Metastatic Kidney Cancer 2017: New Concepts, New Ideas ...cagpo-annual-conference.ca/documents/435/files/KAPOOR, ANIL.pdf · Metastatic Kidney Cancer 2017: New Concepts, New Ideas,

Metastatic Kidney Cancer 2017:

New Concepts, New Ideas, New Hope

Anil Kapoor, MD

Professor of Surgery (Urology) and Oncology

McMaster University

Head, Genito-Urinary Oncology Program

Juravinski Cancer Centre, Hamilton

Chair, Kidney Cancer Research Network of Canada

Disclosures

Type Company

ConsultingPfizer, Novartis, Amgen, Janssen

Astellas, Bristol-Myers-Squibb

Honoraria Novartis, Pfizer

Research Pfizer, Bristol-Myers-Squibb

Topics

Category Description

1st-Line What is the optimal 1st-line therapy for mRCC?

2nd-Line What is the optimal 2nd-line therapy for mRCC?

Non-clear cellWhat are emerging treatments and strategies for non-clear

cell disease?

Adjuvant What are some emerging strategies for adjuvant treatment?

Surgical What is the status of cytoreductive nephrectomy?

Topics





cell disease?



o >500 patients with mRCC treated with VEGF-targeted therapy: Sunitinib (61%); sorafenib (31%); bevacizumab (8%)

Heng DY, et al. J Clin Oncol. 2009;27:5794-5799. Heng DY, et al. Lancet Oncol. 2013;14:141-148.

Risk stratification for first-line therapy in mRCC: IMDC Criteria

IMDC Criteria Risk Factors[1]

KPS < 80%

Time from diagnosis < 12 mos

Hemoglobin < LLN

Neutrophil count >ULN

Platelet count >ULN

Corrected serum calcium

>ULN

Risk Group by No. of Risk Factors[1]

Favorable (n=133) 0

Intermediate (n=301)

1-2

Poor (n=152) 3 -6

Favorable 43 mons

Intermediate 23 mons

Poor 8 mons

Category 1

Sunitinib

(Temsirolimus)

Bev+ IFNa

Pazopanib

VEGFR-directed TKI are the standard of care for first-line treatment of mRCC in

2017

Comparative Data: COMPARZ

Motzer RJ et al. N Engl J Med. 2013;369:722-731.

KPS, Karnofsky performance status; QoL, quality of life.

Eligibility Criteria

• aRCC or mRCC with

clear cell histology

• Measurable disease

• No prior systemic treatment

• KPS ≥70

Pazopanib

800 mg/day

Sunitinib 50 mg/day

(schedule 4/2)

Primary endpoint: PFS for non-inferiority (independent review)

Secondary endpoints: OS, ORR, PRO, safety, QoL, and

medical resource utilization

N = 1110

R

A

N

D

O

M

I

S

E

n = 553

n = 557



PFS non-inferiority demonstrated if upper bound of 95% CI for HR <1.25

0 4 8 12 16 20 24 28 32 36

0

0.2

0.4

0.6

0.8

1.0

40

Pazopanib (n = 557) 8.4 months (8.3-10.9) 10.5 months (8.3-11.1)

Sunitinib (n = 553) 9.5 months (8.3-11.1) 10.2 months (8.3-11.1)

HR, 1.05 HR, 1.00

(95% CI, 0.90-1.22) (95% CI, 0.86-1.15)

PFS Assessment

Independent Investigator

Months

PF

S p

robabili

ty

*Per protocol population was consistent with the intent to treat (ITT population)



Pazopanib (n=554), % Sunitinib (n=548), %

All grades Grade 3/4 All grades Grade 3/4

Any event* >99 59 / 15 >99 57 / 17

Diarrhoea 63 9 / 0 57 7 / <1

Fatigue 55 10 / <1 63 17 / <1

Thrombocytopaenia 41 3 / <1 78 6 / 0

Hypertension 46 15 / <1 41 15 / <1

Nausea 45 2 / 0 46 2 / 0

Decreased appetite 37 1 / 0 37 3 / 0

ALT increased 31 10 / 2 18 2 / <1

Hair colour changes 30 0 / 0 10 <1 / 0

Hand−foot syndrome 29 6 / 0 50 11 / <1

Taste alteration 26 <1 / 0 36 0 / 0

Comparative Data: PISCES

Escudier B et al. J Clin Oncol. 2014;32:1412-1418.

2-week washout Period 2Period 1

Off study

Randomisation

N = 169 Sunitinib 50 mg QD 4 weeks on, 2 weeks off

10 weeks

Pazopanib 800 mg QD continual dosing

10 weeks

Time, weeks

0 12 2210

Double-blind

Sunitinib 50 mg QD4 weeks on, 2 weeks off

10 weeks

Pazopanib 800 mg QD continual dosing

10 weeks

1:1Patient choiceof treatment

to progression

Comparative Data: PISCES

Escudier B et al. J Clin Oncol. 2014;32:1412-1418.

Patients were still blind to the results of their disease assessment when they stated their

preference

Pa

tie

nts

, %

P < 0.001

70% 22%

8%

“Now that you have completed both

treatments, which of the two drugs

would you prefer to continue to take as

treatment for your cancer, assuming

that both drugs work equally well?”

0

10

20

30

40

50

60

70

80

90

100

Preferred pazopanib Preferred sunitinib No preference

Comparative Data: IMDC (Real World Data)

Ruiz-Morales JM et al. BJU Int. 2015. doi: 10.1111/bju.13365.

Overa

ll surv

ival (O

S)

Time starting from treatment in months

Sunitinib n=3226; 20.1 months (18.76 – 21.42) n=3226

Pazopanib n=380; 23.68 months (19.54 – 28.81) n=380

HR 0.95 adjusted for 6 prognostic factors; p = 0.19

Overall survival of first-line Sunitinib vs. Pazopanib

1.00

0.75

0.50

0.25

0.00

0 20 40 60 80 100 120 140

Immunotherapy Combinations in 1st-Line

Control Comparator

Sunitinib Axitinib + Avelumab

Sunitinib Bevacizumab + Atezolizumab

Sunitinib Nivolumab + Ipilimumab

Sunitinib Sunitinib + AGS-003

Given CABOSUN results, is sunitinib the right

comparator?

Randomized Phase II Assessment of Front-Line Cabozantinib

Choueiri TK et al:CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with

metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups (ESMO 2016)







Cabozantinib Sunitinib

(N=79) (N=78)

Objective response rate, n (%) 36 (46%) 14 (18%)

95% CI (%) 34%-57% 10%-28%

Best overall response, n

Complete response 1 1

Partial response 35 13

Stable disease 26 28

Progressive disease 14 20

Not evaluable or missing* 3 16

*No post-baseline imaging performed for the following reasons:

Cabozantinib: clinical progression (1), withdrew consent (1), initiation of alternative therapy (1)

Sunitinib: clinical progression (2), withdrew consent (7), adverse event (4), death (2), initiation of alternative therapy (1)




Immunotherapy Combinations in 1st-Line

Control Comparator

Sunitinib Axitinib + Avelumab

Sunitinib Bevacizumab + Atezolizumab

Sunitinib Nivolumab + Ipilimumab

Sunitinib Sunitinib + AGS-003

Given CABOSUN results, is sunitinib the right

comparator?

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%

• We report the first results from the phase III CheckMate 214 study of NIVO + IPI versus sunitinib (SUN) for treatment-naïve aRCC

Introduction

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


• KPS ≥70%

• Tumor tissue

available for PD-L1

testing

TreatmentPatients

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)

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)

Pro

gre

ssio

n-F

ree S

urv

ival

(Pro

bab

ilit

y)

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)

Overa

ll S

urv

ival

(Pro

bab

ilit

y)

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

0.018 21 24 27 30 3315129630

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 3–4Rash 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

Summary and conclusions

• In IMDC intermediate/poor risk treatment-naïve aRCC, CheckMate 214 demonstrated

– Statistically significant OS benefit with NIVO + IPI versus SUN, with a 37% reduction in the

risk of death

– Significantly improved ORR with NIVO + IPI versus SUN, with a 9.4% complete response

rate and durable responses

– Median PFS improvement of >3 months with NIVO + IPI versus SUN

• In the intention to treat patients, statistically significant OS benefit and improved ORR

were observed with NIVO+IPI versus SUN

• In exploratory analyses, patients with tumor PD-L1 ≥1% demonstrated a higher ORR and

improved PFS with NIVO + IPI versus SUN

• In exploratory analyses, favorable-risk patients achieved higher response rates and longer

PFS with SUN versus NIVO + IPI

Summary and conclusions

• The safety profile of NIVO + IPI was manageable and consistent with previous studies

– More high-grade treatment-related adverse events were observed with SUN

– Patients reported better symptom control with NIVO + IPI versus SUN

• These results support the use of NIVO + IPI as a new first-line standard of care option for

patients with aRCC

Topics





cell disease?



Second-Line: Is nivolumab superior to everolimus?

Motzer RJ et al: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine, 2015

• Primary Endpoint: OS

• Secondary Endpoint: ORR, PFS, Aes, QOL, and OS by PD-L1 expression





Nivolumab

N = 410

Everolimus

N = 411

Objective response rate, % 25 5

Odds ratio (95% CI)

P value

5.98 (3.68–9.72)

<0.0001

Best overall response, %

Complete response

Partial response

Stable disease

Progressive disease

Not evaluated

1

24

34

35

6

1

5

55

28

12

Median time to response, months

(range)3.5 (1.4–24.8) 3.7 (1.5–11.2)

Median duration of response, months

(range)*12.0 (0–27.6) 12.0 (0–22.2)

Ongoing response, n/N (%) 49/103 (48) 10/22 (45)





Second-Line: Is cabozantinib superior to everolimus?

Choueiri TK et al: Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine, 2015



Pri

mary

Endp

oin

t: P

FS



Cabozantinib Everolimus

(N=187) (N=188)

Objective response rate, % 21 5

95% CI 16‒28 2‒9

P value < 0.001*

Best overall response, %

Complete response 0 0

Partial response 21 5

Stable disease 62 62

Progressive disease 14 27

Not evaluable or missing 3 6

* Cochran-Mantel-Haenszel test

The ORR was consistent in patients who received sunitinib as only prior VEGFR TKI



Secondary

EP

: O

vera

ll S

urv

ival



Comparisons

a Sunitinib, cytokine, VEGF-/VEGFR-directed, or mTOR inhibitor. b OS population; PFS patient population, N = 375.

1. Motzer RJ et al. Cancer. 2010;116:4256-4265. 2. Motzer RJ et al. Lancet Oncol. 2013;14:552-562. 3. Motzer RJ et al. N Engl J Med. 2015;373:1803-1813. 4. Choueiri TK et

al. N Engl J Med 2015;373:1814-1823. 5. Motzer RJ et al. Lancet Oncol. 2015;16:1473-1482. 6. Motzer RJ et al. Lancet Oncol. 2016;17:e4-e5.

RECORD-11 AXIS2 CheckMate

0253 METEOR4 Randomized

Phase 25,6

RegimenEverolimus vs

placebo

Axitinib vs

sorafenib

Nivolumab

vs everolimus

Cabozantinib vs

everolimus

Lenvatinib + everolimus

vs lenvatinib

vs everolimus

Patients, N 416 389 821 658b 153

Risk group, % NR

Favorable 29 _ 36 43 23

Intermediate 56 _ 49 41 37

Poor 14 _ 15 15 40

Prior therapy VEGF-directed Multiplea VEGF-directed VEGFR-directed VEGF-directed

Line of therapy 2nd or higher 2nd 2nd or 3rd 2nd or higher 2nd

Median PFS, mo 4.9 vs1.87 8.3 vs 5.7 4.6 vs 4.4 7.4 vs 3.8 12.8 vs 9.0 vs 5.6

Median OS, mo 14.8 vs 14.4 20.1 vs 19.2 25 vs 19.6 21.4 vs 16.5 25.5 vs 18.4 vs 17.5

Topics





cell disease?



Non-Clear Cell RCC

Other (~5%):

• Collecting Duct

• Unclassified

• Xp11.2 Translocation

Sarcomatoid (10-15%)

The Previous Approach

Lump into a single clinical trial

Sarcomatoid

Chromophobe

Papillary

Clinical Management of Non-Clear Cell RCC: ESPN

mRCC

• Non-clear cell histology

• ECOG PS 0-1


• Adequate organ function

• No prior systemic therapy

• No uncontrolled brain

metastasis

Sunitinib

(Standard schedule)

Everolimus

(Standard schedule)

Sunitinib

(Standard schedule)

Everolimus

(Standard schedule)

Ran

do

miz

ation

Cro

sso

ve

r

• Histologies permitted: Papillary, chromophobe, unclassified, translocation

(Xp11.2) and clear-cell with ≥ 20% sarcomatoid features

• Projected sample size: 108 patients

Clinical Management of Non-Clear Cell RCC: ESPN

No difference in 1st-line PFS

Clinical Management of Non-Clear Cell RCC: ASPEN

mRCC

• Non-clear cell (papillary,

chromophobe and

undifferentiated)

• N=108 (study completed

accrual)

Sunitinib

(Standard schedule)

ASPEN

Everolimus

(Standard schedule)

Sunitinib

(Standard schedule)

Everolimus

(Standard schedule)

Ran

do

miz

ation

Cro

sso

ve

r

• What other data might guide us?

Clinical Management of Non-Clear Cell RCC: ASPEN

Armstrong AJ et al Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre,

open-label, randomised phase 2 trial. The Lancet Oncology.17(3):378-88.

• Histologies permitted: Papillary, chromophobe, or unclassified non-clear cell

renal cell carcinoma

• Sample size: 108 patients

A Better Approach

Understand disease biology

Sarcomatoid

Chromophobe

Papillary Papillary

Apply rationally

selected drugs

Sarcomatoid

Apply rationally

selected drugs

Clinical Management: SWOG 1500 for mPRCC

• PI: S. Pal (COH)

• Translational PI: B. Shuch (Yale)

• BISQFP funding for genomic characterization

• Key assumptions:

• PFSsunitinib = 6 mos, PFScomparator = 10.5 mos

• β = 0.85, 1-sided α = 0.10

• Requires 41 pts/arm 164 pts total*

• Assuming 10% ineligibility 180 pts total

We need you!

Topics





cell disease?



Recurrent Renal Cell Carcinoma

Recurrence rates depend largely on the

characteristics of the primary tumour

Patients with larger tumours and higher

grade are at high risk for developing

recurrence after nephrectomy

Two systems can be used to assess the risk

of progression in localised tumours:

Stage, Size, Grade, and Necrosis (SSIGN)

University of California Los Angeles

Integrated Staging System (UISS)

UISS University of California Los Angeles’ Integrated Staging System

Quantifies stage, tumour grade, and performance status

Predictions for both localized and metastatic disease

Incorporates RCC of various histological subtypes

Not always accurate because each subtype is different

Cannot be evaluated on the same plane

60

• Patient at very high risk of recurrence

• Drug active on microscopic cancer

• Low toxicity

• Inexpensive

• Clinically meaningful outcome

The “Ideal” Adjuvant Therapy Setting

61

• ARISER - girentuximab - negative

• ASSURE – sunitinib vs sorafenib vs placebo -negative

• S-TRAC – adjuvant suntinib – ESMO 2016

• PROTECT – adjuvant pazopanib– 2017

Recent Trials in Adjuvant Therapy for RCC

62

63

ASSURE : Adjuvant Sorafenib or Sunitinib for Unfavorable REnal Carcinoma (ECOG 2805)

ccRCC or ncRCCpT1b (G3-4) Pt2-4

pN+

RANDOMIZATION

Placebo

Sunitib 50 mg PO qd(4/2 schedule) for 1 year

641

641

1:1:1

Primary Endpoint:

DFS (Investigator Review)

Sorafenib 400 mg PO bidfor 1 year

641

ASSURE

No improvement in DFS

Treatment Arm DFS (years)

Sunitinib 5.8

Sorafenib 6.1

Placebo 6.6y

Arms compared Hazard Ratio

Sunitinib vs Placebo 1.02, 97.5%CI 0.85-

1.23, p=0.8038

Sorafenib vs Placebo 0.97, 97.5%CI 0.80-

1.17, p=0.7184

No significant difference in OS

Number at risk

Sunitinib 647 500 397 338 279 194 102 42 7

Sorafenib 649 517 423 357 297 199 114 48 11

Placebo 647 499 414 360 312 200 111 48 7

Dis

ease

-fre

e s

urv

ival (%

)

64

Sunitinib

Sorafenib

Placebo

S-TRAC : Sunitinib TRial in Adjuvant Renal Cancer

ccRCCpT3-4pN+

ECOG 0-2

RANDOMIZATION

Placebo

Sunitinib 50 mg PO qd(4/2 schedule) for 1 year

309

306

1:1

Primary Endpoint:

DFS (Independent Central Review)

65

No. at riskSunitinib 309 225 173 153 144 119 53 10 3 0Placebo 306 220 181 150 135 102 37 10 2 0

Analysis Sunitinib (N = 309) Placebo (N = 306) Hazard Ratio (95% CI)

Median f/u 5.4 y yr (95% CI)

All patients in central review: primary analysis

6.8 (5.8-NR) 5.6 (3.8-6.6) 0.76 (0.59-0.98)

Secondary analysis

All patients in investigatorreview

6.5 (4.7-7.0) 4.5 (3.8-5.9) 0.81 (0.64-1.02)

Higher-risk patients in central review

6.2 (4.9-NR) 4.0 (2.6-6.0) 0.74 (0.55-0.99)

Higher-risk patients in investigator review

5.9 (4.4-7.0) 3.9 (2.8-5.6) 0.76 (0.58-1.01)

Table 2. Median Duration of Disease-free Survival in Primary and Secondary Analyses

Years

Dis

ease

-fre

e s

urv

ival (%

)

Sunitinib

Placebo

Hazard ratio, 0.76 (95% CI, 0.59-0.98)

P-0.03

66

S-TRAC: Sunitinib TRial in Adjuvant Renal Cancer

DISEASE-FREE SURVIVAL OVERALL SURVIVAL

67 Ravaud A et al. NEJM 2016

• Patients on sunitinib had a longer median duration of DFS, 6.8 years vs 5.6 years

• Further study to determine if effect is maintained at 10y

• Overall survival results pending

Conclusions

69

PROTECT : A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma

ccRCCpT2 (G3-4)

pT3-4pN+

RANDOMIZATION

Placebo

Pazopanib800 mg PO qd for 1 year

750

750

1:1

Primary Endpoint:

DFS (Independent Central Review)

71


72


73


74

Recurrence Risk

75

ARISER ASSURE S-TRAC PROTECT

pT1-2 ~ 16%pT3-4 ~ 85%pN+ ~ 7%

pT1-2 ~ 36%pT3-4 ~ 64%pN+ ~ 2%

pT3-4 ~ 92%pN+ ~ 8%

Pending (but pT2 G3-4 were incl.)

*Numbers might not add up to 100% as groups are not mutually exclusive

Chamie K et al. JAMA Oncology. 2016; Haas Net al. Lancet. 2016; Ravaud A et al. NEJM. 2016; NCT01235962

• One study (S-TRAC) showing DFS (OS not mature yet) with adjuvant sunitinib in high risk for recurrence resected RCC

• Negative trials include ASSURE (intermediate and high risk) and PROTECT (not as high risk ?)

Adjuvant Therapy Summary

78

The very high risk for recurrence RCC patient (PT3 and greater, Grade 3 and greater) has a DFS advantage with adjuvant TKI,

and

the motivated patient would benefit from a discussion regarding adjuvant therapy with an oncologist, uro-oncologist, or informed urologist

79

Topics





cell disease?



Debulking Nephrectomy – prospective data from the cytokine era

Flanigan et al. J Urol. 2004;171:1071-1076

Overall survival favored nephrectomy group

(13.6 months vs 7.8 months; P = .002)

Cytoreductive Nephrectomy Plus Interferon-α2b Versus Interferon α2b Alone

IMDC RF

No CN OS, mo (n) CN OS, mo (n) p value

0 insufficient number to compare

1 22.5 (n = 72) 30.4 (n = 178) 0.002

2 10.2 (n = 143) 20.2 (n = 253) <0.001

3 10.0 (n = 113) 15.9 (n = 106) <0.001

4 5.4 (n = 103) 6.0 (n = 67) 0.166

5 3.6 (n = 36) 2.8 (n = 14) 0.504

6 insufficient number to compare

Debulking Nephrectomy: retrospective data from the targeted era – IMDC cohort (n=1,633)

Heng et al., Eur Urol 2014 Oct;66(4):704-10

Cytoreductive Nephrectomy: Fueling the Debate

Cytoreductive nephrectomy?Yes No

SWOG 8949

EORTC 30947

SURTIME

CARMENA

IMDC

Cytokines have

waning relevance

SURTIME and

CARMENA

accrual/attrition?

Retrospective studies

are subject to bias

Topics





cell disease?



Conclusions – management of advanced RCC

• The natural history of mRCC is heterogeneous –systemic therapy is not always required as the first step in clincal management.

• Risk stratification models can help guide decision making around cytoreductive nephrectomy and active surveillance.

• TKI therapy remains the first-line standard of care for the majority of patients with metastatic disease.

• Sunitinib and pazopanib have similar efficacy in the first-line setting. The COMPARZ and PISCES trials suggest that pazopanib is better tolerated by most patients.

Conclusions – management of advanced RCC

• Sunitinib has the most robust data across various non-clear cell RCC variants, but clearly more work is needed in this space.

• Checkpoint-inhibitor combination regimens are intensely studied in the first-line space and are already challenging sunitinib on numerous phase III trials.

• Adjuvant Sunitinib increases DFS post resection of high-risk for recurrence RCC – OS ?

Canadian Consensus Guidelines 2017

Table 1. Therapeutic options for advanced clear cell RCC

Setting PatientsTherapy

(Level 1 evidence)Other options

(<level 1 evidence)

UntreatedGood/Intermediate risk

SunitinibPazopanib

Bevacizumaba + IFN

High-dose IL-2Sorafenib

Cabozantiniba/b

Observation

Poor riskSunitinib

TemsirolimusSunitinib

Pazopanib

Second-LineCytokinerefractory

SorafenibPazopanib

Axitinib

Sunitinib,Bevacizumaba + IFN

Prior VEGFtargetedtherapyor Prior mTOR

NivolumabAxitinib

Cabozantiniba

Everolimusc

Targeted therapy not previously used(Lenvatinib + everolimus)a/b/c

Third-Lined AnyNivolumab

Cabozantiniba

Everolimus

AxitinibChemotherapy

IFN: interferon; IL = interleukin; VEGF: vascular endothelial growth factor; VEGFr: : vascular endothelial growth factor receptor; mTOR: mammalian target of rapamycin;

TKI: tyrosine kinase inhibition.

a not approved in Canada for RCC but is approved in the United States

b phase II data only

c If prior mTOR not used in first-line

d no drug has Health Canada approval for third-line

Reaume MN et al, 2017 - submitted

Documents

Metastatic Kidney Cancer 2017: New Concepts, New Ideas ...cagpo-annual-conference.ca/documents/435/files/KAPOOR, ANIL.pdf · Metastatic Kidney Cancer 2017: New Concepts, New Ideas,