrupted and can be restarted at full (grade 2) or reduced (grade 3) dose. Grade 4: Treatment should be discontinued permanently in most cases. Investigation to rule out herpes and fungal infection may be helpful[37]. Skin rash Usually papulopustular/maculopapular, can be pruritic. Avoid heavy sun exposure. Grade 1 (covering < 10% BSA) and grade 2 (covering > 10% to < 30% BSA) toxicity can be managed with topical moisturizers and steroids. Grade 3 toxicity (covering > 30% BSA) may require dose interruption and treatment with low-dose systemic steroids (eg, 10–20 mg prednisolone). Noninfectious pneumonitis Characterized by noninfectious, nonmalignant pulmonary inflammatory infiltrates[21,38]. If preexisting pulmonal morbidity, consider baseline LuFT. Grade 1 (radiological findings only): Clinical follow-up sufficient. Grade 2 (cough, SOB, no oxygen requirement): Workup for other causes of symptoms including chest imaging. Grade 3 (interference with ADL or oxygen requirement): Interrupt treatment and start steroids (prednisolone 0.75–1 mg/kg). Treatment can be restarted with a reduced dose. Grade 4 (life-threatening pneumonitis): Start treatment with intravenous steroids (eg, methylprednisolone 2–5 mg/kg). Discontinue treatment permanently. Workup including BAL is recommended. Endocrine: Hyperglycemia Hyperlipidemia Hypophosphatemia Common, educate patients regarding symptoms of hyperglycemia, measure and correct according to standard guidelines[39–41]. Grade 2 and 3 hyperglycemia (glucose > 8.9 mmol/L): Treat according to guidelines, focus on avoiding symptomatic hyper- and hypoglycemia. Infections Increased risk (candidiasis, pneumonia, invasive fungal infections, and infection reactivation). If high risk, hepatitis and HIV serology and prior TB exposure should be checked and active infection treated. ADLs: activities of daily living; BAL: bronchoalveolar lavage; BSA: body surface area; LuFT: lung function test; mTOR: mammalian target of rapamycin; SOB: shortness of breath; TRAEs: treatment-related adverse events. 488SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma http://SIUJ.org T cells in peripheral tissues[42]. While inhibiting these pathways enables the immune system to recognize and attack the patient’s cancer, inf lammation of normal tissues through the production of cytokines, autoreactive T cells, and autoantibodies may occur, resulting in irAEs[43,44]. Range of Immune-Related Adverse Events The spectrum of irAEs experienced depends on whether the CPI is used in combination or alone and according to the malignancy being treated, alongside yet poorly understood host factors such as an individual’s genetics, epigenetics, and microbiome. Overall, dermatological, gastrointestinal, endocrinological, musculoskeletal, and pu lmonar y irAEs are more common, w it h renal, hematological, ophthalmological, cardiac, and neurological irAEs seen more rarely[45,46]. IrAEs have a variable and wide range of onset, although typically dermatitis and colitis present early, followed by hepatitis and endocrinopathies, with pneumonitis and nephritis presenting later[47,48]. Fatal irAEs are fortunately rare, with reported rates ranging from 0.36% with anti–PD-1 antibodies to 1.23% in combination with CTLA4[49]. Given the increasing use of CPIs in the treatment of solid cancers in general, and in renal cancer in particular, an absolute increase in irAEs and also the occurrence of rare irAEs are to be expected in these patients[50]. The frequency and severity of irAEs do not appear to be dose-dependent and there is no role for dose reduction following CPI toxicity. Immune-Related Adverse Events in RCC Landmark clinical trials demonstrate that small percentages of patients experience grade 3 or 4 toxicities, with overall benefits for health-related quality of life[51-53] (Table 4). Check Mate 025 investigated nivolumab versus everolimus as second- or subsequent- line treatment in patients with advanced RCC[33], Check Mate 214 investigated the combination of nivolumab and ipilimumab versus sunitinib in the first- line treatment of patients with advanced RCC[2], and KEYNOTE-564 investigated adjuvant pembrolizumab versus placebo following nephrectomy[2]. TR AEs leading to discontinuation of CPI occurred in between 8% to 22% of patients in these trials, as outlined in Table 4. Management of CPI-Associated Toxicities General Principles for Management of Immune- Related Adverse Events The management of irAEs in patients with RCC is the same as in other solid tumors, and detailed guidelines are available from European Society for Medical Oncolog y (ESMO), American Society of Clinical Oncology (ASCO), Society for Immunotherapy of Cancer (SITC), and the National Comprehensive Cancer Network (NCCN)[46,54-56]. The guidelines have been developed based on consensus opinion from specialist physicians and oncologists, are regularly updated, and are strongly recommended to guide management of specific toxicities. The overarching principle of management is to control the inflammation that has precipitated the irAE. Management is directed by the severity of the irAE and typically involves prompt immunosuppression with corticosteroids, treatment interruption, with hospita lization and specia list management in more serious cases. Corticosteroids and Corticosteroid-Sparing Agents in Immune-Related Adverse Events In general, for CTCAE grade 1 irAEs, corticosteroids are not required, and immunotherapy may be continued[46]. For grade 2 irAEs, oral prednisone (or equivalent) may be considered, starting at 0.5–1 mg/kg daily, increasing to 2 mg/kg daily if required. For grade ≥3 irAEs, oral prednisone at 1–2 mg/kg daily, or equivalent intravenous methylprednisolone, is commenced. Immunotherapy is paused until the irAE has resolved to grade 1 or less and steroids have been weaned, usually over 4 to 6 weeks. In severe or refractory cases, or where steroid sparing is desirable, other immunomodulatory agents may be considered. These agents may have specific immune targets such as TNFα (infliximab), IL-6 (tocilizumab), or α4 integrin (vedolizumab), or be nonselective, such as mycophenolate mofetil[57]. In such cases, liaising with specialist physicians is of paramount importance. Restarting immunotherapy treatment may be consid- ered on a case-by-case basis after a grade 3 irAE, but immunotherapy is discontinued after grade 4 irAEs. Most irAEs are reversible with steroid treatment, but endocrinopathies, especially hypothyroidism and diabe- tes, may require lifelong hormone replacement, although these rarely require steroid treatment[58,59]. RCC Outcomes in Patients Who Experience Immune-Related Adverse Events Although the development of irAEs is not required to benefit from CPI, there are some data, including in RCC, to suggest that patients who experience irAEs have better outcomes, particularly with anti–PD-1 and anti– PD-L1 treatment[60-65]. High-dose steroid treatment is not thought to impact outcomes negatively, although there are conf licting reports in the literature, and patients receiving high-dose corticosteroids at baseline do appear to experience inferior outcomes[43,61] Immunosuppression with steroids may be associated with side effects including hyperglycemia, weight gain, hypertension, edema, gastritis, anxiety, adrenal insufficiency, osteoporosis, glaucoma, proximal muscle weakness, and opportunistic infections[43]. Supportive 489 SIUJ • Volume 3, Number 6 • November 2022 SIUJ.ORG 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES http://SIUJ.org TABLE 4. Safety outcomes reported in pivotal registration clinical trials of immune checkpoint inhibitors in renal cell carcinoma Nivolumab mRCC, second or later line, CheckMate 025, NCT01668784 n = 406[33] Nivolumab & ipilimumab mRCC, first line, CheckMate 214, NCT02231749, n = 547[2,52] Pembrolizumab adjuvant setting, KEYNOTE-564, NCT03142334 n = 488[5] TRAE leading to discontinuation in % 8 22 21 Death due to TRAE— n (%) None 8 (1) 2 (< 1) Toxicity in % All Grade 3/4 All Grade 3/4 All Grade 3/4 Any 79 19 93 46 79 19 Fatigue 33 2 37 4 30 1 Pruritis 14 0 28 < 1 23 < 1 Nausea 14 < 1 20 1 16 < 1 Diarrhea 12 1 27 4 25 2 Reduced appetite 12 < 1 14 1 - - Rash 10 < 1 22 1 20 1 Cough 9 0 –* – 16 0 Dyspnea 7 1 – –* – – Pneumonitis 4 1 – –* – – Hypothyroidism – – 16 < 1 21 < 1 Asthenia – – 13 1 10 < 1 Vomiting – – 11 < 1 – – Arthralgia – – – – 22 < 1 Headache – – – – 14 0 Hyperthyroidism – – – – 12 < 1 Increased creatinine – – – – 10 < 1 *While cough, dyspnea, and pneumonitis were not reported, in the combination arm of the CheckMate 214 study, 1 patient died from pneumonitis, 1 with pneumonia, 1 with immune-mediated bronchitis, and 1 with lung infection. mRCC: metastatic renal cell carcinoma; NR: not reported in paper; TRAE: treatment-related adverse event. 490SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma http://SIUJ.org therapies must therefore be considered for all patients on steroids, including gastric protection, calcium and vitamin D, and pneumocystis pneumonia prophylaxis, particularly for patients requiring a longer course. Toxicities of Combination VEGFR TKI/CPI Regimens Regimens that combine a VEGFR TKI with a CPI have become a standard of care in first-line therapy of advanced RCC due to improved cancer outcomes c omp a re d w it h T K I monot her apy[1,4 , 6 6 , 6 8]. Collectively, these regimens are regarded as having acceptable safety profiles with manageable toxicity. Given the impressive cancer control conferred by these regimens, patients are often on treatment for many months or years, thus good toxicity management is of great importance for durable good quality of life. Spectrum and Frequency of Toxicities with TKI/CPI Combination Regimens T he reg ist r at ion t r ia ls of approved T K I /CPI combinations have repor ted a variet y of safet y endpoints and toxicities, each compared with sunitinib monotherapy. Although there are differences across both the trial populations and the toxicity measures reported, the data illustrate the acceptable tolerability of each of the regimens in trial populations (Table 5). The rate of of grade ≥3 TRAEs reported with the TKI/ CPI combinations in registration studies was 57% to 72% (compared with 51% to 59% for the comparator suni- tinib in these trials). Across all trials, the most frequently occurring TRAEs were consistently hypertension, raised transaminases, and diarrhea. Discontinuation of at least one of the agents due to TRAEs occurred in 15% to 37% of patients and discontinuation of both in 3% to 13%. Management of Toxicities Associated with TKI/CPI Combination Regimens Optimal management of the toxicities from TKI/CPI combination regimens requires appreciation of the expected range of side effects of each agent. However, there is additional complexity because some toxicities may be caused by both TKIs and CPIs. This requires an approach for identifying the more likely cause. The common and serious toxicities resulting from VEGFR TKIs and CPIs are described above. Toxicity caused by VEGFR TKIs most commonly manifests in the first few weeks following treatment initiation, whereas toxicities caused by immune CPIs can start acutely or many months into treatment. However, there is considerable variation at the individual patient level, and the toxicity profiles do overlap considerably, there- fore despite best efforts, reliable attribution can be chal- lenging. Points to consider include: 1. VEGFR TKIs have considerably shorter half-lives than CPIs. Axitinib has the shortest half-life at 2.5–6 hours, those of lenvatinib and cabozantinib are 28 hours and 100–120 hours, respectively. The half-lives of both pembrolizumab and nivolumab are around 26 days. Thus, VEGFR TKI–driven toxicity, espe- cially from axitinib, typically starts to improve within a few days of treatment interruption, including when used in an axitinib plus CPI combination[69]. 2. In some cases, directed investigation may help to differentiate the cause, assess impact and sever- ity, and guide management such as sigmoidoscopy and biopsy for evaluation of colitis; assessment of the pituitary fossa by magnetic resonance imaging (MRI) for hypophysitis; and cardiac MRI to identify immune-mediated myocarditis. Toxicities should be managed in accordance with the strategies described earlier in this article, including treatment interruption, dose reduction (for TKIs but not CPIs), and treatment discontinuation when indicated. As a general principle, grade 1 and 2 toxicities may not require any intervention other than supportive therapies and monitoring. Grade 3 and higher toxicities usually require at least temporary treatment interruption. When treatment interruption of a TKI/CPI regimen is required and there is uncertainty about the cause, the following pragmatic approach is suggested: • First stop the TKI. Improvement in toxicity should be seen within a few days if the toxicity is TKI related. • If there is no improvement after 5 to 7 days, or less for axitinib, interruption of the CPI and initiation of steroids should be considered following a recognized irAE guideline. • Consider immediate interruption of both agents for severe, clinically significant toxicities. • Continue to use appropriate supportive measures according to the toxicity. • Ongoing regular assessment is required until improve- ment or resolution with vigilance for reemergence during steroid wean or following further treatment. Toxicities of Novel Therapeutic Approaches Ongoing clinical trials are investigating new agents and combinations that will require attention to their tolerability and emergent toxicities. COSMIC-313 (NCT03937219) is a fully recruited, randomized trial assessing the triplet combination of cabozantinib plus ipilimumab and nivolumab in 840 patients with intermediate- and poor-risk advanced RCC[70]. While there should be scrutiny of the tolerability of this triplet regimen, it has been successfully delivered in 491 SIUJ • Volume 3, Number 6 • November 2022 SIUJ.ORG 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES http://SIUJ.org a pan-genitourinary phase 1B trial with acceptable tolerability[71]. The hy poxia-inducible factor (HIF)-2α inhibitor belzutifan was approved by the FDA in 2021 for the treatment of von Hippel-Lindau (VHL)-associated metastatic renal cell carcinoma (mRCC)[72], and its role in sporadic mRCC is being evaluated in a phase 3 trial after promising initial results (NCT04195750)[73]. Belzutifan is relatively well tolerated, although grade ≥ 3 AEs were reported in 25% of patients and included grade ≥ 3 anemia (related to inhibition of the erythropoietin gene) a nd hy pox ia , t hu s mon itor i ng for a nd management of these toxicities is essential[72] including blood transfusion and/or the use of erythropoietin- stimulating agents[74]. Patient Selection and Toxicity Prediction Good patient selection is an important tool in ensuring the optima l ba lance of eff icacy with acceptable toxicity and quality of life. The toxicities associated with treatment of RCC are not insignificant, leading to discontinuation of VEGFR TKI therapy in 12% to 24%[75,76], combination nivolumab plus ipilimumab in 22%[2,52], and TKI/CPI combinations in 6% to11%[1,4,66,68]. Therefore, understanding predictors of toxicity is an important focus of research. Most research in this field to date has evaluated clinical and genomic predictors of toxicity to VEGFR TKI therapy with low body surface area, older age, and female gender identified as possible clinical predictors[77]. Several studies have focused on the role of single- nucleotide polymorphisms (SNPs) in genes related to pharmacodynamic properties of VEGFR TKIs[78–80]. While research has not yet yielded practice-influencing results, it is hoped that large collaborative projects such as the EuroTARGET cohort[81], incorporating analysis of genomic, transcriptomic, and clinical parameters, will produce clinically useful information. Currently, there are no defined biomarkers that predict toxicity to immune CPIs, although it is appar- ent that some patients are at greater risk of experienc- ing irAEs[45,49]. Historically, patients thought to be at higher risk for irAEs have been excluded from clini- cal trials, so data are lacking, but as real-world experi- ence grows, multidisciplinary strategies for managing such patients are evolving. Patients with chronic viral infections such as hepatitis and HIV, mild-to-moderate organ dysfunction, autoimmune disease, and even trans- plant recipients have been successfully treated with CPIs in some circumstances, although a personalized discus- sion regarding potential risks and benefits is import- ant[60]. There is growing interest in the role of the gut microbiome in modulating both the efficacy and toxic- ity of CPI therapy. In patients with advanced melanoma who received ipilimumab plus nivolumab, enrichment with Bacteroides intestinalis and Intestinibacter bartlet- tii was seen in patients who developed grade ≥3 adverse events versus those who did not[82]. Investigation of this field continues, including in mRCC. In the future, as doublet, and potentially triplet, combination regimens are increasingly used, effective strategies to manage toxicity will be needed to transfer clinical trial regimens to more diverse real-world patient populations. Genomic approaches may offer the possi- bility of refining treatment selection for patients accord- ing to expected toxicity profiles. However, at present, there are no robust or validated genomic predictors, therefore selection is reliant on traditional measures of performance status and comorbidities. Summary Toxicity management is an essential component of effective cancer control. In the past 15 years, considerable experience has been gained in the management of the side effects of molecularly targeted therapies, with strategies including dose modification, schedule modification, switching between agents, and use of supportive therapies. Immune checkpoint inhibitors are also now used widely in treatment of mRCC. This advance has necessitated RCC oncologists to develop an understanding of a new range of toxicities and become familiar with new strategies and algorithms that have evolved to manage irAEs, including use of corticosteroids and steroid-sparing agents, as well as increasing involvement of other organ- or system- specific specialists. Combination regimens of CPIs and VEGFR TKIs are now increasingly used, but careful management can balance treatment delivery with tolerable side effects. It is hoped that ongoing research will identify robust means of prospectively identifying those at increased risk for treatment-related toxicities to allow for improved therapy selection at an individual level. 492SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma http://SIUJ.org TABLE 5. Safety outcomes reported in pivotal clinical trials for the combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors in first line metastatic renal cell carcinoma and occurred in at least 15% of patients who received the VEGFR TKI / CPI combination Axitinib + pembrolizumab First line, KEYNOTE-426, NCT02853331, n = 429[4] Axitinib + avelumab First line, JAVELIN Renal-101, NCT02684006, n = 442[67] Cabozantinib + nivolumab First line, CheckMate 9ER, NCT03141177 n = 322[1] Lenvatinib + pembrolizumab First line, CLEAR, NCT02811861 n = 355[3] Treatment discontinuation for TRAE in % Both drugs Either 8 26 8 NR 3 15 13 37 Treatment-related deaths— n (%) 4 (< 1) 3 (< 1) 1 (< 1) 4 (1) Toxicity in % All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Any 96 63 100 71 100 61 100 82 Diarrhea 54 9 62 7 64 7 61 10 Hypertension 45 22 50 26 35 13 55 30 Fatigue 39 3 42 4 32 3 40 4 Hypothyroidism 35 < 1 25 < 1 34 < 1 47 1 Decreased appetite 30 3 26 2 28 2 40 4 Hand–foot syndrome 28 5 33 6 40 8 29 4 Nausea 29 1 34 1 27 1 36 3 ALT increased 27 13 17 6 28 5 12 4 AST increased 26 7 15 4 25 3 11 3 Dysphonia 25 < 1 31 1 17 < 1 30 0 Cough 21 < 1 23 < 1 17 0 20 0 Constipation 20 0 18 0 12 1 25 1 Arthralgia 18 1 20 1 18 < 1 28 1 Weight decreased 18 3 20 3 11 1 30 8 Proteinuria 18 3 – – 10 3 30 8 Dyspnea 16 2 20 3 – – 15 3 Table 5 shows the safety outcomes that were reported in the referenced pivotal trials and occurred in at least 15% of patients who received the VEGFR TKI / CPI combination. ALT: alanine transaminase; AST: aspartate transaminase; CPI: immune checkpoint inhibitor; TRAE: treatment-related adverse event; VEGFR TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor. continued on page 494 493 SIUJ • Volume 3, Number 6 • November 2022 SIUJ.ORG 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES http://SIUJ.org TABLE 5. Safety outcomes reported in pivotal clinical trials for the combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors in first line metastatic renal cell carcinoma and occurred in at least 15% of patients who received the VEGFR TKI / CPI combination Axitinib + pembrolizumab First line, KEYNOTE-426, NCT02853331, n = 429[4] Axitinib + avelumab First line, JAVELIN Renal-101, NCT02684006, n = 442[67] Cabozantinib + nivolumab First line, CheckMate 9ER, NCT03141177 n = 322[1] Lenvatinib + pembrolizumab First line, CLEAR, NCT02811861 n = 355[3] Treatment discontinuation for TRAE in % Both drugs Either 8 26 8 NR 3 15 13 37 Treatment-related deaths— n (%) 4 (< 1) 3 (< 1) 1 (< 1) 4 (1) Toxicity in % All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Stomatitis 16 1 24 2 17 3 35 2 Headache 16 1 21 < 1 16 0 23 1 Vomiting 15 < 1 18 1 17 2 26 3 Asthenia 15 3 15 3 22 < 1 22 5 Pruritis 15 < 1 14 0 19 < 1 17 < 1 Rash 14 < 1 14 1 22 2 27 4 Back pain 13 1 18 1 18 2 17 1 Mucosal inflammation 13 1 14 1 21 1 – – Pyrexia 13 0 13 0 12 1 15 1 Abdominal pain 11 1 14 1 16 2 2 2 Dysgeusia 11 < 1 13 0 24 0 12 < 1 Increased lipase – – – – 17 6 18 13 Hyponatremia – – – – 16 9 – – Increased amylase – – – – 15 3 18 9 Table 5 shows the safety outcomes that were reported in the referenced pivotal trials and occurred in at least 15% of patients who received the VEGFR TKI / CPI combination. ALT: alanine transaminase; AST: aspartate transaminase; CPI: immune checkpoint inhibitor; TRAE: treatment-related adverse event; VEGFR TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor. , Cont'd 494SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma http://SIUJ.org References 3. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med.2021 Mar 4;384(9):829–841. 4. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med.2018 Apr 5;378(14):1277–1290. 5. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med.2021 Apr 8;384(14):1289–1300. 6. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116–1127. 7. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med.2021;385(8):683–694. doi: 10.1056/NEJMoa2106391 8. Shao J, Markowitz JS, Bei D, An G. Enzyme- and transporter-mediated drug interactions with small molecule tyrosine kinase inhibitors. J Pharm Sci.2014 Dec;103(12):3810–3833. 9. Cancer Institute N. Common terminology criteria for adverse events (CTCAE) v5.0. 2017. Available at: https://www.meddra.org/. Accessed February 24, 2022. 10. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (A XIS): a randomised phase 3 t r ial. Lan cet . 2 011; 3 7 8 (9 8 0 7) :19 31–19 3 9. doi: 10.1016 / S0140-6736(11)61613-9 11. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol.2015;16(15):1473–1482. doi: 10.1016/ S1470-2045(15)00290-9 12. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol.2017 Feb 20;35(6):591–597. 13. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061–1068. 14. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol.2013 Oct 20;31(30):3791–3799. doi: 10.1200/JCO.2012.47.4940 15. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med.2007 Jan 11;356(2):115–124. doi: 10.1056/ NEJMoa065044. 16. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med.2007 Jan 11;356(2):125-34. doi: 10.1056/NEJMoa060655 17. Lee JL, Kim MK, Park I, Ahn JH, Lee DH, Ryoo HM, et al. RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial. Ann Oncol.2015;26(11):2300-2305. doi: 10.1093/annonc/mdv357 18. Chen C, Fang H, Jiao Y, Zhou Y, Guo Q, Lv Z. Clinical efficacy and complication rate of sunitinib 2/1 versus 4/2 schedule for the treatment of metastatic renal cell cancer: a systematic review and meta-analysis. Clin Genitourin Cancer.2019 Oct;17(5):319-331. doi: 10.1016/j.clgc.2019.06.002 19. Deng H, Li M, Wu Q, Wang L, Hong Z, Yi F, et al. A 2/1 sunitinib dosing schedule provides superior antitumor effectiveness and less toxicity than a 4/2 schedule for metastatic renal cell carcinoma: a systematic review and meta-analysis. Front Oncol.2020;10:313. doi: 10.3389/ fonc.2020.00313. eCollection 2020. 20. Thiery-Vuillemin A, Gravis G, Schlürmann F, Bompas E, Rolland F, Gross-Goupil M, et al. Randomized phase II study to assess the efficacy and tolerability of sunitinib by dose administration regimen in anti-angiogenic naïve patients with metastatic renal cell carcinoma (mRCC): Final analysis of SURF study. J Clin Oncol.2022 Feb 20;40(6_suppl):344–344. 21. Rini BI, Melichar B, Ueda T, Grünwald V, Fishman MN, Arranz JA, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol.2013 Nov ;14(12):1233–1242. doi: 10.1016/S1470-2045(13)70464-9 22. Sternberg CN, Motzer RJ, Hutson TE, Choueiri TK, Kollmannsberger C, Bjarnason GA, et al. COMPARZ post hoc analysis: characterizing pazopanib responders with advanced renal cell carcinoma. Clin Genitourin Cancer.2019 Dec 1;17(6):425-435.e4. 23. Rodriguez-Pascual J, Cheng E, Maroto P, Duran I. Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs.2010 Jun;21(5):478-86. doi: 10.1097/cad.0b013e32833760bf 24. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med.2007;356(22):2271-2281. doi: 10.1056/ NEJMoa066838 25. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet.2008;372(9637):449-456.doi: 10.1016/S0140-6736(08)61039-9 26. Paluri RK, Sonpavde G, Morgan C, Rojymon J, Mar AH, Gangaraju R. Renal toxicity with mammalian target of rapamycin inhibitors: A meta-analysis of randomized clinical trials. Oncol Rev.2019;13(2):455. doi: 10.4081/oncol.2019.455 495 SIUJ • Volume 3, Number 6 • November 2022 SIUJ.ORG 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES http://SIUJ.org 27. Rini BI, Melichar B, Fishman MN, Oya M, Pithavala YK, Chen Y, et al. Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma. Ann Oncol.2015;26(7):1372-1377. doi:10.1093/ ANNONC/MDV103 28. Schmidinger M. Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors. EJC Suppl.2013.11(2):172- 191. doi:10.1016/j.ejcsup.2013.07.016 29. 2Ianiro G, Rossi E, Thomas AM, Schnizari G, Masucci L, Quaranta G, et al. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat Commun.2020;11(1):4333. doi:10.1038/ s41467-020-18127-y 30. Anderson R, Jatoi A, Robert C, Wood LS, Keating KN, Lacouture ME. Search for evidence-based approaches for the prevention and palliation of hand–foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs). Oncologist.2009;14 (3):291-302. doi:10.1634/ theoncologist.2008-0237 31. Brown TJ, Gupta A. Management of cancer therapy-associated oral mucositis. JCO Oncol Pract.2020;16(3):103-109. doi:10.1200/ JOP.19.00652 32. Wolter P, Stefan C, Decallonne B, Dumez H, Bex M, Carmeliet P, et al. The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer.2008;99(3):448-454. doi:10.1038/ sj.bjc.6604497 33. Soefje SA, Karnad A, Brenner AJ. Common toxicities of mammalian target of rapamycin inhibitors. Target Oncol.2011. 6(2):125-9.doi: 10.1007/s11523-011-0174-9 34. Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer.2011 Jun;47(9):1287–1298. 35. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med.2015 Nov 5;373(19):1803–1813. doi: 10.1056/ NEJMoa1510665 36. Rini BI, Battle D, Figlin RA, George DJ, Hammers H, Hutson T, et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J Immunother Cancer.2019 Dec 20;7(1):354. doi: 10.1186/ s40425-019-0813-8 37. Grünwald V, Weikert S, Pavel ME, Hörsch D, Lüftner D, Janni W, et al. Practical management of everolimus-related toxicities in patients with advanced solid tumors. Onkologie.2013;36(5):295-302. doi:10.1159/000350625 38. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, Ouwerkerk J,Logan RM, Brakenhoff JA, et al. Oral adverse events associated with t yrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist.2012;17(1):135-144. doi:10.1634/theoncologist.2011-0111 39. Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol.2015;26 Suppl 5:v139-151.doi:10.1093/annonc/mdv202 40. Albiges L, Chamming’s F, Duclos B, Stern M, Motzer RJ, Ravaud A, et al. Incidence and management of motor inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann Oncol.2012;23(8)1943-1953. doi:10.1093/annonc/mds115 41. American Diabetes Association. Improving care and promoting health in populations: standards of medical care in diabetes−2021. Diabetes Care. 2021;44(Suppl 1):S7-S14. doi:10.2337/dc21-s001 42. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/ E AS Guidelines for the management of dyslipidaemias: ipid modification to reduce cardiovascular risk. Eur Heart J.2020;41(1):111-188. doi:10.1093/eurheartj/ehz455 43. Gaasbeek A, Meinders AE. Hypophosphatemia: an update on its etiology and treatment. Am J Med.2005;118(10):1094-1101. doi:10.1016/J.AMJMED.2005.02.014 44. Chen DS, Mellman I. Elements of cancer immunity and the cancer– immune set point. Nature.2017 Jan 18;541(7637):321-330. doi: 10.1038/nature21349 45. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med.2018 Jan 11;378(2):158–168. doi: 10.1056/NEJMra1703481 46. Khan S, Gerber DE. Autoimmunity, checkpoint inhibitor therapy and immune-related adverse events: a review. Semin Cancer Biol.2020;64:1044–1579. doi.org/10.1016/j.semcancer.2019.06.012 47. Teufel A, Zhan T, Härtel N, Bornschein J, Ebert MP, Schulte N. Mini- review management of immune related adverse events induced by immune checkpoint inhibition. Cancer Lett.2019 Aug 1;456:80-87. doi: 10.1016/j.canlet.2019.04.018 48. Puzanov I, Diab A, Abdallah K, Bingham CO, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer.2017 Nov 21;5(1): doi: 10.1186/s40425-017-0300-z 49. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019 Sep;16(9):563- 580. doi: 10.1038/s41571-019-0218-0 50. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev.2016 Mar 1;44:51–60. 51. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol.2018;4(12):1721–1728. 52. Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2(5):e192535. 496SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma http://SIUJ.org 53. Cella D, Grünwald V, Nathan P, Doan J, Dastani H, Taylor F, et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol.2016 Jul 1;17(7):994–1003. 54. Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: Extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open.2020 Nov 27;5(6): e001079. doi: 10.1136/esmoopen-2020-001079. 55. Cella D, Grünwald V, Escudier B, Hammers HJ, George S, Nathan P, et al. Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019 Feb 1;20(2):297–310. doi: 10.1016/S1470-2045(18)30778-2 56. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol.2017;28:iv119–142. 57. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins; Sherry, Anadkat M, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update. J Clin Oncol.2021;39(36):4073-4126. doi: 10.1200/ JCO.21.01440 58. Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, et al. Management of Immunotherapy-Related Toxicities, Version 1.2019. J Natl Compr Canc Netw.2019 Mar 1;17(3):255–289. doi: 10.6004/jnccn.2019.0013 59. Martins F, Sykiotis GP, Maillard M, Fraga M, Ribi C, Kuntzer T, et al. New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol.2019;20(1):e54-e64. doi: 10.1016/S1470-2045(18)30828-3 60. Haanen J, Ernstoff M, Wang Y, Menzies A, Puzanov I, Grivas P, et al. Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy. J Immunother Cancer.2020 Jun;8(1):e000604. doi: 10.1136/jitc-2020-000604 61. Rzeniewicz K, Larkin J, Menzies AM, Turajlic S. Immunotherapy use outside clinical trial populations: never say never? Ann Oncol.2021 Jul 1;32(7):866–880. doi: 10.1016/j.annonc.2021.03.199 62. Cortellini A, Buti S, Agostinelli V, Bersanelli M. A systematic review on the emerging association between the occurrence of immune-related adverse events and clinical outcomes with checkpoint inhibitors in advanced cancer patients. Semin Oncol. 2019;46:362–371. doi. org/10.1053/j.seminoncol.2019.10.003 63. Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer.2019 Nov 15;7(1):306. doi: 10.1186/s40425-019-0805-8 64. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother.2007 Nov;30(8):825–830. 65. Ishihara H, Takagi T, Kondo T, Homma C, Tachibana H, Fukuda H, et al. Clinical-kidney cancer association between immune-related adverse events and prognosis in patients with metastatic renal cell carcinoma treated with nivolumab. Urol Oncol.2019;37:355.e21–355.e29. doi: 10.1016/j.urolonc.2019.03.0032019 66. Verzoni E, Cartenì G, Cortesi E, Giannarelli D, de Giglio A, Sabbatini R, et al. Real-world efficacy and safety of nivolumab in previously- treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program. J Immunother Cancer.2019 Apr 3;7(1):99. doi: 10.1186/ s40425-019-0579-z 67. Martini DJ, Hamieh L, McKay RR, Harshman LC, Brandao R, Norton CK, et al. Durable clinical benefit in metastatic renal cell carcinoma patients who discontinue pd-1/pd-l1 therapy for immune-related adverse events. Cancer Immunol Res.2018 Apr 1;6(4):402–408. doi: 10.1158/2326-6066.CIR-17-0220 68. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med.2021 Apr 8;384(14):1289–1300. 69. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol.2020;31(8):1030-1039. doi:10.1016/J.ANNONC.2020.04.010 70. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med.2019 Mar 21;380(12):1103–1115. 71. Rini BI, Atkins MB, Choueiri TK, Thomaidou D, Rosbrook B, Thakur M, et al. Time to resolution of axitinib-related adverse events after treatment interruption in patients with advanced renal cell carcinoma. Clin Genitourin Cancer.2021 Oct 1;19(5):e306–312. 72. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma - full text view - ClinicalTrials.gov [Internet]. Available at: https://clinicaltrials.gov/ct2/show/NCT03937219 73. Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastatic urothelial carcinoma and other genitourinary tumors. J Clin Oncol. 2020;38:3672–3684. doi: 10.1200/JCO.20.01652 74. Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. Belzutifan for Renal Cell Carcinoma in von Hippel– Lindau Disease. N Engl J Med.2021 Nov 25;385(22):2036–2046. 75. Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med.2021 May 1;27(5):802–805. 76. Aapro M, Beguin Y, Bokemeyer C, Dicato M, Gascón P, Glaspy J, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol.2018;29(Suppl 4):iv96-iv110. doi: 10.1093/annonc/mdx758 497 SIUJ • Volume 3, Number 6 • November 2022 SIUJ.ORG 2022 WUOF/SIU INTERNATIONAL CONSULTATION ON UROLOGICAL DISEASES http://SIUJ.org 77. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med.2013 Aug 22;369(8):722–731. 78. Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer.2018 May 1;94:115–125. 79. van der Veldt AAM, Boven E, Helgason HH, van Wouwe M, Berkhof J, de Gast G, et al. Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer. Br J Cancer.2008 Jul 22;99(2):259–265. 80. Diekstra MHM, Swen JJ, Boven E, Castellano D, Gelderblom H, Mathijssen RHJ, et al. CYP3A5 and ABCB1 polymorphisms as predictors for sunitinib outcome in metastatic renal cell carcinoma. Eur Urol.2015 Oct 1;68(4):621–629. 81. de Velasco G, Gray KP, Hamieh L, Urun Y, Carol HA, Fay AP, et al. Pharmacogenomic markers of targeted therapy toxicity in patients with metastatic renal cell carcinoma. Eur Urol Focus.2016 Dec 15;2(6):633–639. 82. Diekstra MH, Belaustegui A, Swen JJ, Boven E, Castellano D, Gelderblom H, et al. Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma. Pharmacogenomics.2017 Jan 1;17(1):42–46. doi: 10.1038/tpj.2015.100 83. van der Zanden LFM, Vermeulen SH, Oskarsdottir A, Maurits JSF, Diekstra MHM, Ambert V, et al. Description of the EuroTARGET cohort: A European collaborative project on TArgeted therapy in renal cell cancer—GEnetic- and tumor-related biomarkers for response and toxicity. Urol Oncol.2017 Aug 1;35(8):529.e9-529.e16. 84. Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, Chen WS, Derosa L, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med.2021 Aug 1;27(8):1432–1441. ORCID iDs Kate Young: 0000-0002-9500-2046, Andreas M. Schmitt: 0000-0002-9568-8164 Deborah Mukherji: 0000-0002-0192-5828 Manuela Schmidinger: 0000-0002-2567-2749 Lisa M. Pickering: 0000-0002-7579 -340X 498SIUJ.ORG SIUJ • Volume 3, Number 6 • November 2022 Management of Toxicity and Side Effects of Systemic Therapy for Renal Cell Carcinoma https://orcid.org/0000-0002-9500-2046 http://SIUJ.org