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Finding the Path to Clinically Meaningful Outcomes Among Expanding Treatment Options in Renal Cell Carcinoma

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Hans Hammers, MD, PhD, Tri Le, MD, and patient Robert Wilonsky prepared useful practice aids pertaining to RCC for this CME/MOC/CNE/CPE activity titled "Finding the Path to Clinically Meaningful Outcomes Among Expanding Treatment Options in Renal Cell Carcinoma." For the full presentation, monograph, complete CME/MOC/CNE/CPE information, and to apply for credit, please visit us at https://bit.ly/3aRrKzu.CME/MOC/CNE/CPE credit will be available until June 12, 2021.

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Finding the Path to Clinically Meaningful Outcomes Among Expanding Treatment Options in Renal Cell Carcinoma

  1. 1. Access the activity, “Finding the Path to Clinically Meaningful Outcomes Among Expanding Treatment Options in Renal Cell Carcinoma,” at PeerView.com/KSB40 IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; LLN: lower limit of normal; mOS: median overall survival; MSKCC: Memorial Sloan Kettering Cancer Center; RCC: renal cell carcinoma; ULN: upper limit of normal. 1. https://www.mdcalc.com. 2. Heng DY et al. J Clin Oncol. 2009;27:5794-5799. 3. Motzer RJ et al. J Clin Oncol. 2002;20:289-296. 4. NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 2.2020. https://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. PRACTICE AID Criteria for Evaluating Risk in RCC: Risk Calculators1-4 Guidance From IMDC and MSKCC: Know Your Risk IMDC Risk Model for Metastatic RCC MSKCC Risk Model for Metastatic RCC Prognostic Factor Yes No Diagnosis to systemic treatment interval <1 y £ £ Karnofsky Performance Status <80% £ £ Hemoglobin <LLN (Normal: 120 g/L or 12 g/dL) £ £ Corrected serum calcium >ULN (Normal: 8.5-10.2 mg/dL) £ £ Neutrophils >ULN (Normal: 2.0-7.0 x 109 /L) £ £ Platelets >ULN (Normal: 150,000-400,000 cells/mcL) £ £ No. of Factors Risk Group mOS 0 Favorable 43.2 mo 1-2 Intermediate 22.5 mo 3-6 Poor 7.8 mo No. of Factors Risk Group mOS 0 Favorable 20 mo 1-2 Intermediate 10 mo 3-5 Poor 4 mo Prognostic Factor Yes No Diagnosis to systemic treatment interval <1 y £ £ Karnofsky Performance Status <80% £ £ Hemoglobin <LLN (Normal, men: 13.5-17.5 g/dL; women: 12.0-15.5 g/dL) £ £ Corrected serum calcium >10 mg/dL £ £ Lactate dehydrogenase x ULN >1.5 (Normal: 140 U/L) £ £ Calculating risk score is important for treatment decisions; multiple risk criteria are available
  2. 2. Access the activity, “Finding the Path to Clinically Meaningful Outcomes Among Expanding Treatment Options in Renal Cell Carcinoma,” at PeerView.com/KSB40 1. https://kccure.org/. 2. https://clinicaltrials.gov/ct2/show/NCT03141177. 3. https://www.urotoday.com/recent-abstracts/urologic-oncology/renal-cancer/120904-phase-3-checkmate-9er-trial- evaluating-opdivo-nivolumab-in-combination-with-cabometyx-cabozantinib-in-previously-untreated-advanced-renal-cell-carcinoma-demonstrates-positive-results.html. PRACTICE AID Kidney Cancer Resources for Patients and Caregivers Kidney Cancer Treatment Options Have you been diagnosed with metastatic or advanced kidney cancer? The US FDA has approved 14 therapies for the treatment of metastatic kidney cancer and one adjuvant therapy for high-risk localized kidney cancer following surgery. The following table lists the three combinations approved for advanced kidney cancer treatment in the frontline setting; please see this section of the website for information on all 14 options. Kidney Cancer Types This page describes the different types of kidney cancer. The most common form of cancer found in the kidney is renal cell carcinoma (RCC), but there are different subtypes. A pathologist identifies these subtypes or histologies by looking at your tumor tissue under a microscope following surgery or a biopsy. Knowing your subtype is important because it could impact decisions about surveillance and treatment. Generic Names How It Works FDA Approval Mainly Used Ipilimumab + nivolumab Dual immunotherapy: anti–CTLA-4 inhibitor/ anti–PD-1 checkpoint inhibitor; infusion In 2018, for intermediate- and high-risk metastatic RCC 1st line Pembrolizumab + axitinib Immunotherapy (anti–PD-1 checkpointinhibitor) + targeted therapy (tyrosine kinase inhibitor); infusion and oral In 2019, for metastatic RCC 1st line Avelumab + axitinib Immunotherapy (anti–PD-L1 checkpointinhibitor) + targeted therapy (tyrosine kinase inhibitor); infusion and oral In 2019, for metastatic RCC 1st line The Kidney Cancer Research Alliance (KCCure)1 provides answers to questions that patients and caregivers are asking. Wherever they are in their diagnosis, patients can visit kccure.org to find updated information on different types of kidney cancer, new treatment options, and more. Clear cell Translocation Collectingduct ~70% of RCC 3-4% of RCC <3% of RCC Papillary Unclassified Clearcellpapillary ~10-15% of RCC 3-4% of RCC <3% of RCC Chromophobe Renal medullary Cystic ~5% of RCC Rare 2.5% of RCC Stay Up to Date! CheckMate -9ER2,3 (cabozantinib + nivolumab) reported positive results; data will be out soon. CHECKMATE-214KEYNOTE-426JAVELIN101
  3. 3. Access the activity, “Finding the Path to Clinically Meaningful Outcomes Among Expanding Treatment Options in Renal Cell Carcinoma,” at PeerView.com/KSB40 PRACTICE AID Guide to Managing Adverse Events Associated With Immune Checkpoint Inhibitors and TKIs1,2 • In general, checkpoint inhibitor therapy should be continued with close monitoring, with the exception of some neurologic, hematologic, and cardiac toxicities Minimal or no symptoms; diagnostic changes only Grade 1 • Hold checkpoint inhibitor therapy for most grade 2 toxicities • Consider resuming immunotherapy when symptoms and/or laboratory values revert to grade 1 or lower • Corticosteroids (initial dose of 0.5-1 mg/kg/d of prednisone or equivalent) may be administered Grade 3 toxicities: • Hold checkpoint inhibitor therapy • Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d) • If symptoms do not improve with 48-72 hours of high-dose corticosteroids, infliximab may be offered for some toxicities • Taper corticosteroids over the course of at least 4-6 weeks • When symptoms and/or laboratory values revert to grade 1 or lower, rechallenging with immunotherapy may be offered; however, caution is advised, especially in those patients with early-onset irAEs. Dose adjustments are not recommended Grade 4 toxicities: • In general, permanent discontinuation of checkpoint inhibitor therapy is warranted, with the exception of endocrinopathies that have been controlled by hormone replacement Grade 2 Mild to moderate symptoms Severe or life-threatening symptoms Grades 3/4 Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic enhancement can also lead to a unique spectrum of immune-related adverse events (irAEs) irAEs are often diagnosed by exclusion; other causes should be ruled out (including AEs of other therapies used), but immunotherapy-related toxicity should always be included in the differential There should be a high level of suspicion that new symptoms are treatment related; early recognition, evaluation, and treatment of irAEs plus patient education are essential for best outcome Depending on severity of irAEs, management may require corticosteroid or other immunosuppressive treatment as well as interruption or discontinuation of therapy If appropriate, immunosuppressive treatment is used; patients generally recover from irAEs How should irAEs be diagnosed and managed? What are the general recommendations for management? What is the spectrum of potential irAEs? Pancreatitis, autoimmune diabetes Colitis Enteritis Encephalitis, aseptic meningitis Thyroiditis, hypothyroidism, hyperthyroidism Dry mouth, mucositis Hypophysitis Uveitis Pneumonitis Thrombocytopenia, anemia Hepatitis Adrenal insufficiency Nephritis Vasculitis Arthralgia Neuropathy Rash, vitiligo Myocarditis Any organ system can be affected; commonly occurring are pulmonary (pneumonitis), dermatologic (rash, pruritus, blisters, ulcers, vitiligo), gastrointestinal (diarrhea, enterocolitis, transaminitis, hepatitis, pancreatitis), and endocrine (thyroiditis, hypophysitis, adrenal insufficiency) irAEsWhy do irAEs occur? “Taking the brakes off” of the immune system can help the body fight cancer, but it can also lead to toxicity from a“supercharged” immune system.
  4. 4. Access the activity, “Finding the Path to Clinically Meaningful Outcomes Among Expanding Treatment Options in Renal Cell Carcinoma,” at PeerView.com/KSB40 PRACTICE AID Guide to Managing Adverse Events Associated With Immune Checkpoint Inhibitors and TKIs1,2 ADL: activities of daily living; AMS: altered mental status; HFSR: hand–foot skin reaction; IO: immunotherapy; irAE: immune-related adverse event; PRES: posterior reversible encephalopathy syndrome; TKI: tyrosine kinase inhibitors. 1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. 3. Walko CM et al. Semin Oncol. 2014;41(suppl 2):s17-s28. 4. CTCAE version 5.0. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. 5. McLellan B et al. Ann Oncol. 2015;26:2017-2026. 6. Brose MS et al. Semin Oncol. 2014;41(suppl 2):s1-s16. 7. Lacouture ME et al. Oncologist. 2008;13:1001-1011. 8. https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-kidney-cancer/119282-asco-gu-2020-toxicity-profiles- and-side-effect-management-of-first-line-treatment-options-of-renal-cell-carcinoma.html. Common adverse events associated with TKIs include diarrhea, fatigue, and hand−foot skin reaction3,4  Monitor bowel habits, and report any increase in activity above normal  Avoid spicy or fatty foods; plain, simple foods are best  Avoid fruit and caffeine  Maintain adequate fluid intake to avoid dehydration  Monitor/manage electrolytes  Loperamide is usually effective  If loperamide is ineffective, consider diphenoxylate/atropine Diarrhea4 Hand–Foot Skin Reaction5-7 For frequent, watery, bloody, or nocturnal stools, or any diarrhea or abdominal distress, patients should notify medical team immediately. Fatigue4 IO + TKI Combination Toxicities8 Educating your patients on managing fatigue is essential. Be aware of overlapping toxicities that can occur with IO + TKI combination therapy. Patient Education  Staying as active as possible helps regulate sleep  Maintain a normal work and social schedule  Take breaks as needed  Tell your medical team if activity is intolerable or fatigue worsens  Erythema with or without blisters; hyperkeratotic lesions on palms and soles  Commonly accompanied by dysesthesia (burning, pain, tingling)  Perform full-body skin examination, focusing on deformities and hyperkeratotic areas on palms and soles, before treatment initiation  Have patients remove their shoes and examine their feet during each visit  Recommend podiatrist evaluation (can help with removal of calluses and hyperkeratotic regions) and orthotist evaluation and use of orthotic devices in patients with abnormal weight bearing  During early therapy (2-4 wk), encourage rest and avoidance of vigorous exercise and traumatic activity Medical Intervention General Management Symptoms Prophylaxis Immunotherapy VEGF TKI Pruritus Pneumonitis Myocarditis Adrenal crisis Hypertension Taste changes Stomatitis Dyspepsia Cytopenias HFSR Rash Diarrhea Hepatitis Hypothyroid AMS Encephalitis PRES

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