Renal Cell Carcinoma R Pia Chowdry MD LSU

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Renal Cell Carcinoma R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018

Renal Cell Carcinoma R. Pia Chowdry, MD LSU Health Sciences Center 08/29/2018

Epidemiology Kidney & renal pelvis cancer � 3. 8% new cancer cases/year in US

Epidemiology Kidney & renal pelvis cancer � 3. 8% new cancer cases/year in US �Median age: dx = 64 death = 71 � 70% found incidentally � 30 -40% p/w or will develop mets � 2018 estimates: 65, 340 diagnosed with RCC 14, 970 will die of RCC Incidence rising 0. 7% / yr Death rate falling 0. 9% / yr since 2005…

Epidemiology continued �Risk factors: Smoking Obesity HTN Hereditary (approx. 2% of cases. VHL most

Epidemiology continued �Risk factors: Smoking Obesity HTN Hereditary (approx. 2% of cases. VHL most common) � 5 yr survival (SEER) 92. 6% localized 11. 7% advanced (7% in pre-TKI era)

Renal mass �~90% of renal tumors are RCC �Benign renal tumors Angiomyolipoma, cyst, leiomyoma

Renal mass �~90% of renal tumors are RCC �Benign renal tumors Angiomyolipoma, cyst, leiomyoma �Other malignant renal tumors Renal sarcoma or peri-renal sarcoma Lymphoma Wilms tumor Urothelial CA

Histology � 80% clear cell histology �Papillary �Chromophobe �Collecting duct / medullary assoc w/

Histology � 80% clear cell histology �Papillary �Chromophobe �Collecting duct / medullary assoc w/ SC trait �Oncocytoma (benign) �Sarcomatoid features – worse prognosis �Metastases lung, LN, bone, liver, adrenals, brain

Medscape. com

Medscape. com

PFS: Oncocytoma > Chromophobe > Type I Papillary > Type II Papillary > Clear

PFS: Oncocytoma > Chromophobe > Type I Papillary > Type II Papillary > Clear Cell Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Molecular / cytogenetic abnormalities in RCC Histology Cytogenetics Molecular Abnormality Familial Syndrome Clear Cell

Molecular / cytogenetic abnormalities in RCC Histology Cytogenetics Molecular Abnormality Familial Syndrome Clear Cell Loss of heterozygosity 3 p / mutation of 3 p 25 (VHL) 1. VHL inactivating mutation or hypermethyl 2. PBRM 1 3. SETD 2 4. BAP 1 5. TORC 1 VHL Disease Papillary +7, +17, -Y, complex cytogenetics 1. C-MET mutation (7 q 31) 2. Fumarate hydratase (1 q 42) inactivation 1. Hereditary Papillary RCC 2. Hereditary leiomyomatosis RCC Chromophobe -1, -2, -6, -10, -13, -17, - FLCN mutation 17, -21 TP 53 mutations ND 5 mutations Birt-Hogg Dube Syndrome (FLCN mutation) Oncocytoma -1, -Y, CCND 1, loss of 14 q Birt-Hogg Dube Familial Oncocytoma

Role of VHL �Tumor suppressor gene �Encodes for a protein destruction of HIF-1α �HIF

Role of VHL �Tumor suppressor gene �Encodes for a protein destruction of HIF-1α �HIF encodes for VEGF, PDGF-B �No VHL or mutated VHL HIF accumulation �Increased VEGF & PDGF �Tumor cell growth, angiogenesis �m. TOR also overactive in RCC incr HIF

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

VHL Syndrome �Von Hippel Lindau syndrome AD familial cancer syndrome Mutation in 3 p

VHL Syndrome �Von Hippel Lindau syndrome AD familial cancer syndrome Mutation in 3 p cc. RCC, retinal angiomas, spinal & cerebellar hemangioblastomas, pheo, pancr CA, renal cysts 40% will have RCC. Retinal & CNS findings precede RCC leading cause of death in VHL syndrome �Can also have sporadic defects in VHL gene Mutation Gene silencing via methylation

Birt-Hogg Dube Syndrome �Mutation in FLCN gene �Chromosome 17 �Kidney tumors (chromophobe common) �Hair

Birt-Hogg Dube Syndrome �Mutation in FLCN gene �Chromosome 17 �Kidney tumors (chromophobe common) �Hair follicle tumors �Spontaneous pneumothorax, lung cysts

Other hereditary syndromes �Hereditary Papillary RCC Papillary type 1 RCC C-Met mutations Bilateral, multifocal

Other hereditary syndromes �Hereditary Papillary RCC Papillary type 1 RCC C-Met mutations Bilateral, multifocal �Hereditary Leiomyomatosis RCC Papillary type 2 RCC Uterine leiomyomas or leiomyosarcomas Germline mutation in fumarate hydratase Solitary aggressive tumors

Presentation + workup � Painless hematuria, flank pain, +/- wt loss � Enhancing mass

Presentation + workup � Painless hematuria, flank pain, +/- wt loss � Enhancing mass on CT – classic appearance of RCC � Consider needle bx for small questionable mass � CT c/a/p +/- brain MRI for staging � Refer to Urology for resection � FDG-PET not good for RCC G 250 PET scan has high Se and Sp for cc. RCC G 250 - a MAb binds to carbonic anhydrase IX (TM protein active in hypoxia, sustains tumor growth)

RCC intratumor heterogeneity �Gerlinger et al. NEJM 2012: Multi-region gene sequencing analysis on mulitple

RCC intratumor heterogeneity �Gerlinger et al. NEJM 2012: Multi-region gene sequencing analysis on mulitple biopsy samples taken from two patients with met RCC Most mutations were not uniformly expressed at all tumor sites Some mutations were unique to a specific region Can express both favorable and unfavorable mutations in different regions of same tumor VHL found to be ubiquitous Can pose a challenge for tx response

Gerlinger et al. N Engl J Med 2012; 366: 883 -892

Gerlinger et al. N Engl J Med 2012; 366: 883 -892

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Stage I disease � Small unilateral tumors (up to 7 cm, T 1) Curative

Stage I disease � Small unilateral tumors (up to 7 cm, T 1) Curative surgery Long term complications of radical nephrectomy Partial nephrectomy (nephron-sparing surgery) ▪ Equally effective compared to radical nephrectomy in tumors < 7 cm ▪ Preferred over radical nephrectomy

Partial vs Radical nephrectomy No statistically significant differences in cancer specific survival and distant

Partial vs Radical nephrectomy No statistically significant differences in cancer specific survival and distant metastases-free survival between patients treated with NSS and RN for RCC tumors 4 -7 cm. Leibovich BC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. J Urol. 2004 Mar; 171(3): 1066 -70

Stage I �Non-surgical options: Usually for T 1 a small tumors Active surveillance Ablative

Stage I �Non-surgical options: Usually for T 1 a small tumors Active surveillance Ablative techniques (cryo, RFA) Usually for elderly, multiple co-morbidities Associated w/ increased risk of local recurrence

Stage II and III �Radical nephrectomy Preferred tx for tumors that extend to IVC

Stage II and III �Radical nephrectomy Preferred tx for tumors that extend to IVC Includes resection of perirenal fat, regional LN, and adrenalectomy Complete LN dissection is controversial ▪ Did not prolong OS in 1 prospective RCT

Predicting recurrence post-op � 20 -30% pts will relapse � Most within 3 yrs

Predicting recurrence post-op � 20 -30% pts will relapse � Most within 3 yrs � Multiple nomograms, based on size, Furhman grade, TNM stage � UCLA Integrated Staging System (UISS) � MSKCC Moetzer Criteria Lam JS, et al. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol. 2005 Aug; 174(2): 466 -72; discussion 472; quiz 801.

Adjuvant? � Almost 1/3 pts will relapse � Higher grade, T-stage more likely to

Adjuvant? � Almost 1/3 pts will relapse � Higher grade, T-stage more likely to relapse � Most common site of distant relapse lungs � Median time to relapse after surgery 1 -2 yrs � No FDA approved adjuvant tx after nephrectomy – for a long time… � S-TRAC trial

Smaldone M, et al. Adjuvant and neoadjuvant therapies in high-risk renal cell carcinoma. Hematol

Smaldone M, et al. Adjuvant and neoadjuvant therapies in high-risk renal cell carcinoma. Hematol Oncol Clin North Am. 2011 Aug; 25(4): 765 -91.

TKI adjuvant trials Pinto, A. Adjuvant Therapy for Renal Cell Carcinoma. Clin Genitourin Cancer.

TKI adjuvant trials Pinto, A. Adjuvant Therapy for Renal Cell Carcinoma. Clin Genitourin Cancer. 2014 Jun 21. pii: S 1558 -7673(14)00123 -2. doi: 10. 1016/j. clgc. 2014. 06. 012. [Epub ahead of print]

ASSURE - DFS Haas, N et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic

ASSURE - DFS Haas, N et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E 2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Onc Volume 387, Issue 10032, 2016, 2008– 2016 http: //dx. doi. org/10. 1016/S 0140 -6736(16)00559 -6 Arm 5 -yr DFS Sunitinib 53. 8% Sorafenib 52. 8% Placebo 55. 8%

ASSURE - OS Haas, N et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic

ASSURE - OS Haas, N et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E 2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet Onc Volume 387, Issue 10032, 2016, 2008– 2016 http: //dx. doi. org/10. 1016/S 0140 -6736(16)00559 -6 Arm 5 -yr OS Sunitinib 76. 9% Sorafenib 80. 7% Placebo 78. 7%

Conclusions from ASSURE �No survival benefit of sunitinib/sorafenib compared to placebo in this phase

Conclusions from ASSURE �No survival benefit of sunitinib/sorafenib compared to placebo in this phase 3 RCT �Toxicities of TKIs can lead to treatment discontinuation �Could the biology of cancer recurrence be independent of angiogenesis?

S-TRAC Trial OCT 16, 2016 RAVAUD, MOETZER ET AL. NEJM High risk – Stage

S-TRAC Trial OCT 16, 2016 RAVAUD, MOETZER ET AL. NEJM High risk – Stage III, positive LN N=615

S-TRAC DFS Arm m. DFS Sunitinib 6. 8 yrs Placebo 5. 6 yrs HR

S-TRAC DFS Arm m. DFS Sunitinib 6. 8 yrs Placebo 5. 6 yrs HR 0. 76 95% CI 0. 59 -0. 98 P = 0. 03 Ravaud A et al. N Engl J Med 2016. DOI: 10. 1056/NEJMoa 1611406

S-TRAC trial Conclusions �OS data not mature at the time of data cutoff �More

S-TRAC trial Conclusions �OS data not mature at the time of data cutoff �More grade 3 -4 adverse events in sutent arm �More dose reductions/interruptions in sutent �For pts w/ locoregional cc. RCC at high risk for recurrence s/p nephrectomy, adjuvant sutent x 1 yr led to a SS increase in m. DFS

Adjuvant Sutent �FDA approved for high risk cc. RCC following nephrectomy �Approved 11/2017 based

Adjuvant Sutent �FDA approved for high risk cc. RCC following nephrectomy �Approved 11/2017 based on S-TRAC data �NCCN cat 2 B � 50 mg daily 4 weeks on/2 weeks off x 9 cycles (~1 year)

PROTECT trial �p. T 2 or p. T 3 cc. RCC s/p nephrectomy �Adj

PROTECT trial �p. T 2 or p. T 3 cc. RCC s/p nephrectomy �Adj pazopanib vs placebo x 1 yr � 10 endpoint DFS in 600 mg arm �Starting dose of 800 mg following tx of ~400 pts was reduced to 600 mg to improve tolerability �DFS for the ITT 600 arm was not significant � 31% reduction in recurrence in ITT 800 arm Secondary endpoint

PROTECT Moetzer, et al. JCO Dec 10 2017

PROTECT Moetzer, et al. JCO Dec 10 2017

Follow-up after nephrectomy �More aggressive f/u for higher risk �H&P q 3 -6 mo

Follow-up after nephrectomy �More aggressive f/u for higher risk �H&P q 3 -6 mo x 2 -3 yrs, then annually �Baseline C/A/P scans within 3 mo s/p surgery �Higher risk disease imaging every 6 mo for at least 3 years

Advanced Stage �Mets Lung Bone Abdomen Liver Brain Adrenal

Advanced Stage �Mets Lung Bone Abdomen Liver Brain Adrenal

Stage IV Disease � Prognostic models for advanced disease: MSKCC most widely used 5

Stage IV Disease � Prognostic models for advanced disease: MSKCC most widely used 5 variables: ▪ ▪ ▪ � Interval dx to tx < 1 year KPS < 80% LDH> 1. 5 x ULN Corrected Ca >ULN Hgb < LLN # Risk factors Risk Group Median OS (months) 0 Favorable / low 29. 6 1 -2 Intermediate 13. 8 >3 Poor 4. 9 Newer models: IMDC criteria Thrombophilia Neutrophilia Mekhail TM, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005 Feb 1; 23(4): 832 -41.

Surgery for Stage IV �Cytoreductive nephrectomy shown to be beneficial before systemic therapy in

Surgery for Stage IV �Cytoreductive nephrectomy shown to be beneficial before systemic therapy in pts with (limited) metastatic disease �Ideal patient: Primary RCC + solitary metastases Solitary recurrence after prolonged DFS s/p nephrectomy Good prognostic features Good PS

SWOG 8949 – NEJM 2001 246 m. RCC pts: • Eligible for nephrectomy •

SWOG 8949 – NEJM 2001 246 m. RCC pts: • Eligible for nephrectomy • Good PS • No prior chemo R a n d o m i z e d Cytoreductive Surgery + IFN-a No surgery + IFN-a Primary Endpoint: Survival Secondary Endpoint: Response to treatment Flanigan RC, et. al. Nephrectomy Followed by Interferon Alfa-2 b Compared with Interferon Alfa-2 b Alone for Metastatic Renal. Cell Cancer. NEJM 2001 345: 1655 -1659.

SWOG 8949 - Survival among All Eligible Patients, According to Treatment-Group Assignment. Arm Median

SWOG 8949 - Survival among All Eligible Patients, According to Treatment-Group Assignment. Arm Median Survival Surgery + IFN-a 11. 1 mo IFN-a 8. 1 mo p= 0. 05 Flanigan RC et al. N Engl J Med 2001; 345: 1655 -1659.

SWOG 8949 + EORTC 30947 � Combined analysis of both trials showed median survival

SWOG 8949 + EORTC 30947 � Combined analysis of both trials showed median survival to favor surgery + IFN-a group 13. 6 vs 7. 8 mo for IFN-a alone � Ongoing trials for surgery + TKI � Keep in mind the ideal patient (low burden of mets, good PS) � Can also consider surgical metastatectomy � ‘neoadjuvant TKI’ under investigation

CARMENA trial

CARMENA trial

CARMENA �Randomized phase III trial � 450 pts w/ m. RCC (intermediate / poor

CARMENA �Randomized phase III trial � 450 pts w/ m. RCC (intermediate / poor risk) CN followed by sunitinib Sunitinib alone � 10 endpoint was OS �Sunitinib alone is non-inferior to CN + sunitinib �OS was surprisingly longer in sunitinib alone group (~18 mo) vs CN + sunitinib (~14 mo)

Other CN trials �SURTIME Surgery upfront Sunitinib followed by surgery

Other CN trials �SURTIME Surgery upfront Sunitinib followed by surgery

Systemic treatment FDA 2015 -2018: • Nivolumab • Cabozantinib • Lenvatinib + Everolimus •

Systemic treatment FDA 2015 -2018: • Nivolumab • Cabozantinib • Lenvatinib + Everolimus • Ipi +Nivo Adapted from Koletsky, A. Recent Advances in the treatment of renal cell carcinoma. New Orleans Summer Cancer Meeting, 2014.

Cytokine therapy �Prior to 2005 HD IL-2 or IFN-a �Modest clinical benefit �High toxicities

Cytokine therapy �Prior to 2005 HD IL-2 or IFN-a �Modest clinical benefit �High toxicities �Durable CR rate seen with HD IL-2

IL-2 �Major responses in 10 -15% pts with cc. RCC �Durable responses in 4

IL-2 �Major responses in 10 -15% pts with cc. RCC �Durable responses in 4 -5% pts �Better in younger, good PS patients �Higher dose more effective �Substantial toxicity requires inpatient stay �Increased vascular permeability often leading to hypotension, shock. � 4% incidence of treatment-related death

Who gets IL-2? �Younger age �Good performance status �Few medical co-morbidities �Not rapidly growing

Who gets IL-2? �Younger age �Good performance status �Few medical co-morbidities �Not rapidly growing mets �Presence of clear cell histology �Proximity to an IL-2 specialty center �Patient motivation Adapted from Koletsky, A. Recent Advances in the treatment of renal cell carcinoma. New Orleans Summer Cancer Meeting, 2014.

IFN-alpha � 10 -20% response rate �No durable response �Higher response rate in small

IFN-alpha � 10 -20% response rate �No durable response �Higher response rate in small volume disease, primarily limited to lung �IFN+IL-2 no better than IL-2 alone �Maximal response with dose 5 -20 mil units

Targeted Therapies

Targeted Therapies

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Currently approved � First line: Sunitinib Pazopanib Bevacizumab + IFN-a Sorafenib Temsirolimus (poor risk)

Currently approved � First line: Sunitinib Pazopanib Bevacizumab + IFN-a Sorafenib Temsirolimus (poor risk) Axitinib New Ipi + Nivo New cabozantinib � Second Line Everolimus Nivolumab Cabozantinib Lenvatinib + Everolimus Any 1 st line TKI choice Choosing targeted therapy tumor histology and risk stratification

Sunitinib � Multikinase inhibitor: VEGF-1, 2, 3 receptor PDGFR alpha, beta receptor C-kit FLT-3

Sunitinib � Multikinase inhibitor: VEGF-1, 2, 3 receptor PDGFR alpha, beta receptor C-kit FLT-3 RET � Inhibits angiogenesis and proliferation

Sunitinib vs IFN-alpha

Sunitinib vs IFN-alpha

Sunitinib vs IFN-a for 1 st line tx of met RCC Eligibility • Met

Sunitinib vs IFN-a for 1 st line tx of met RCC Eligibility • Met cc. RCC • Untreated • Most were favorable or intermed risk • ECOG 0 -1 N=750 R A N D O M I Z E D N=375 Sunitinib 50 mg po 4 wks on 2 wks off IFN-alpha 9 M units SQ 3 x/week Primary Endpoint: PFS Secondary Endpoint: RR, OS, Patient reported outcomes, safety

Kaplan–Meier Estimates of Progression-free Survival Arm m. PFS Sunitinib 11 mo IFN-a 5 mo

Kaplan–Meier Estimates of Progression-free Survival Arm m. PFS Sunitinib 11 mo IFN-a 5 mo Arm RR Sunitinib 31% IFN-a 6% No statistically significant difference in OS, but trend towards sunitinib 26. 4 mo vs 21. 8 mo , p=0. 051 Motzer RJ et al. N Engl J Med 2007; 356: 115 -124.

Adverse events �Grade 3 -4 in Sunitinib group: Pancytopenia Diarrhea Hand-foot syndrome HTN (presence

Adverse events �Grade 3 -4 in Sunitinib group: Pancytopenia Diarrhea Hand-foot syndrome HTN (presence of HTN good response) �Grade 3 -4 in IFN group: Flu-like symptoms

Pazopanib �Oral angiogenesis inhibitor targeting: VEGF 1 -3, PDGFR alpha & beta, c-kit.

Pazopanib �Oral angiogenesis inhibitor targeting: VEGF 1 -3, PDGFR alpha & beta, c-kit.

Pazopanib vs placebo � 435 pts w/met clear cell RCC untreated OR 1 prior

Pazopanib vs placebo � 435 pts w/met clear cell RCC untreated OR 1 prior cytokine therapy �Randomized to Pazopanib vs placebo � 10= PFS � 20= OS, RR, safety �PFS (ss): 9. 2 vs 4. 2 mo �RR: 30% vs 3 % �No ss differences in OS �Possibly related to cross over

Pazopanib vs placebo PFS Treatment naïve group 11 vs 2. 8 mo Pre-treated with

Pazopanib vs placebo PFS Treatment naïve group 11 vs 2. 8 mo Pre-treated with cytokine 7. 4 vs 4. 2 mo

Pazopanib toxicities �Diarrhea (52%) �HTN (40%) �Hair color changes (26%) �Nausea (26%) �Grade 3

Pazopanib toxicities �Diarrhea (52%) �HTN (40%) �Hair color changes (26%) �Nausea (26%) �Grade 3 hepatotoxicity AST elevated (21%) ALT elevated (30%) Must monitor LFTs while on pazopanib

Pazopanib vs Sunitinib � COMPARZ trial (NEJM 8/2013) � Non-inferiority study � 1110 pts

Pazopanib vs Sunitinib � COMPARZ trial (NEJM 8/2013) � Non-inferiority study � 1110 pts w/untreated m. RCC randomized to P or S � No ss differences in OS or PFS � S more fatigue, hand-foot, thrombocytopenia, more alterations in taste � P more LFT abnormalities � Both have similar efficacy � Results supported by smaller phase III PISCES trial � Safety profile and quality of life domains favored Pazopanib

COMPARZ – PFS Pazopanib is noninferior to Sunitinib in terms of PFS OS was

COMPARZ – PFS Pazopanib is noninferior to Sunitinib in terms of PFS OS was similar Motzer RJ et al. N Engl J Med 2013; 369: 722 -731.

Pazopanib favored Adapted from Koletsky, A. Recent Advances in the treatment of renal cell

Pazopanib favored Adapted from Koletsky, A. Recent Advances in the treatment of renal cell carcinoma. New Orleans Summer Cancer Meeting, 2014.

Bevacizumab + IFN alpha �AVOREN trial (Lancet 12/2007) � 649 pts randomized �Bev+ IFN

Bevacizumab + IFN alpha �AVOREN trial (Lancet 12/2007) � 649 pts randomized �Bev+ IFN vs placebo + IFN �PFS: 10. 2 vs 5. 4 mo �Response Rate 30. 6% vs 12. 4% �No statistically significant differences in OS 23. 3 vs 21. 3 mo �More fatigue and asthenia in Bev group �AE: HTN, proteinuria

AVOREN – OS, PFS: 10. 2 vs 5. 4 mo; HR 0. 63; p<0.

AVOREN – OS, PFS: 10. 2 vs 5. 4 mo; HR 0. 63; p<0. 001 No ss diff in OS Escudier B, et al. Bevacizumab plus interferon alfa-2 a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. The Lancet. Dec 2007 Volume 370, Issue 9605, 2008, 2103– 2111

Anti-VEGF TKI toxicities � Sunitinib / pazopanib / sorafenib / axitinib Fatigue HTN Diarrhea

Anti-VEGF TKI toxicities � Sunitinib / pazopanib / sorafenib / axitinib Fatigue HTN Diarrhea Hand-foot syndrome Thrombocytopenia Hypothyroidism CHF Hepatotoxicity Pazopanib Hair color changes Pazopanib SBP > 140 assoc w/better response to sunitinib ‘-ib’ CYP 3 A 4, watch for drug-drug interactions

Temsirolimus � m. TOR regulates micronutrients, cell growth, angiogenesis frequently activated in RCC Temsirolimus

Temsirolimus � m. TOR regulates micronutrients, cell growth, angiogenesis frequently activated in RCC Temsirolimus is m. TOR inhibitor � ARCC trial (NEJM – May 2007) � 626 previously untreated m. RCC pts w/ >3 poor prognostic factors: LDH, hgb, Ca, PS, timing <1 yr, #metastases � Randomized to Temsirolimus 25 mg IV weekly IFN-a (3 MU TIW) Both (Tem 15 mg IV weekly + 6 MU IFN TIW) � Primary endpoint = OS

ARCC - OS (Panel A) and PFS (Panel B). Pts who received temsirolimus alone

ARCC - OS (Panel A) and PFS (Panel B). Pts who received temsirolimus alone had longer OS (HR for death, 0. 73; p=0. 008) and PFS (p<0. 001) than did patients who received interferon alone Arm m. OS Tem 10. 9 mo IFN-a 7. 3 mo Both 8. 4 mo Combo arm = no better than Tem alone. Did not increase survival and was more toxic Hudes G et al. N Engl J Med 2007; 356: 2271 -2281.

ARCC – adverse events �More common in Tem arm: Rash Peripheral edema Hyperglycemia Hyperlipidemia

ARCC – adverse events �More common in Tem arm: Rash Peripheral edema Hyperglycemia Hyperlipidemia �Asthenia was more common w/ IFN �More grade 3 -4 in combo group �Tem FDA approved for 1 st line poor risk

Check. Mate 214 – Ipi/Nivo vs Sunitinib in m. RCC � 1096 pts intermediate

Check. Mate 214 – Ipi/Nivo vs Sunitinib in m. RCC � 1096 pts intermediate to poor risk Ipilimumab (1 mg/kg) + nivolumab (3 mg/kg) q 3 weeks x 4 cycles nivo maintenance q 2 wks sunitinib 50 mg - 4 wks on/2 wks off � 10 endpoint – OS, o. RR, PFS 18 mo OS 75% Ipi/Nivo vs 60% S � o. RR 42% Ipi/Nivo vs 27% S Some CR in Ipi/Nivo arm � � Similar rates of adverse events, but more discontinuations in Ipi/Nivo group

Overall Survival and Progression-free Survival among IMDC Intermediate- and Poor. Risk Patients. Ipi/Nivo now

Overall Survival and Progression-free Survival among IMDC Intermediate- and Poor. Risk Patients. Ipi/Nivo now a category 1 rec on NCCN for 1 st line treatment of m. RCC RJ Motzer et al. N Engl J Med 2018; 378: 1277 -1290.

CABO-SUN trial � Cabozantinib vs sunitinib as 1 st line tx met RCC �

CABO-SUN trial � Cabozantinib vs sunitinib as 1 st line tx met RCC � 157 intermediate or poor risk pts � randomized to either cab 60 qd or sutent 50 qd (4 on/2 off) � Primary endpoint PFS � Other endpoints o. RR, OS, safety � m. PFS 8. 2 vs 5. 6 mo � o. RR 33% vs 12% � Similar adverse events in both arms Diarrhea, fatigue, HTN, PPE � Cabozantinib 1 st line FDA approved 12/2017 Intermediate-poor risk m. RCC

Second line / subsequent therapies

Second line / subsequent therapies

Current FDA approved � First line: � Second Line Ipi/Nivo Everolimus Sunitinib Nivolumab Pazopanib

Current FDA approved � First line: � Second Line Ipi/Nivo Everolimus Sunitinib Nivolumab Pazopanib Cabozantinib Bevacizumab + IFN-a Lenvatinib + Everolimus Sorafenib (poor data for 1 st line) Any 1 st line TKI choice Temsirolimus Axitinib (traditionally 2 nd line)

Sorafenib �Inhibits VEGF, PDGFR, c-kit, FLT-3, RET �Phase III study (TARGET, NEJM 2007) showed

Sorafenib �Inhibits VEGF, PDGFR, c-kit, FLT-3, RET �Phase III study (TARGET, NEJM 2007) showed efficacy for 2 nd line (after cytokine failure) �Phase II study for 1 st line Untreated pts randomized to sorafenib vs IFN No SS difference in PFS m. PFS 5. 7 vs 5. 6 mo (HR=0. 88, p=0. 504) �Nccn category 2 a for 1 st line and second line

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

SS diff in PFS led to large crossover, therefore no initial diff in OS.

SS diff in PFS led to large crossover, therefore no initial diff in OS. However, with censoring of crossover data, there was a significant diff in OS: 17. 8 vs 14. 3 months (HR=0. 78; p=0. 0287) Side effects: grade 3 -4 hand foot, fatigue, HTN Bajorian, D. Renal cell carcinoma. GW Hematology and Medical Oncology Best Practices Course 2015

Axitinib � 2 nd gen VEGFR 1, 2 inhibitor � 2 nd line tx

Axitinib � 2 nd gen VEGFR 1, 2 inhibitor � 2 nd line tx - AXIS trial (Lancet, 2011) 723 pts who failed 1 prior tx (cytokine or sunitinib) Randomized to ▪ Axitinib 5 mg BID ▪ Sorafenib 400 mg BID PFS 6. 7 vs 4. 7 mo (HR= 0. 66, p<0. 0001) PFS favored Axitinib in both pre-treated groups No signif difference in OS HTN, fatigue, dysphonia = more in Axitinib Hand-foot, rash, alopecia, anemia = more in Sorafenib

Axitinib as first line � Phase III trial in Lancet Oncol 2013 � Newly

Axitinib as first line � Phase III trial in Lancet Oncol 2013 � Newly diagnosed, untreated � Axitinib vs Sorafenib � m. PFS 10. 1 mo vs 6. 5 mo not statistically significant Clinical activity as 1 st line with acceptable toxicity � Phase II trial in Lancet Oncol 2013 on dose titration of Axitinib (5, 7, 10 mg bid) Higher RR in dose-titrated group � Category 2 a rec on NCCN for 1 st line m. RCC

Everolimus �Oral m. TOR inhibitor � 2 nd line tx - RECORD 1 trial

Everolimus �Oral m. TOR inhibitor � 2 nd line tx - RECORD 1 trial (Lancet, 2008) �Phase III double blind RCT � 410 pts who failed TKI sunitinib or sorafenib �Randomized everolimus vs placebo � 10 endpoint PFS

RECORD-1 PFS Arm m. PFS Everolimus 4 mo Placebo 1. 9 mo HR=0. 3;

RECORD-1 PFS Arm m. PFS Everolimus 4 mo Placebo 1. 9 mo HR=0. 3; p<0. 0001 Probability for being progression-free at 6 mo 26% vs 2% Side effects: Stomatitis Rash Fatigue Pneumonitis Moetzer, et al. Lancet 2008

Cabozantinib � Targets VEGF, MET, AXL � FDA approved for medullary thyroid CA �

Cabozantinib � Targets VEGF, MET, AXL � FDA approved for medullary thyroid CA � Phase I studies for heavily pre-treated m. RCC � Phase III METEOR trial (Chouri, et al. NEJM 2015) Exelixis. com

METEOR - PFS Arm m. PFS Cabozantinib 7. 4 mo Everolimus 3. 8 mo

METEOR - PFS Arm m. PFS Cabozantinib 7. 4 mo Everolimus 3. 8 mo Final analysis showed SS increase in OS for Cabo arm. m. OS 21. 4 vs 16. 5 mo (HR=0. 66, p=0. 00026) More dose reductions in Cabo arm due to side effects: Diarrhea, hand-foot, fatigue Choueiri TK et al. N Engl J Med 2015; 373: 1814 -1823.

Lenvatinib + Everolimus �Lenvatinib –multikinase agent targeting VEGF, PDGF-α, RET, KIT receptors, and FGF

Lenvatinib + Everolimus �Lenvatinib –multikinase agent targeting VEGF, PDGF-α, RET, KIT receptors, and FGF receptor � Approved for RAI-refractory thyroid CA �Phase II small study, Moetzer et al Lancet 11/2015 �Lenvatinib vs Everolimus vs Both �PFS favored Len+Ev arm vs Ev alone �More side effects with combo arm diarrhea

Lenvatinib ± Everolimus in m. RCC: Randomized, Open-Label Phase II Study Stratified by hemoglobin

Lenvatinib ± Everolimus in m. RCC: Randomized, Open-Label Phase II Study Stratified by hemoglobin (low vs normal) and corrected serum calcium (≥ vs < 10 mg/d. L) Lenvatinib 18 mg QD + Everolimus 5 mg QD (n = 51) Measurable metastatic or advanced RCC; following progression ≤ 9 mos after 1 prior VEGF therapy (N = 153) Lenvatinib 24 mg QD (n = 52) Treated until PD or unacceptable toxicity Everolimus 10 mg QD (n = 50) � � Primary endpoint: PFS with lenvatinib ± everolimus vs everolimus alone Secondary endpoints: PFS with combination vs lenvatinib alone, ORR, OS, safety/tolerability Motzer R, et al. ASCO 2015. Abstract 4506. Reprinted with permission.

Lenvatinib ± Everolimus in m. RCC: Efficacy Response Median PFS, mos ORR, % Median

Lenvatinib ± Everolimus in m. RCC: Efficacy Response Median PFS, mos ORR, % Median OS, * mos Lenvatinib/ Everolimus (n = 51) Lenvatinib (n = 52) Everolimus (n = 50) 14. 6 HR: 0. 40; P <. 001 vs everolimus 7. 4 HR: 0. 61; P =. 048 vs everolimus 5. 5 43 27 P <. 001 vs everolimus P =. 007 vs everolimus 25. 5 HR: 0. 51; P =. 024 vs everolimus *Updated analysis. Motzer R, et al. ASCO 2015. Abstract 4506. Reprinted with permission. 19. 1 HR: 0. 68; P =. 118 vs everolimus 6 15. 4

Nivolumab �Blocks PD-1 and PDL-1 interactions, unleashing immune response �Approved for lung, melanoma, renal,

Nivolumab �Blocks PD-1 and PDL-1 interactions, unleashing immune response �Approved for lung, melanoma, renal, Hodgkins, head & neck �Checkmate 025 phase III RCT

Check. Mate 025: Phase III Study Design Pts with advanced cc. RCC, KPS ≥

Check. Mate 025: Phase III Study Design Pts with advanced cc. RCC, KPS ≥ 70%, 1 -2 previous antiangiogenic agents, progression ≤ 6 mos before enrollment (N = 803) Progressed (n = 316) Nivolumab 3 mg/kg IV Q 2 W (n = 406) Everolimus 10 mg PO QD (n = 397) Did not progress (n = 90) Progressed (n = 320) Did not progress (n = 77) Treated beyond progression (n = 153) Treated briefly beyond progression (n = 18) Not treated beyond progression (n = 145) Treated beyond progression (n = 65) Treated briefly beyond progression (n = 111) Not treated beyond progression (n = 144) Primary endpoint: OS � Secondary endpoints: ORR, safety � Subgroup analyses: efficacy, safety from baseline to first progression, at and after first progression � Escudier BJ, et al. ASCO 2016. Abstract 4509. Slide credit: clinicaloptions. com

Checkmate 025 - OS Arm m. OS Nivolumab 25 mo Everolimus 19. 6 mo

Checkmate 025 - OS Arm m. OS Nivolumab 25 mo Everolimus 19. 6 mo Nivolumab appeared to increase OS in patients treated beyond progression as well (ASCO GU 2016) More grade 3 -4 adverse events in everolimus group Motzer RJ et al. N Engl J Med 2015; 373: 1803 -1813.

Sequencing treatment

Sequencing treatment

Optimal sequencing � Pazopanib / Sunitinib / Ipi+Nivo 1 st line � Nivolumab/Cabozantinib 2

Optimal sequencing � Pazopanib / Sunitinib / Ipi+Nivo 1 st line � Nivolumab/Cabozantinib 2 nd line � Everolimus or other TKI 3 rd line � Depends on side effects, tolerability, duration of response � Concurrent use of 2 targeted agents may improve RR but w/ increased toxicities � Combination studies failed to show benefits in PFS, whereas sequential use dose improve PFS and OS

Non-clear cell RCC �Less studied, most trials were on clear cell �Clinical trial favored

Non-clear cell RCC �Less studied, most trials were on clear cell �Clinical trial favored �Start with TKI �Sunitinib & Sorafenib phase II trials �Temsirolimus ARCC trial included subset of non-clear cell pts �Everolimus phase II trials �Erlotinib Small study in papillary RCC pts 11% partial response rate

Chemotherapy in RCC �RCC resistant to chemo except sarcomatoid, medullary or collecting duct CA

Chemotherapy in RCC �RCC resistant to chemo except sarcomatoid, medullary or collecting duct CA �RCC with sarcomatoid features: Gemcitabine + Adriamycin ▪ Phase II study: ORR 16%, m. PFS 3. 5 mo, m. OS 8. 8 mo Gemcitabine + Capecitabine �Medullary CA & Collecting Duct CA Gemcitabine + Cis or Carboplatin ▪ ORR 26%, OS 10. 5 mo

Supportive Care � Bone mets occur in 30 -40% pts w/advanced RCC � Radiation

Supportive Care � Bone mets occur in 30 -40% pts w/advanced RCC � Radiation to bony mets � Zometa or Denosumab delays time to SRE � Stereotactic XRT vs surgery vs whole brain XRT for brain mets � Pts with treated brain mets may safely receive tx with multikinase inhibitors

New studies in RCC � Other immune checkpoint inhibitors: Pembrolizumab +/- TKI Atezolizumab +/-

New studies in RCC � Other immune checkpoint inhibitors: Pembrolizumab +/- TKI Atezolizumab +/- TKI Avelumab � Ixazomib - proteosome inhibitor � Crizotinib - ALK inhibitor � Tivantinib - MET inhibitor � Dovitinib – multikinase inhibitor � Foretinib - MET/VEGF inhibitor for papillary RCC

PROSPER - RCC �Phase III RCT �Perioperative Nivolumab vs observation in patients with localized

PROSPER - RCC �Phase III RCT �Perioperative Nivolumab vs observation in patients with localized RCC undergoing nephrectomy Pre-op Nivo Surgery Post-op Nivo Surgery Observation

Case � 66 yo male p/w L flank pain and hematuria x 1 mo.

Case � 66 yo male p/w L flank pain and hematuria x 1 mo. CT scan shows 7. 8 cm L renal enhancing mass, suspicious for RCC. No other distant mets or LNs. Of note, his PMHx includes Stage II cc. RCC in R kidney diagnosed in 2007 s/p radical nephrectomy. Had no e/o recurrence for past 7 years until now. He is refusing dialysis.

Neoadjuvant therapy with TKI • 12 patients were given TKI (sunitinib) before NSS •

Neoadjuvant therapy with TKI • 12 patients were given TKI (sunitinib) before NSS • Mean pretreatment tumor diameter was 7. 1 cm • All tumors shrunk after TKI. Mean reduction in max diameter of 1. 5 cm • NSS was achievable in all. • Postoperative dialysis was not required in any patients. • Final pathology revealed negative tumor margins in all • Need more randomized data

Summary � RCC is a heterogeneous disease � Angiogenesis is a key molecular target

Summary � RCC is a heterogeneous disease � Angiogenesis is a key molecular target VEGF m. TOR � NSS preferred over radial nephrectomy � Cytoreductive nephrectomy may be beneficial in stage IV � IL-2 - durable response � TKIs increase PFS � Sunitinib or Pazopanib or Ipi/nivo 1 st line � Nivolumab or cabozantinib 2 nd line (both are better than everolimus) � Limited data on non-clear cell histologies � Chemo doesn’t work