Providing Optimal Care for Patients With Advanced Renal Cell Carcinoma Using New Clinical Insights and Shared Decision Making This program is supported by educational grants from Novartis and Pfizer.

Core Faculty Thomas E. Hutson, DO, PharmD, FACP Professor of Medicine  Department of Medicine Texas A&M College of Medicine Director, GU Oncology Program Texas Oncology Baylor-Sammons Cancer Center Dallas, Texas Thomas E. Hutson, DO, PharmD, FACP, has disclosed that he has received consulting fees from Bayer, Novartis, and Pfizer; fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speakers’ bureaus) from Astellas, Bayer, Novartis, and Pfizer; and funds for research support from Novartis and Pfizer. This slide lists the faculty who were involved in the production of these slides.

Core Faculty Brian Rini, MD, FACP Staff Physician Department of Solid Tumor Oncology and Urology Cleveland Clinic Taussig Cancer Institute Professor of Medicine CCR/CWRU Lerner College of Medicine Cleveland, Ohio Brian Rini, MD, FACP, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Merck, Novartis, and Pfizer and funds for research support from Bristol-Myers Squibb, Genentech, and Pfizer. This slide lists the faculty who were involved in the production of these slides.

Agenda When is systemic therapy needed? Initial systemic therapy for advanced clear-cell RCC Subsequent systemic therapy options for advanced clear- cell RCC Management of treatment-related toxicities

Background and Treatment of mRCC ~ 61,560 new cases of kidney/renal pelvis cancers will be diagnosed in the US in 2015 with an estimated 14,080 deaths[1] ~ 75% are clear-cell RCC[2] ~ 25% to 30% of pts with RCC are diagnosed with metastatic disease[2] Before the Era of Targeted Agents Cytokine-based therapy was associated with a median PFS of 3-5 mos[3-5] and median OS of up to 17 mos[6] mRCC, metastatic renal cell carcinoma; OS, overall survival; PFS, progression-free survival. Current Situation Targeted agents have resulted in substantial improvements in treatment outcomes for pts with mRCC[5,7] Median OS of up to 29 mos with targeted therapy[8] 1. Siegel RL, et al. CA Cancer J Clin. 2015;65:5-29. 2. Motzer RJ, et al. N Engl J Med. 1996;335:865-875. 3. Rini BI, et al. J Clin Oncol. 2008;26:5422-5428. 4. Escudier B, et al. Lancet. 2007;370:2103-2111. 5. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 6. McDermott DF, et al. J Clin Oncol. 2005;23:133-141. 7. Coppin C, et al. BJU Int. 2011;108:1556-1563. 8. Motzer RJ, et al. N Engl J Med. 2013;369:722-731.

RCC Therapy: Targeting VEGF at Multiple Levels Cell stimuli (eg, growth factors) Sunitinib Sorafenib Pazopanib Axitinib Bevacizumab Temsirolimus Everolimus VEGFR VEGF PI3K Inactivated VHL tumor suppressor gene AKT VHL mTOR HIFɑ Hypoxia PDGF PDGFR Endothelial Cell HIFɑ HIFɑ Cell growth survival HIFɑ HIFɑ Tumor Adapted from Rini BI, et al. Lancet. In press.

When should you start therapy?

Poor Risk Factors in Advanced Untreated RCC: MSKCC Criteria MSKCC Criteria Risk Factors[1] KPS < 80% Time from diagnosis to treatment with IFN-α < 12 mos Hemoglobin < LLN LDH > 1.5 x ULN Corrected serum calcium > 10.0 mg/dL[2] Risk Group by No. of Risk Factors[1] Favorable Intermediate 1 or 2 Poor 3 or more IFN, interferon; KPS, Karnofsky performance status; LDH, lactate dehydrogenase; LLN, lower limit of normal; MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma; ULN, upper limit of normal; VEGF, vascular endothelial growth factor. Platelet and neutrophil counts > ULN identified as adverse prognostic factors for pts treated with VEGF-targeted therapies[3] Externally validated, concordant with other prognostic models[4] 1. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296. 2. Mekhail TM, et al. J Clin Oncol. 2005;23:832 841. 3. Heng DY, et al. J Clin Oncol. 2009;27:5794-5799. 4. Heng DY, et al. Lancet Oncol. 2013;14:141-148.

Observation Before Systemic Therapy Safe for a Subset of Pts With mRCC Phase II study of pts with mRCC and no previous systemic therapy Observation with periodic CT assessment; initiation of systemic treatment per discretion of physician and pt Unaffected by IMDC risk group (P = .57), location or number of metastases 100 Meas. burden ≤ 3.0 cm (n = 19) Meas. burden > 3.0 cm or nontarget lesions only (n = 27) 80 Median mos of observation until start of systemic therapy: 14.1 mos 60 Pts Still Under Observation (%) 40 20 P = .05 6 12 18 24 30 36 42 48 Mos From Study Entry Rini B, et al. ASCO 2014. Abstract 4520.

Window of Opportunity to Discuss Treatment Options With Pts Role of nephrectomy When to initiate therapy Treatment decisions based on: Selective efficacy Therapeutic index Response to previous therapy Potential new agents and clinical trials

Debulking Nephrectomy in mRCC Pts most likely to benefit from cytoreduction[1] include those with: Good performance status with adequate end-organ function Potentially surgically resectable primary tumor mass representing at least 75% of total tumor burden Good prognostic features No central nervous system metastases Current recommendations based on data from trials incorporating IFN alfa-2b[2] 1. NCCN. Clinical practice guidelines in oncology: kidney cancer. v.3.2015. 2. Flanigan RC, et al. J Urol. 2004;171:1071-1076.

CARMENA: Phase III Study of Sunitinib ± Nephrectomy in First-line mRCC Sunitinib 50 mg/day (schedule 4/2) Pts with mRCC and no previous treatment for kidney cancer (N = 576) RANDOM I Z A T ON Sunitinib 50 mg/day (schedule 4/2) mRCC, metastatic renal cell carcinoma; OS, overall survival; PFS, progression-free survival; Primary endpoint: OS Secondary endpoints: clinical response, PFS, compliance ClinicalTrials.gov. NCT00930033.

First-line Systemic Therapy

Current Management of Advanced RCC First-line Therapy Second-line Therapy Favorable or intermediate risk Sunitinib or pazopanib or bevacizumab + IFN* (or other TKI, HD IL-2, or temsirolimus) Everolimus or axitinib (after TKI) (or other TKI, temsirolimus, or bevacizumab) Axitinib, sorafenib, sunitinib, or pazopanib (after cytokine) (or temsirolimus or bevacizumab) Poor risk Temsirolimus or sunitinib or pazopanib Unknown (clinical trial, supportive care) HD IL-2, high-density interleukin 2; IFN, interferon; TKI, tyrosine kinase inhibitor. *Category 1 recommendations in bold. NCCN. Clinical practice guidelines in oncology: kidney cancer. v.3.2015.

Phase III COMPARZ: First-line Pazopanib vs Sunitinib for Clear-Cell mRCC Pazopanib 800 mg/day Pts with mRCC clear-cell histology and no previous systemic therapy (N = 1110) Sunitinib 50 mg/day (schedule 4/2) CT, computed tomography; mRCC, metastatic renal cell carcinoma; MRI, magnetic resonance imaging; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life. Primary endpoint: PFS Secondary endpoints: OS, ORR, time to response, safety, QoL, medical resource utilization Motzer RJ, et al. N Engl J Med. 2013;369:722-731. 15

COMPARZ: Efficacy Outcomes N Median PFS, Mos (95% CI) Pazopanib 557 8.4 (8.3-10.9) Sunitinib 553 9.5 (8.3-11.1) HR: 1.05 (95% CI: 0.90-1.22) N Median OS, Mos (95% CI) Pazopanib 557 28.3 (26.0-35.5) Sunitinib 553 29.1 (25.4-33.1) HR: 0.92 (95% CI: 0.79-1.06); P = .24 100 100 80 80 60 60 OS (%) PFS (%) 40 40 Pazopanib Sunitinib 20 20 Pazopanib Sunitinib CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. 4 8 12 16 20 24 28 32 36 40 8 16 24 32 40 48 56 64 Mos Mos Since Randomization Mean change from baseline in 11 of 14 health-related QoL during first 6 mos of treatment favored pazopanib (P < .05 for all 11 comparisons) Significantly less fatigue and foot soreness with pazopanib than with sunitinib Motzer RJ, et al. N Engl J Med. 2013;369:722-731. Motzer RJ, et al. N Engl J Med. 2014;370:1769-1770.

COMPARZ: Most Common Adverse Events (Treatment Emergent) Increased risk for sunitinib Fatigue, pyrexia Hand–foot syndrome, rash, stomatitis, mucosal inflammation, yellow skin Dysgeusia, constipation, dyspepsia, GERD Hypothyroidism, ↑ LDH, ↑ thyrotropin Pain in limb, edema, epistaxis Various laboratory abnormalities Increased risk for pazopanib Change in hair color Weight loss Alopecia ↑ AST/ALT ↑ bilirubin ↑ alkaline phosphatase Hypoglycemia AE, adverse events; ALT, alanine aminotransferase. Motzer RJ, et al. N Engl J Med. 2013;369:722-731.

PISCES Primary Endpoint: Pt Preference Primary Analysis Population 90 Difference (pazopanib vs sunitinib), % 49.3 95% CI for difference 34.7-63.8 P value < .001 80 70 60 70% 50 Pts (%) 40 30 CI, confidence interval. 20 10 22% 8% Pazopanib Preferred Sunitinib Preferred No Preference Escudier BJ, et al. J Clin Oncol. 2014;32:1412-1418.

Temsirolimus Phase III Trial in Poor-Risk RCC* IFN-α 3 MU-18 MU (n = 207) KPS 60-70 Initial diag to random < 1 yr Multiple sites of mets LDH > 1.5 x ULN Hb < LLN Ca2+ > 10 mg/dL mRCC with ≥ 3 of 6 Poor-Risk Features: Tem 25 mg QW (n = 209) IFN-α 3 MU-6 MU + Tem 15 mg QW (n = 210) 1.0 Median OS, Mos IFN-α 7.3 Tem 10.9 IFN-α + Tem 8.4 0.8 P = .008 0.6 OS (%) CR, complete response; IFN, interferon; KPS, Karnofsky Performance Scale; LDH, lactate dehydrogenase; LLN, lower limit of normal; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan Kettering Cancer Center; MU, million units; OS, overall survival; PR, partial response; QW, each week; SD, stable disease; Tem, temsirolimus; ULN, upper limit of normal. P = .70 0.4 0.2 5 10 15 20 25 30 35 Mos to Death *Modified MSKCC poor risk. Hudes G, et al. N Engl J Med. 2007;356:2271-2281. 19

What Is the Current Role of mTOR Inhibitors in mRCC? INTORSECT Trial: worse OS with temsirolimus vs sorafenib in VEGFR TKI failures[1] RECORD-3 Trial: worse PFS, OS with everolimus vs sunitinib in first-line setting[2] BEST Trial: combination approach with temsirolimus showed decreased therapeutic index[3] Most RCCs, even with VEGFR TKI resistance, are not driven by mTOR mTOR inhibitors potentially limited to pts with tumors driven by the mTOR pathway (elevated pS6, pAKT, elevated LDH, specific mutations) 1. Hutson TE, et al. J Clin Oncol. 2014;32:760-767. 2. Motzer RJ, et al. J Clin Oncol. 2014;32:2765-2772. 3. Flaherty KT, et al. J Clin Oncol. 2015;33:2384-2391.

Second-line Systemic Treatment

Continue Your Discussion With Your Pts Individualizing each pt-centered discussion is imperative Selecting therapy after disease progression based on: Response to previous therapy Pt preferences Therapeutic index of treatment options Traditional treatments New approaches

Pivotal Phase III Data in Second Line Drug Control Study Design PFS, Mos OS, Mos VEGF Inhibitors Sorafenib[1,2] Placebo Pts previously treated with IL-2 or IFN-α 5.5 vs 2.8 (HR: 0.44; P < .000001) 17.8 vs 15.2 (HR: 0.88; P = .146) 17.8 vs 14.3‡ (HR: 0.78; P = .029) Axitinib[3,4] Sorafenib Pts previously treated with sunitinib, bevacizumab with IFN-α, temsirolimus, or cytokines 8.3 vs 5.7† (HR: 0.66; P < .0001) 20.1 vs 19.2 (HR: 0.97; P = .374) mTORi Everolimus[5] Pts previously treated with VEGFR TKI 4.9 vs 1.9* (HR: 0.33; P < .001)* 5.5 vs 1.9† (HR: 0.32; P < .001)† 14.8 vs 14.4 (HR: 0.87; P = .162) Temsirolimus[6] Pts previously treated with sunitinib 4.3 vs 3.9* (HR: 0.87; P = .19) 12.3 vs 16.6† (HR: 1.31; P = .01) HR, hazard ratio; IF- or IFN- , interferon alpha; IL-2, interleukin 2; mTORi, mammalian target of rapamycin inhibitor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor *Independent review. †Investigator. ‡Post-crossover placebo-censored OS data. 1. Escudier B, et al. N Engl J Med. 2007;356:125-134. 2. Escudier B, et al. J Clin Oncol. 2009;27:3312-3318. 3. Rini BI, et al. Lancet. 2011;378:1931-1939. 4. Motzer RJ, et al. Lancet Oncol. 2013;14:552-562. 5. Motzer R, et al. Cancer. 2010;116:4256-4265. 6. Hutson TE, et al. J Clin Oncol. 2014;32:760-767.

Emerging Options in mRCC

Cabozantinib 60 mg/day* (n = 324) Phase III METEOR Trial: Cabozantinib vs Everolimus in RCC After PD on VEGFR TKI Cabozantinib 60 mg/day* (n = 324) Treat until clinical benefit no longer evident or unacceptable toxicity Patients with clear-cell RCC with measurable disease and progression within 6 mos of treatment with a VEGFR TKI, Karnofsky PS > 70% (N = 658) Everolimus 10 mg/day* (n = 324) *Dose reductions as needed for AEs: cabozantinib 40 mg then 20 mg, everolimus 5 mg then 2.5 mg AE, adverse event; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Primary endpoint: PFS Secondary endpoints: OS, ORR Choueiri T, et al. N Engl J Med. 2015;[Epub ahead of print].

Phase III METEOR: PFS of Cabozantinib vs Everolimus After VEGFR TKI Pts, n Median PFS, Mos (95% CI) Events, n 100 Cabozantinib Everolimus 187 188 7.4 (5.6-9.1) 3.8 (3.7-5.4) 121 126 80 HR: 0.58 (95% CI: 0.45-0.75); P < .001 60 PFS (%) 40 Cabozantinib PD, progressive disease; PFS, progression-free survival; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. 20 Everolimus 3 6 9 12 15 18 Mos Choueiri T, et al. N Engl J Med. 2015;[Epub ahead of print].

Phase III METEOR: Safety of Cabozantinib vs Everolimus After PD on VEGFR TKI AEs as expected and managed with dose reductions: occurred in 60% with cabozantinib, 25% with everolimus Cabozantinib Most common grade 3/4 AEs Hypertension (15%) Diarrhea (11%) Fatigue (9%) Most common leading to d/c Diarrhea (16%) Hand–foot syndrome (11%) Fatigue (10%) Everolimus Most common grade 3/4 AEs Anemia (16%) Fatigue (7%) Hyperglycemia (5%) Most common leading to d/c Pneumonitis (4%) Fatigue (3%) Stomatitis (3%) AE, adverse event; d/c, discontinuation; PD, progressive disease; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Choueiri T, et al. N Engl J Med. 2015;[Epub ahead of print].

CheckMate 025 Phase III Study: Nivolumab vs Everolimus in Advanced RCC Nivolumab 3 mg/kg q2w (n = 329) Treat until clinical benefit no longer evident or unacceptable toxicity Pts with advanced clear-cell RCC and 1-2 prior regimens with antiangiogenic treatment (N = 658) Everolimus 10 mg PO QD (n = 329) ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PO, orally; q2w, every 2 weeks; QD, once daily; RCC, renal cell carcinoma. Primary endpoint: OS Secondary endpoints: ORR, PFS, OS by PD-L1 status, safety Motzer RJ, et al. N Engl J Med. 2015;[Epub ahead of print].

CheckMate 025: Efficacy of Nivolumab vs Everolimus in Advanced RCC Pts, n Median OS, Mos (95% CI) Deaths, n Median PFS, Mos (95% CI) Progression, n Nivolumab Everolimus 410 411 25.0 (21.8-NE) 19.6 (17.6-23.1) 183 215 4.6 (3.7-5.4) 4.4 (3.7-5.5) 318 322 1.0 HR: 0.73 (98.5% CI: 0.57-0.93; P < .002) 1.0 HR: 0.88 (95% CI: 0.75-1.03; P = .11) 0.8 0.8 0.6 0.6 Probability of OS Probability of PFS 0.4 0.4 DOR, duration of response; Eve, everolimus; Nivo, nivolumab; ORR, overall response rate; OS, overall survival; PR, partial response; RCC, renal cell carcinoma. 0.2 0.2 3 6 9 12 15 18 21 24 27 30 33 3 6 9 12 15 18 21 24 27 30 33 Mos Mos Motzer RJ, et al. N Engl J Med. 2015;[Epub ahead of print].

CheckMate 025: Efficacy of Nivolumab vs Everolimus in Advanced RCC Pts, n Median OS, Mos (95% CI) Deaths, n Median PFS, Mos (95% CI) Progression, n Nivolumab Everolimus 410 411 25.0 (21.8-NE) 19.6 (17.6-23.1) 183 215 4.6 (3.7-5.4) 4.4 (3.7-5.5) 318 322 Please note that after this recording, on November 23, 2015, the FDA approved nivolumab to treat patients with mRCC whose disease has progressed while on an antiangiogenic therapy. 1.0 HR: 0.73 (98.5% CI: 0.57-0.93; P < .002) 1.0 HR: 0.88 (95% CI: 0.75-1.03; P = .11) 0.8 0.8 0.6 0.6 Probability of OS Probability of PFS 0.4 0.4 DOR, duration of response; Eve, everolimus; Nivo, nivolumab; ORR, overall response rate; OS, overall survival; PR, partial response; RCC, renal cell carcinoma. 0.2 0.2 3 6 9 12 15 18 21 24 27 30 33 3 6 9 12 15 18 21 24 27 30 33 Mos Mos Motzer RJ, et al. N Engl J Med. 2015;[Epub ahead of print].

CheckMate 025: Efficacy of Nivolumab vs Everolimus By PD-L1 Status Pts With ≥ 1% PD-L1 Expression Pts With < 1% PD-L1 Expression Pts, n Median OS, Mos (95% CI) Pts, n Median OS, Mos (95% CI) Nivolumab Everolimus 94 87 21.8 (16.5-28.1) 18.8 (11.9-19.9) Nivolumab Everolimus 276 299 27.4 (21.4-NE) 21.2 (17.7-26.2) 1.0 1.0 0.8 0.8 0.6 0.6 Probability of OS Probability of OS 0.4 0.4 0.2 0.2 HR: 0.79 (95% CI: 0.53-1.17) HR: 0.77 (95% CI: 0.60-0.97) 3 6 9 12 15 18 21 24 27 30 33 3 6 9 12 15 18 21 24 27 30 33 Mos Mos Motzer RJ, et al. N Engl J Med. 2015;[Epub ahead of print].

CheckMate 025: Safety of Nivolumab vs Everolimus After PD on VEGFR TKI Tx-related AEs of any grade: 79% with nivolumab and 88% with everolimus Tx-related AEs leading to d/c: 8% with nivolumab and 13% with everolimus Nivolumab Most common tx-related AEs Fatigue (33%) Nausea (14%) Pruritus (14%) Most common grade 3/4 AEs Fatigue (2%) Everolimus Most common tx-related AEs Fatigue (34%) Stomatitis (29%) Anemia (24%) Most common grade 3/4 AEs Anemia (8%) AE, adverse event; d/c, discontinuation; PD, progressive disease; PFS, progression-free survival; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; Tx, treatment; VEGFR, vascular endothelial growth factor receptor. Choueiri T, et al. N Engl J Med. 2015;[Epub ahead of print].

Treatment-Related Adverse Events and Their Management

Key Issues in Treatment-Related Toxicity Management in Advanced RCC Maximizing exposure to therapeutic agents correlates with improved clinical outcomes for pts with advanced RCC AEs can be associated with efficacy in mRCC; a goal of therapy should be to maintain dose and successfully manage AEs Dose reduction/discontinuation should be limited to pts with grade 3/4 AEs that do not resolve to ≤ grade 1 by withholding therapy Emergent AEs should be aggressively managed Monitor LFTs in pts receiving TKI therapy (especially pazopanib) Symptomatic management of dermatological and gastrointestinal toxicities such as rash, diarrhea, mucositis LFT, liver function test; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor.

Options for Dose Adjustments and Schedule Changes for VEGF Inhibitors Sunitinib Pazopanib Axitinib Dose adjustment: 37.5 mg/day Alternative schedule: 2 wks on/1 wk off Phase II studies on alternate schedule, dose escalation ongoing Dose adjustment: 400 mg/day Additional dose decrease or increase in 200 mg steps Dose adjustment: 3 mg BID Additional dose decrease to 2 mg BID, if necessary Conversely, dose can be increased to 7 mg in pts without AEs or HTN

Pt Education to Manage VEGF Inhibitor-Related Adverse Events Tx-Related AEs Pt Education Fatigue Plan for adequate rest Maintain optimal hydration Maintain exercise, even if minimal Skin changes* (rash, loss of pigmentation, dry skin) Instruct on varying presentations (skin yellowing: sunitinib; loss of hair pigmentation: VEGF inhibitors) Recommend emollient creams w/o fragrance, alcohol Hand–foot syndrome Instruct on aggressive, proactive hand/foot care Recommend emollient creams without fragrance or alcohol Use preventive foot care (wider shoes, gel inserts, activity planning) Hypertension* Use home BP monitoring device; instruct on use and daily BP diary Monitor accuracy of BP readings *Instruct on reporting guidelines and supply provider contact information. mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor. Esper P. Semin Oncol Nurs. 2012;28:170-179.

Pt Education to Manage mTOR Inhibitor-Related Adverse Events Tx-Related AEs Pt Education Fatigue Plan for adequate rest Maintain optimal hydration Maintain exercise, even if minimal Skin changes* (rash, dry skin, pruritis) Instruct on varying presentations Recommend emollient creams w/o fragrance, alcohol Diarrhea* Instruct on use of at-home antidiarrheal medication Instruct on dietary modifications Oral mucositis/ Stomatits* Attempt to address dentition problems before treatment Use mouth rinses Avoid irritating foods/substances (alcohol-based mouthwash) Opportunistic infections* Instruct on increased risk of infection due to immunosuppression Notify provider for new cough, increased shortness of breath, appearance of skin pustules, or temperature > 100○F *Instruct on reporting guidelines and supply provider contact information. mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor. Esper P. Semin Oncol Nurs. 2012;28:170-179.

Online Toolbox for Using SDM for Pts With Advanced RCC http://www.clinicaloptions.com/Oncology/AdvancedRCCToolbox

Patient Case Discussion: Integrating Shared Decision Making Into Care of Patients With Advanced RCC

Pt Case 1: Introduction A 51 yr old male is diagnosed with clear-cell RCC Undergoes nephrectomy Staging: grade 2, pT2, pN1 11 mos after nephrectomy, the pt presented with retroperitoneal lymph node metastases While discussing his options, the pt indicates desire to start therapy as soon as possible

Pt Case 1: MSKCC Risk Assessment LDH: Normal Hemoglobin: 14.2 g/dL Corrected calcium: normal Time from diagnosis to first treatment: < 1 yr KPS: 100 MSKCC risk: intermediate (1-2 risk factors)

Which of the following treatment choices would you recommend for this pt? Sunitinib Pazopanib Bevacizumab + IFN Everolimus Temsirolimus Clinical trial of new agents Unsure

Engaging Your Pts in Treatment Decisions Choice Talk Option Talk Decision Talk Clarify reasonable treatment options available Emphasize importance of individual preferences and the role of uncertainty “Now that you have been presented options for treatment, it is time to consider what to do next” Provide more detailed information about options Check knowledge → review options as stated by pt → provide pt decision support → summarize Value in reviewing what pt had heard, clarifying misconceptions, and restating problem Support process of deliberating on best option Discuss on preferences → obtain pt’s preference → move to a decision → offer review Move forward with treatment decision and re-evaluate at each visit SDM, shared decision making. Friesen-Storms JH, et al. Int J Nurs Stud. 2015;52:393-402.

Pt Case 1: Outcome Your pt initiates sunitinib 50 mg/day (schedule 4 wks on/2 wks off) 3 wks into therapy, he experiences grade 3 fatigue but mentions that he still wants to be aggressive in his treatment approach

Which of the following management decisions would you discourage in your clinical practice? Discontinue sunitinib and switch to another agent Hold sunitinib until fatigue lessens to grade 1 Reduce the dose of sunitinib to 37.5 mg/day Alter the schedule of sunitinib to 2 wks on/1 wk off Unsure

MSKCC risk: poor (3 or more risk factors) Pt Case 1: What If Your Pt Was Poor Risk? (same preferences and treatment goals) LDH: 2 x ULN Hemoglobin: 10 g/dL Corrected calcium: normal Time from diagnosis to first treatment: < 1 yr KPS: 70% MSKCC risk: poor (3 or more risk factors) 51-yr-old male with clear-cell RCC; 11 mos after nephrectomy, the pt presented with retroperitoneal lymph node metastases; the pt desires aggressive therapy for his cancer

Which of the following treatment choices would you recommend for this pt with poor risk features? Sunitinib Pazopanib Bevacizumab + IFN Everolimus Temsirolimus Clinical trial of new agent Unsure

Pt Case 2: Profile 78-yr-old male; ECOG PS: 1 Past medical history: gastric ulcer, lumbar hernia Diagnosed with mRCC (T1bN0M1) Sites of metastases: lung, adrenal glands, right femur, muscle Clinical symptoms: cough, shortness of breath

What next step would you recommend for this pt? Observation Debulking nephrectomy Systemic therapy Other Unsure

You discuss the available treatment options with this pt You discuss the available treatment options with this pt. All of the following statements accurately reflect the risks and benefits of the available options EXCEPT which one? The dose of pazopanib may have to be reduced for unmanageable toxicities While on pazopanib, it is important to periodically check for liver dysfunction through ongoing blood testing Hand–foot syndrome and mucositis are more common with pazopanib than with sunitinib Pazopanib may have a more tolerable adverse event profile than sunitinib The efficacy of pazopanib and sunitinib are similar Unsure

Which treatment would you recommend for this pt now? Sunitinib Pazopanib Bevacizumab + IFN Everolimus Temsirolimus Clinical trial Unsure

Supporting Self-Efficacy Can Encourage Pt Engagement and Improve Outcomes Encourage pt, caregiver to use support networks List current sources of support; consider how each source might assist with specific tasks Give knowledge/skills to mitigate stressors and decrease symptom burden Attend/join support group for RCC survivors Explain how to prepare for provider visit Encourage communication and give examples SDM, shared decision making; MM, multiple myeloma. Makoul G, et al. Patient Educ Couns. 2006;60:301-312. McCray AT. J Am Med Inform Assoc. 2005;12;152-163.

Pt Case 2: Outcomes Pt begins therapy with pazopanib 800 mg/day After 3 mos on therapy, good control of lung, adrenal, femur, and muscle metastases

Pt Case 2: Outcomes The pt experienced grade 3 fatigue and sinusitis Pazopanib dose reduced to 400 mg/day Stable disease No dyspnea No coughing

Pt Case 3: Case History A 64-yr-old male with history of metastatic RCC Pt underwent left nephrectomy and adrenalectomy Confirmed clear-cell RCC with mets in adrenal gland He presented with a recurrence of lung nodules consistent with clear-cell RCC Pt was observed due to low-volume, indolent disease, and desire to avoid toxicity Systemic therapy with sunitinib 50 mg 4/2 was initiated following continued indolent growth and increase in total tumor burden along with new paratracheal LN

Pt Case 3: Current Presentation Pt tolerated sunitinib reasonably well with fatigue and mild diarrhea After 1 yr on sunitinib, pt presented with progressive lung nodules and mediastinal LN However, your pt is concerned about possibilities for toxicity while on therapy, and is hesitant to change therapy

What would you recommend for this pt now? Continue sunitinib Change to axitinib Change to everolimus Change to temsirolimus Change to pazopanib Change to sorafenib Unsure

Pt Case 3: Second-line Therapy Your pt starts axitinib 5 mg BID Tolerates well with minimal symptoms reported BP 130/70 mm Hg at baseline; over first 4 wks of therapy no real change (120-135/70-75) Pt presents at Wk 4 and asks about escalation of axitinib dose

What would you recommend for management at this time? Continue axitinib at 5 mg BID since well tolerated and you don’t yet have CT scans to know if pt is responding Obtain a CT scan to decide if this is the right dose to shrink tumors Empirically dose escalate to 7 mg BID based on lack of BP elevation or other toxicity Measure axitinib drug level so you know if you are in the therapeutic range Unsure

Pt Case 3: Escalating Treatment Dose The dose of axitinib is empirically escalated to 7 mg BID Tolerates well with grade 1 diarrhea, grade 1 fatigue, and mildly increased soreness of feet CT scan at 8 wks reveals regression of LN

Ongoing Strategies for Pt Engagement Support health literacy using continuum-based individualized approach Provide education relevant to pt needs at each point in time Supply referrals and recommendations to vetted information sources Build trust: listen, individualize pt engagement strategies at each point in care, provide reassurance at each step SDM, shared decision making; MM, multiple myeloma. Makoul G, et al. Patient Educ Couns. 2006;60:301-312. McCray AT. J Am Med Inform Assoc. 2005;12;152-163.

Summary Pazopanib and sunitinib remain first-line VEGFR TKIs of choice; axitinib is preferred second-line treatment in pts who experience some benefit from first-line therapy Ongoing clinical trials show promising new treatment approaches for mRCC Combination approaches New agents (targeted agents, immune checkpoint inhibitors) In the future, threshold for stopping therapy may be lowered (any toxicity, stable disease at first scan) to proceed to newer agents

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