Updates in Kidney Cancer, Diagnosis and Treatment Daniel George, MD Professor of Medicine and Surgery Director, Genitourinary Oncology Duke Cancer Institute

AJCC Staging for Renal Cell Carcinoma

NCCN. 2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed October 17, 2017.

Treatment by Stage • Stage 1, 2:

– Nephrectomy • Stage 3, Node positive:

-- S-TRAC: adjuvant sunitinib increased DSF* 1

Other adjuvant treatment strategies are under investigation2

• Stage 4: – Cytoreductive nephrectomy for patients with performance

status 0 or 1, and resectable primary tumor3 – Avoid doing nephrectomy on patients with high disease

burden, poor performance status – Systemic therapy, as per guidelines

*On 11/13/17 FDA approved sunitinib for use as an adjuvant therapy in patients with RCC who have undergone nephrectomy and are at high risk for recurrence. 1. Ravaud A, et al. N Engl J Med 2016;375:2246-2254. 2. Massari F, et al. Cancer Treat Rev. 2017 ;60:152-157. 3. Heng DY, et al. Eur Urol. 2014;66:704-710.

Study A6181109 (S-TRAC) Study Design

Enrollment Criteria • Clear cell RCC • ≥T3 and/or N+ • ECOG PS 0-2 • Lack of residual disease by BICR

Factors balanced at randomization

• UISS risk group • ECOG PS (<2 vs 2) • Country

Sunitinib 50 mg po on Schedule

4/2 for 9 cycles

Placebo

RANDOM I ZAT I ON

1:1

Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC): A Randomized Double-Blind Phase 3 Study of Adjuvant Sutent vs. Placebo in Patients at High Risk

of Recurrent RCC

BICR=Blinded Independent Central Review; ECOG=Eastern Cooperative Oncology Group; PS=Performance Status; RCC=Renal Cell Carcinoma; UISS=University of California Los Angeles Integrated Staging System

MA-4

External Data Monitoring Committee performed regular data reviews

N=600 planned N=615 enrolled

S-TRAC Primary Endpoint: Disease-Free Survival By Blinded Independent Central Review

Prop

ortio

n Di

seas

e-Fr

ee

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 1 2 3 4 5 6 7 8 9

Disease-Free Survival, Years Number at Risk Sunitinib 309 225 173 153 144 119 53 10 3 0 Placebo 306 220 181 150 135 102 37 10 2 0

a. Two-sided p-value from log-rank test stratified by UISS high-risk group

3-year DFS rate:

64.9%

59.5%

5-year DFS rate:

59.3%

51.3%

S-TRAC Overall Survival Su

rviv

al D

istr

ibut

ion

Func

tion

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 1 2 3 4 5 6 7 8 9 10

Survival Time, Years Number at Risk Sunitinib 309 278 258 236 222 205 160 82 16 1 0 Placebo 306 289 269 250 231 210 172 82 23 1 0

Data cutoff date: January 31, 2017

Sunitinib Placebo

Hazard ratio (95% CI) 0.918 (0.659, 1.279)

p-value 0.612

S-TRAC Overall Summary of Adverse Events (All Causality)a

Sunitinib N=306 n (%)

Placebo N=304 n (%)

Patients with AEs 305 (99.7) 269 (88.5) Patients with Serious AEs 67 (21.9) 52 (17.1) Patients with Grade 5 AEs 5 (1.6) 5 (1.6) Patients with Grade 3 or 4 AEs 189 (61.8) 61 (20.1) Patients temporarily discontinued due to AEs 142 (46.4) 40 (13.2) Patients dose reduced due to AEs 105 (34.3) 6 (2.0) Patients permanently discontinued due to AEs 86 (28.1) 17 (5.6)

a. Includes data collected throughout the follow-up period after last dose of study drug

S-TRAC Common Treatment-Emergent Adverse Events (TEAEs)a

Sunitinib N=306

%

Placebo N=304

% All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4

Any adverse event 99.7 48.4 12.1 88.5 15.8 3.6 Diarrhea 56.9 3.9 0 21.4 0.3 0 Palmar-Plantar Erythrodysesthesia (PPE) 50.3 15.0 1.0 10.2 0.3 0

Hypertension 36.9 7.8 0 11.8 1.0 0.3 Fatigue 36.6 4.2 0.7 24.3 1.3 0 Nausea 34.3 2.0 0 13.8 0 0 Dysgeusia 33.7 0 0 5.9 0 0 Mucosal inflammation 33.7 4.6 0 8.2 0 0 Dyspepsia 26.8 1.3 0 6.3 0 0 Stomatitis 26.5 1.6 0.7 4.3 0 0 Neutropenia 23.5 7.5 1.0 0.7 0 0 Asthenia 22.5 3.6 0 12.2 0.7 0.3 Hair color change 22.2 0 0 2.3 0 0 Thrombocytopenia 20.9 4.9 1.3 1.6 0.3 0

a. Experienced by ≥20% of patients in the sunitinib arm. PPE=Palmar-Plantar erythrodysesthesia syndrome

Summary

• Pros • Sutent decreased

recurrence by 24% • 8% greater rate of

disease-free at 5 years • Side effects are

reversible

• Cons • Side effects including

diarrhea, HTN, PPE are common

• Overall survival benefit is inconclusive

• Up to 1 year of treatment

Adverse Prognostic Factors and IMDC Risk for mRCC

• Time from initial diagnosis to initiation of therapy <1 year

• Performance status <80% (Karnofsky)

• Hgb < LLN (<12.0 g/dL) • Serum-corrected Ca >ULN

(>10.2 mg/dL) • Absolute neutrophil count

>ULN (>7 x 109/L) • Platelet count >ULN

(>4 x 106/µL)

No. of Adverse Factors

IMDC Risk Category

0 Favorable 1-2 Intermediate 3-6 Poor

IMDC = International Metastatic Renal Cell Carcinoma Database Consortium. Heng DYC, et al. J Clin Oncol. 2009;27:5794-5799. Ko JJ, et al. Lancet Oncol. 2015;16:293-300.

Case Presentation

• 65 yo man presents with cough and 10 lb weight loss. CXR reveals enlarged mediastinal adenopathy and multiple pulmonary nodules

• CT of CAP reveals a 10 cm left renal mass with retroperitoneal and mediastinal adenopathy, and multiple lung nodules up to 2 cm in size.

• A debulking nephrectomy is performed revealing clear cell RCC with sarcomatoid features, G3 with invasion through the capsule. 3 of 7 regional lymph nodes are positive for cancer (pT3,N1,Mx).

• 4 weeks following surgery restaging studies reveal increase in his lung and mediastinal nodes, an a lytic lesion in his anterolateral right 7th rib

• A CBC reveals Hgb 11.5; CMP Creatinine 1.6 otherwise WNL

11

If all of the following treatments were available to you which option would you consider next? 2017 • Sunitinib • Pazopanib • Temsirolimus • HD-IL2

2018 + • Sunitinib • Pazopanib • Cabozantinib • Nivolumab/ipilimumab* • Bevacizumab/Atezolizumab*

12 * Not yet FDA approved

Cabozantinib • Oral TKI inhibiting VEGF

receptors, MET, & AXL

• In the randomized phase 3 METEOR trial, cabozantinib improved PFS, OS, and response rate compared to everolimus

• CABOSUN evaluated cabozantinib compared to sunitinib in previously untreated poor and intermediate risk RCC patients

• Clinical Trials.gov identifier: NCT01835158

Yakes FM et al., Mol Cancer Ther, 2011 Choueiri TK et al., NEJM 2015 and Lancet Oncol 2016

mOS 21.4 mos vs. 16.5 mos HR 0.66 (95% CI 0.53-0.83) p=0.00026

CABOSUN: Study Design

Stratification: • IMDC risk group: intermediate, poor • Bone metastases: yes, no

Advanced RCC (N=150) • Clear cell component • Measurable disease • No prior systemic therapy • ECOG PS 0-2 • IMDC intermediate or poor risk groups

Cabozantinib 60 mg qd

orally (6 week cycles)

Sunitinib 50 mg qd

orally (4 weeks on/2 weeks off)

Randomization 1:1 No cross-over allowed

Tumor assessment by RECIST 1.1 every other cycle Treatment until disease progression or intolerable toxicity

Primary endpoint: PFS (investigator assessment) Secondary endpoints:

Overall survival (OS) Objective response rate (ORR) Safety

Choueiri, TK et al, ESMO Annual Congress 2017

PFS and OS per independent review committee (IRC)

All-Causality Adverse Events

Choueiri TK et al, J Clin Oncol, 2016

Bernard Escudier,1 Nizar M. Tannir,2 David F. McDermott,3 Osvaldo Arén Frontera,4 Bohuslav Melichar,5 Elizabeth R. Plimack,6 Philippe Barthelemy,7 Saby George,8 Victoria Neiman,9 Camillo Porta,10

Toni K. Choueiri,11 Thomas Powles,12 Frede Donskov,13 Pamela Salman,14 Christian K. Kollmannsberger,15 Brian Rini,16 Sabeen Mekan,17 M. Brent McHenry,17 Hans J. Hammers,18 Robert J. Motzer19

1Gustave Roussy, Villejuif, France; 2University of Texas, MD Anderson Cancer Center Hospital, Houston, TX, USA; 3Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA; 4Centro Internacional de Estudios Clinicos, Santiago, Chile; 5Palacky University, and University

Hospital Olomouc, Olomouc, Czech Republic; 6Fox Chase Cancer Center, Philadelphia, PA, USA; 7Hôpitaux Universitaires de Strasbourg, Strasbourg, France;

8Roswell Park Cancer Institute, Buffalo, NY, USA; 9Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel, and Tel Aviv University, Tel Aviv, Israel; 10IRCCS San Matteo University Hospital Foundation, Pavia, Italy; 11Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical

School, Boston, MA, USA; 12Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London, UK; 13Aarhus University Hospital, Aarhus, Denmark; 14Fundación Arturo López Pérez, Santiago, Chile; 15British Columbia Cancer

Agency, Vancouver, BC, Canada; 16Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 17Bristol-Myers Squibb, Princeton, NJ, USA; 18Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA; 19Memorial Sloan Kettering Cancer Center, New York, NY, USA

CheckMate 214: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Sunitinib for Treatment-Naïve Advanced or Metastatic Renal Cell Carcinoma, Including IMDC Risk and PD-L1 Expression Subgroups

LBA5

• Nivolumab is a PD-1 inhibitor approved for previously treated advanced (a) RCC

• Nivolumab + ipilimumab (CTLA-4 antibody) combination therapy (NIVO + IPI) has shown manageable safety and high antitumor activity in previously treated and treatment-naïve patients with aRCC in the phase Ib CheckMate 016 study1

– ORR: 40%

– Ongoing responses: 42%

– Median PFS: 7.7 months

– 2-year OS rate: 67%

Background

1. Hammers HJ et al. J Clin Oncol 2017;JCO2016721985. CTLA-4, cytotoxic T-lymphocyte antigen-4

CheckMate 214: Study design

IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; Q2W, every 2 weeks; Q3W, every 3 weeks

Treatment until progression or unacceptable

toxicity

• Treatment-naïve advanced or metastatic clear-cell RCC

• Measurable disease • KPS ≥70% • Tumor tissue

available for PD-L1 testing

Treatment Patients

Randomize 1:1

Arm A 3 mg/kg nivolumab IV +

1 mg/kg ipilimumab IV Q3W for four doses, then

3 mg/kg nivolumab IV Q2W

Arm B 50 mg sunitinib orally once

daily for 4 weeks (6-week cycles)

Stratified by • IMDC prognostic score (0 vs 1–2 vs 3–6)

•Region (US vs Canada/Europe vs Rest of World)

• In IMDC intermediate- and poor-risk patients – ORR (per independent radiology review committee, IRRC) – PFS (per IRRC) – OS

• Statistical analyses – Overall alpha is 0.05, split among the three co-primary endpoints – 0.001 for ORR, 0.009 for PFS, and 0.04 for OS – PFS analysis had ~80% power and OS analysis had 90% power to detect a statistically

significant difference between treatment arms – The number of patients randomized was estimated to be ~1,070, 820 of whom would

have IMDC intermediate/poor risk

Co-primary endpoints

Baseline characteristics IMDC intermediate/poor risk Intention to treat

Characteristic NIVO + IPI N = 425

SUN N = 422

NIVO + IPI N = 550

SUN N = 546

Median age, years 62 61 62 62

Male, % 74 71 75 72

IMDC prognostic score (IVRS), % Favorable (0) Intermediate (1–2) Poor (3–6)

0

79 21

0

79 21

23 61 17

23 61 16

Region (IVRS), % USA Canada/Europe Rest of the world

26 35 39

26 35 39

28 37 35

28 36 36

Quantifiable tumor PD-L1 expression, %

<1% ≥1%

n = 384 74 26

n = 392 71 29

n = 499 77 23

n = 503 75 25

• Baseline characteristics in favorable-risk patients were similar, except tumor PD-L1 expression was lower than the intermediate/poor-risk patients and ITT population

ORR and DOR: IMDC intermediate/poor risk

N = 847

Outcome NIVO + IPI N = 425

SUN N = 422

Confirmed ORR,a % (95% CI) 42 (37–47) 27 (22–31)

P < 0.0001 Confirmed BOR,a %

Complete response Partial response Stable disease Progressive disease Unable to determine/not reported

9b 32 31 20 8

1b

25 45 17 12

aIRRC-assessed ORR and BOR by RECIST v1.1; bP < 0.0001 SUN

NIVO + IPI No. at Risk

177 146 120 55 3

112 75 52 17 0

0 .0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .7

0 .8

0 .9

1 .0

0 6 12 18 24 Months

Dur

atio

n of

Res

pons

e (P

roba

bilit

y)

Co-primary endpoint: ORR

Median duration of response, months (95% CI)

Patients with ongoing response, %

NIVO + IPI NR (21.8–NE) 72 SUN 18.2 (14.8–NE) 63

0 3 6 9 12 15 18 21 24 27 30

PFS per IRRC: IMDC intermediate/poor risk

Hazard ratio (99.1% CI), 0.82 (0.64–1.05) P = 0.0331

Median PFS, months (95% CI)

NIVO + IPI 11.6 (8.7–15.5)

SUN 8.4 (7.0–10.8)

Prog

ress

ion-

Free

Sur

viva

l (Pr

obab

ility

)

425 304 233 187 163 149 118 46 17 3 0 422 282 191 139 107 86 57 33 11 1 0

No. at Risk NIVO + IPI

SUN

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Co-primary endpoint

OS: IMDC intermediate/poor risk

Hazard ratio (99.8% CI), 0.63 (0.44–0.89) P < 0.0001

Median OS, months (95% CI)

NIVO + IPI NR (28.2–NE)

SUN 26.0 (22.1–NE)

Ove

rall

Surv

ival

(Pro

babi

lity)

425 399 372 348 332 318 300 241 119 44 2 0 422 387 352 315 288 253 225 179 89 34 3 0

No. at Risk NIVO + IPI

SUN

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 18 21 24 27 30 33 15 12 9 6 3 0

Co-primary endpoint

Treatment-related adverse events: All treated patients NIVO + IPI

N = 547 SUN

N = 535 Event, % Any grade Grade 3–5 Any grade Grade 3–5a Treatment-related adverse events in ≥25% of patients 93 46 97 63

Fatigue 37 4 49 9 Pruritus 28 <1 9 0 Diarrhea 27 4 52 5 Nausea 20 2 38 1 Hypothyroidism 16 <1 25 <1 Decreased appetite 14 1 25 1 Dysgeusia 6 0 33 <1 Stomatitis 4 0 28 3 Hypertension 2 <1 40 16 Mucosal inflammation 2 0 28 3 Palmar-plantar erythrodysesthesia syndrome 1 0 43 9

Treatment-related AEs leading to discontinuation, % 22 15 12 7 Treatment-related deaths n = 7b n = 4c

aTwo patients had grade 5 cardiac arrest. bPneumonitis, immune mediated bronchitis, lower GI hemorrhage, hemophagocytic syndrome, sudden death, liver toxicity, lung infection. cCardiac arrest (n = 2), heart failure, multiple organ failure

Secondary endpoint

Immune-mediated adverse events: All treated patients

NIVO + IPI N = 547

Category, % Any grade Grade 3–4 Rash 17 3 Diarrhea/colitis 10 5 Hepatitis 7 6 Nephritis and renal dysfunction 5 2 Pneumonitis 4 2 Hypersensitivity/infusion reaction 1 0 Hypothyroidism 19 <1 Hyperthyroidism 12 <1 Adrenal insufficiency 8 3 Hypophysitis 5 3 Thyroiditis 3 <1 Diabetes mellitus 3 1

Immune-mediated AE analyses included events, regardless of causality, occurring <100 days of the last dose. These analyses were limited to patients who received immune modulating medication for treatment of the event, except endocrine events that were included in the analysis regardless of treatment since these events are often managed without immunosuppression

• 60% of patients treated with NIVO + IPI required systemic corticosteroids for an adverse event • Secondary immunosuppression with infliximab (3%) and mycophenolic acid (1%) was reported

So how would I treat this patient?

• Would offer Nivolumab/ipilimumab in first line setting if available and no contraindications

• Would switch to cabozantinib if either not available, not tolerable or progressive disease.

• Reasons to consider cabozantinib over nivolumab/ipilimumab –Presence of active autoimmune disease –Presence of untreated brain metastases –Symptomatic bulky tumor –Symptomatic bone metastasis

Summary

• Adjuvant sunitinib is a treatment option for motivated patients with high risk disease (Stage III or node positive)

• First-line standard of care for mRCC is changing depending on risk stratification from sunitinib or pazopanib to cabozantinib or nivolumab and ipilimumab. Other regimens with VEGFR-TKI and PD-1/PDL-1 underdevelopement

• Proactive AE management for all agents is important • Overall survival is improving for mRCC; many patients will

receive multiple agents during the course of treatment • Clinical trials are needed to define the best sequence of

treatment