A 2020 Renal Cancer update

Malcolm Brigden MD FRCP
Associate Clinical Professor of Medical oncology
University of Calgary
A 2020 Renal CancerUP DATE
A Constantly Evolving Pallet of Therapeutic Opportunities

A Holy Trinity of Canadian Renal Cancer Gurus

Topics To Be Covered
Category Description
Biology of renal
cancer
Some basic renal cancer biology and pathophysiology
1st-Line What is the optimal 1st-line therapy for mRCC?
2nd-Line What is the optimal 2nd-line therapy for mRCC?
Non-clear cell
What 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?
The future “Is yet to come” Yogi Berra

Renal Cell Carcinoma (RCC)
•Originates in the renal cortex
•Most common solid lesion occurring in the kidney (80-
85% of all primary renal neoplasms)
Diseased Kidney

Some RCC Statistics
• An estimated 24,000 Canadians with a history of kidney
and renal pelvis cancer were alive in 2004
• RCC incidence increasing
• 5-year survival has improved
• 50.9% 19751977
• 65.7% 19962003
• Most tumors are localized at initial diagnosis

NA Yearly Kidney and Renal Pelvis Cancer
Incidence and Mortality
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1975 1980 1985 1990 1995 2000
Year
RatePer100,000Individuals
Incidence
Mortality
Ries LAG et al. SEER Cancer Statistics Review, 1975-2004;2007.

Extent of Disease at Diagnosis
Most renal cancers are diagnosed when the disease is
still localized to primary site
National Cancer Institute. SEER cancer statistics fact sheet. Accessed 2008.

Incidental vs Non-incidental Detection
• Today, >50% of RCCs are incidentally detected during
noninvasive imaging used to evaluate nonspecific
symptoms
• Incidentally detected tumors tend to be smaller and of
lower stage than those detected in symptomatic patients
• Average size: 5 vs 8.5 cm Average pathologic stage T1/T2:
75% vs 43%

Etiology of RCC
• Environmental and clinical risk factors
• Smoking
• Obesity
• Acquired cystic disease of the kidney (usually in
association with dialysis)
• Analgesic abuse nephropathy
• Occupational exposure to toxic compounds
• Genetic predisposition
Most important factors recognized

Stages of RCC
Stage I: Cancer is in the
kidney only, size of
tumor is ≤7.0 cm in
diameter
Stage II: Cancer is in
the kidney only, but
size of the tumor is
>7.0 cm in diameter
Stage III: Tumor in the
kidney may be any size,
but extends beyond
layer of tissue (Gerota’s
fascia) that
encapsulates kidney
and adrenal gland.
Cancer may have
spread to blood vessels
and one regional lymph
node.
Stage IV: Tumor in
the kidney extends
beyond Gerota’s
fascia and/or cancer
has spread to one or
more lymph nodes
near kidney. Cancer
may have spread to
other organs such as
lungs, liver, brain, or
bones.

Prognostic Factors and RCC-the Heng Criteria
(Based on International mRCC Database Consortium)
Clinical
• Low Karnofsky performance (<80%)
• Time from diagnosis to treatment <1 year
Laboratory
• Low haemoglobin (< LLN)
• High “corrected” serum calcium (> ULN)
• High neutrophils (> ULN)
• High levels of platelets (> ULN)

Adapted from Heng DY, et al. J Clin Oncol 2009; 27:5794-9.
Scoring and Interpretation of The Heng
(IMDC) Model for Risk Stratification in mRCC
Scoring
Score
No Yes
Time from diagnosis to treatment <1 year 0 +1
Karnofsky performance status <80% 0 +1
Hemoglobin < LLN 0 +1
Calcium > ULN 0 +1
Neutrophils > ULN 0 +1
Platelets > ULN 0 +1
Interpretation
Total Score Prognosis
0 Favorable
1-2 Intermediate
≥3 PoorIMDC: International mRCC database consortium; LLN: lower limit of
normal; mRCC: metastatic renal cell carcinoma; ULN: upper limit of
normal

Heng DY, et al. Lancet Oncol 2013; 14:141-8.
Overall Survival by Risk Group: Heng (IMDC)
Model
Poor:
8 mos
Intermediate:
23 mos
Median OS
Favorable:
43 mos
IMDC: International mRCC database consortium; OS: overall survival

How Might We Use Prognostic Factors?
Patient counselling
• Clinical trial stratification and adjustment methods in
retrospective studies
Patient treatment
• Can help choose first-line therapy (predictive markers)
• Can help determine prognosis for deciding whether
cytoreductive nephrectomy can be helpful

Renal cancer is actually a variety of diseases
Presented By W. Marston Linehan at 2015 Genitourinary Cancers Symposium

Newer understanding of RCC pathophysiology-1
• renal cell cancer is actually a metabolic disease with
abnormalities of a number of signalling pathways
• The commonest genetic abnormality associated with renal
cancer is mutation of the Von Hippel-Lindau(VHL) gene
• VHL mutation→up-regulation of VEGF and platelet-derived
growth factor
• These mutations are powerful stimulants for angiogenesis and
proliferation
• In non-hereditary renal cancer→acquired VHL mutation results
in dropping of the gene or its abnormal methylation
• VHL mutation by itself does not produce renal cancer→
subsequent additional mutations are required

VHL
Von Hippel Lindau
HIF1a
Transcription of Genes
Associated with
Angiogenesis and
Proliferation

• VEGF binds to its receptors
(VEGFRs) on endothelial cell
surfaces
• Promotes endothelial cell
migration and proliferation for the
development of new tumour-
induced blood vessels
• VEGF and VEGFR have proven to
be attractive molecular targets for
for RCC because they play key
roles in tumour angiogenesis
The Role of VEGF in RCC

• Cancer cells express mutated
proteins (neoantigens) recognised
by the immune system with anti-
tumour responses
• T-cells play a key role but immune
checkpoint pathways reduce
inappropriate or sustained T-cell
activation in healthy cells
• Tumour cells can evade the immune
system by exploiting immune
checkpoint pathways
The Immune System and RCC
• 1. Atkins MB, et al. Ann Oncol 2017;28:1484–
94.
MHC
PD-L1
PD-1 PD-1
T-cell
receptorT-cell
receptor
PD-L1
MHC
CD28 B7.1
T-cell
NFκB
Other
Dendritic
cell
Tumour cell
IFNγ
IFNγR
Shp-2 Shp-2
PI3K

So what are targeted therapies in RCC ?
• If we use the analogy of pesticides: empiric therapy
would be “Raid” while targeted therapy is the “Roach
Hotel.”
Dr. David Gandara
• A “smart” bomb versus a “cluster” bomb.
Dr. Nevin Murray

Targeted Pathways in RCC treatment
VEGF and TKIs PD-1 and mTOR inhibitors
• From RJ. N Engl J Med 2017;376:354–66;
.
• mTOR, mammalian target of
rapamycin; TKI, tyrosine kinase
inhibitor

Targeted Therapies have Improved Overall Survival in Advanced
RCC Compared to Chemotherapy/Cytokine Therapies
Patients Alive
Cytokine therapy 396 48
Chemotherapy 274 9
0.75
0.53
0.07
Proportionsurviving
0
0
20
40
60
80
100
Years following systemic therapy
2 5 7 9 11 13 15 171 4 6 8 10 12 143 16
Median overall survival according to
MSKCC risk criteria1 (months)
Favourable 27
Intermediate 12
Poor 6
20001 – Chemotherapy/Cytokine Era
Median OS: 10 months
Overallsurvival(probability)
0
0
20
40
60
80
100
Time since therapy initiation (months)
24 6012 4836
Median overall survival according to
Heng’s risk criteria2 (months)
Favourable Not reached
Intermediate 27
Poor 8.8
20092 – Targeted Therapies Era
Median OS: 22 months
Favourable
Intermediate
Poor

Lenvatinib8 +
Everolimus
Historic Timeline for Licensing of Various RCC Treatments
in Canada
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
Sunitinib2 Pazopanib5
Sorafenib1
Temsirolimus3
Cabozantinib10Axitinib6Everolimus4 Nivolumab7
VEGF-binding
mAB
VEGFR
TKI
mTOR
inhibitor
Checkpoint
inhibitor
First-line
Second-line
Mode
of action
Nivolumab7 +
Ipilimumab9

The way it was-First-line Treatment of Metastatic RCC:
2017-18 Canadian Guidelines
Treatment
Status
Patient Status
Therapy
(Level 1 evidence)
Other Options
(≥ Level 2)
First Line
Good or
intermediate risk
Sunitinib
Bevacizumab +
IFN
Pazopanib
High-dose IL-2
(Sorafenib)
Observation
Clinical Trial
Poor risk Temsirolimus*
Sunitinib
Clinical trial

How have these evolved in 2019??
With caveats: A VEGFR-directed TKI
remains a standard of care for first-line
treatment of mRCC in 2019 in Canada-so
how might Pazopanib compare to
Sunitinib
in this regard
the Comparz and Pisces Trials

Comparative Data: COMPARZ
Eligibility Criteria
• aRCC or mRCC with
clear cell histology
• Measurable disease
• No prior systemic treatment
• KPS ≥70
Pazopanib
Sunitinib 50 mg/day
Primary endpoint: PFS for non-inferiority (independent review)
Secondary endpoints: OS, ORR, PRO, safety, QoL, and
medical resource utilization
KPS, Karnofsky performance status; QoL, quality of life.
N = 1110
R
A
N
D
O
M
I
S
E
n = 553
n = 557
Motzer RJ et al. N Engl J Med. 2013;369:722-731.

Comparative Data: COMPARZ
PFS non-inferiority demonstrated if upper bound of 95% CI for HR <1.25
36
0
0.2
0.4
0.6
0.8
1.0
40
Pazopanib (n = 557)
Sunitinib (n = 553)
Motzer RJ et al. N Engl J Med. 2013;369:722-731.
8.4 months (8.3-10.9)
9.5 months (8.3-11.1)
10.5 months (8.3-11.1)
10.2 months (8.3-11.1)
HR, 1.05
(95% CI, 0.90-1.22)
HR, 1.00
(95% CI, 0.86-1.15)
PFS Assessment
Independent Investigator
PFSprobability
0 4 8 12 16 20 24 28 32
Months
*Per protocol population was consistent with the intent to treat (ITT population)

Comparative Data: PISCES
Patients,%
P < 0.001
8%
“Now that you have completed both
treatments, which of the twodrugs
would you prefer to continue to takeas
treatment for your cancer, assuming
that both drugs work equallywell?”
10
Escudier B et al. J Clin Oncol. 2014;32:1412-1418.
20
30
40
50
60
70
80
100
90
0
Preferred pazopanib Preferred sunitinib No preference
Patients were still blind to the results of their disease assessment when they stated their
preference

But it is now 2019-The evolving First-line Landscape of RCC
Treatment
Nivolumab/Ipilimumab:
randomized phase III CheckMate214 trial
Pembrolizumab/Axitinib
randomized phase III Keynote 426 trial
Avelumab/Axitinib
randomized phase III Javelin RCC 101
trial
NB: A Change in First-line Therapy Changes all
Subsequent Therapies

Nivolumab / Plus Ipilimumab vs Sunitinib for
Treatment-Naïve Advanced / Metastatic RCC
CheckMate 214: Study design
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/Euro
pe vs Rest of
World)
IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status;
Q2W, every 2 weeks; Q3W, every 3 weeks
Co-primary endpoints: ORR (per IRRC), PFS (per IRRC), OS
In IMDC intermediate- and poor-risk patients
Motzer et al NEJM 2018

CheckMate 214: 30-month Update
on Progression-free Survival
T. Presented at GU-ASCO 2019;
Abstract #547.

CheckMate 214: 30-month Update on Overall Survival
T. Presented at GU-ASCO 2019;
Abstract #547.

Pembrolizumab/Axitinib vs Sunitinib for Treatment-
Naïve Advanced / Metastatic RCC
Keynote 426: Study design
IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status;
Q2W, every 2 weeks; Q3W, every 3 weeks
Co-primary endpoints: PFS, OS
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
Pembrolizumab 200 mg
IV q 3 weeks /
Axitinib 5 mg po BID daily
for up to 24 months
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/Euro
pe vs Rest of
World)
Rini et al NEJM 2019

Pembrolizumab/Axitinib as First-line Treatment for Metastatic RCC
IMDC Favorable Risk
Early analysis: no firm benefit (yet ?)
Rini et al ASCO 2019

Pembrolizumab/Axitinib as First-line Treatment for Metastatic RCC
IMDC Intermediate / Poor Risk
Significant benefit for Pembrolizumab / Axitinib
Rini et al ASCO 2019

Javelin Renal 101
Study Design
R
1:1
Avelumab 10 mg/kg IV Q2W
+
Axitinib 5 mg PO BID
(6-week cycle)
Sunitinib 50 mg PO QD
(4 weeks on, 2 weeks off)
6
Key eligibility criteria:
• Treatment-naive aRCC
with a clear cell
component
• ≥ 1 measurable lesion as
defined by RECIST v1.1
• Tumor tissue available for
PD-L1 staining
• ECOG PS 0 or 1
Stratification:
• ECOG PS (0 vs 1)
• Geographic region
(USA vs Canada/Western
Europe vs ROW)
N =
88
Primary endpoints
PFS by RECIST v1.1 per independent review committee (IRC) in patients with
PD-L1+ tumors (PD-L1+ group)*
OS in the PD-L1+ group

Javelin Renal 101
PFS per IRC in Overall Population
Median PFS (95% CI), months
Avelumab + Axitinib 13.8 (11.1, NE)
Sunitinib 8.4 (6.9, 11.1)
Stratified HR, 0.69 (95% CI: 0.563, 0.840)
P = .0001
80
70
90
100
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20
Progression-freesurvival,%
22 24
Months
Is this enough ?

Javelin Renal 101
Overall Survival (Immature at this Time)
Median OS (95% CI), months
Avelumab + Axitinib
Sunitinib
Not reached
Not reached
Stratified HR, 0.78 (95% CI: 0.554, 1.084)
P = .0679
70
100
90
80
60
50
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time since treatment initiation, months
Overallsurvival,%
40
30
20
10
0
OS data are immature
• 14% of patients with event in the avelumab + axitinib arm
• 17% of patients with event in the sunitinib arm
Overall Survival needs to be awaited

Summary- Immunotherapy Combinations in 1st-Line-But a Caveat??
What About Cabozantinib as a Single Agent-The CABOSUN Study
Control Comparator
Sunitinib Nivolumab + Ipilimumab
Sunitinib Pembrolizumab/Axitinib
Sunitinib Avelumab/Axitinib
The Caveat ,but was Sunitinib the right
comparator in these studies in the first place?

Increased Expression of MET and AXL in RCC is Associated
with Poor Prognosis and Resistance to VEGFR Inhibitors
1. Choueiri TK, et al. N Engl J Med 2015;373:1814–23;
2. Gibney GT, et al. Ann Oncol; 2013;24:343–9;
3. Xie Z, et al. J Cancer 2016; 7:1205-1214.
4. Rankin EB, et al. PNAS 2014;111:13373–8.
5. Zhou L, et al. Oncogene 2016;35:2687–97.

Cabozantinib as an Alternative to Sunitinib or
Pazopanib: Phase 2 CABOSUN Study Design
RANDOMIZATION
1:1
Sunitinib
50 mg qd orally
(4 weeks on/2 weeks off)
Cabozantinib
60 mg qd orally
Advanced RCC (N=150)
• Clear cell component
• No prior systemic therapy
• ECOG PS 0-2
• IMDC intermediate or poor risk
groups
Tumor assessment by
RECIST 1.1
Every other cycle*
Treatment until
disease progression
or intolerable toxicity
Stratification
• IMDC risk group: intermediate, poor
• Bone metastases: yes, no
Choueiri TK, et J Clin Oncol 2017; 35(6):591-7.
*One treatment cycle was defined as 6 weeks.
ECOG: Eastern Cooperative Oncology Group; IMDC, International Metastatic RCC Database Consortium; RCC: renal cell
carcinoma; RECIST: response evaluation criteria in solid tumors

Phase 2 CABOSUN Study:
Overall and Progression-free Survival
Overall Survival: Trend in Favor of
Cabozantinib
Choueiri TK, et al. Eur J Cancer 2018;
94:115-25.
CI: confidence interval; HR: hazard ratio; OS: overall survival; PFS: progression-free survival
PFS: Cabozantinib Significantly Longer
than Sunitinib
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 15 12 15 18 21 24 27 30 33 36 39 42
Time Since Randomisation (Months)
ProbabilityofOS
CABO 79 76 71 64 58 47 45 42 41 31 23 15 8 4 2
SUNI 78 69 61 53 50 46 42 36 29 24 17 12 6 3 0
No. at risk
Median
OS
No. of
Deaths
Cabozantinib (N=79) 26.6 mo 43
Sunitinib (N=78) 21.2 mo 47
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 15 12 15 18 21 24 27 30
Time Since Randomisation (Months)
ProbabilityofPFS
CABO 79 51 37 24 22 18 12 5 2 1 0 79 51 37 24
SUNI 78 36 21 12 9 5 3 2 1 0 0 78 36 21 12
No. at risk
Median
PFS
No. of
Events
Cabozantinib (N=79) 8.6 mo 43
Sunitinib (N=78) 5.3 mo 49
2 Key caveats about CABOSUN:
• Phase 2 trial: validation from a prospective phase 3 study required to be practice-changing
• Limited sample size, relies on investigator reports for PFS

Randomized Phase II Assessment of Front-Line Cabozantinib
Which prognostic groups benefitted the most?
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)

• At the time of analysis,
median PFS was 8.0
months (range: 0.5–10.8
months) irrespective of the
line of treatment
• Median OS was not
reached
• 1-year OS was 65%
• Incidence of Grade 3/4 AEs was 36%
• Most common Grade 3/4 AEs were
diarrhoea (7%), asthenia (7%) and
hypertension (5%)
• Dose was reduced due to AEs in 40
patients (42%)
• 5 patients (5%) discontinued
treatment because of AEs
• AEs leading to a dose
discontinuation were pulmonary
embolism, severe gastrointestinal
bleeding, diarrhoea and fatigue
Conclusions: cabozantinib was effective in everyday clinical practice in large
unselected population of mRCC patients who experienced disease progression
after prior treatment. Cabozantinib treatment was well-tolerated with a manageable
toxicity profile
Procopio G, (2018)- Safety and efficacy of
cabozantinib in mRCC: Real-world data
Best overall response N (%)
PR 35 (36)
SD 33 (34)
PD 28 (30)

First Line Treatment in Metastatic RCC
Some Conclusions
 Our potential first line treatment options are constantly evolving
 Nivolumab/Ipilimumab may become a new standard in
intermediate/poor risk patients
 Pembrolizumab/axitinib may become a new standard in Metastatic
RCC across all risk groups
 Avelumab/axitinib might also represent a new standard in Metastatic
RCC across all risk groups although OS needs to be awaited
The Cabosun study suggests that Cabozanitib might be a superior
first line agent-It remains to be seen whether will be PCODR approved
for first-line indication(the Lenvatinib-Everolimus experience)
 Long term remissions seem possible-but current sequencing strategies
have to be refined

Rini et al ESMO 2018
McDermott et al Nat Med 2018
PD-L1 Expression
P = 0.35
61%
39% 43%
57%
25%
Patients(%)
100%
75%
50%
0%
Favourable Intermediate/Poor
n = 156 n = 667
Patients(%)
100%
75%
50%
25%
0%
n = 156 n = 667
T-effector Gene Signature
P = 0.1
64%
36%
43%
57%
Patients(%)
100%
75%
50%
25%
0%
n = 156 n = 667
P = 8.26e-05
Angiogenesis Gene Signature
26%
74%
57%
43%
AngioLow
AngioHigh
Why might a VEGF TKI Work better in The favorable risk patients?
Angiogenesis Gene Expression is Higher in Favorable MSKCC Risk Group

Optimal subsequent therapy selection for metastatic RCC
There are many factors to consider
Optimal agent
Optimal efficacy
(Available data)
Disease specific factors
Agent specific factors Patient specific factors
Physician experience

Some Comparison Studies in 2nd line therapy
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
Regimen
Everolimus 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
Negative PCODR
recommendation
February 2019
Will NOT be available

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

Second-Line: Is cabozantinib superior to everolimus?
PrimaryEndpoint:PFS
Choueiri TK et al: Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine, 2015

What if I/O used first?
Activity of Targeted Therapy after Immunotherapy
Derosa et al ESMO 2017
Treatment outcomes of the first subsequent
therapy post immune checkpoint inhibitors
Both, cabozantinib and axitinib
are very active drugs post IO
Prior IO does not seem to alter
the safety profile of TKIs

TTF and OS in subsequent therapy after CPI failure
• For all evaluable patients, ORR was
30%, median TTF was 9.4 months)
and median OS was 17.5 months
• ORR with cabozantinib was 41% with
no patients presenting with PD vs
37% ORR for axitinib and 17% PD
• Cabozantinib demonstrated an
acceptable safety profile, with a rate
of treatment discontinuation because
of AEs of 11%
Conclusions: cabozantinib and axitinib
are active after CPI therapy. Prior anti-
PD-1/PD-L1 inhibitor exposure did not
affect the safety parameters for
subsequent cabozantinib therapy
Derosa L, (2017)- Efficacy of cabozantinib after
PD-1/PD-L1 checkpoint inhibitors in mRCC: the
Gustave Roussy experience
100
80
60
40
20
0
0 12 24 30
MONTHS
TIMETOTREATMENTFAILURE
Median TTF
Axitinib: 9.7 mo (95% CI: 5.4–17.2)
Cabozantinib: NR (95% CI: 9.3–NR)
Other: 7.1 mo (95% CI: 3.2–7.9)
100
80
60
40
20
0
0 10 30 40
MONTHS
OVERALLSURVIVAL
Median OS
Axitinib: 17.5 mo (95% CI: 11.5–24.6)
Cabozantinib: NR (95% CI: 9.4–NR)
Other: 12.3 mo (95% CI: 8.5–19.6)
20
Figures adapted from
Derosa L, et al. (2017)

Some Conclusions 2nd Line and beyond Therapy - Sequencing:
 Changing first line choice changes all subsequent lines-ie moving
I/O therapy upfront in poor risk patients
 A number of options exist after first-line TKI including Nivolumab,
cabozantinib, axitinib, lenvatinib/everolimus
 If I/O therapy is used as first line-targeted agents
axitinib/cabozantinib appear very active after immunotherapy
 Overall best sequencing remains uncertain , particularly post IO
 A significant number of patients treated with immunotherapy do
NOT derive benefit
 Benefit of third line options has not yet been proven in
randomized trials

A possible Canadian (Let’s hope for
funding) Future
Potentially allows us 3 lines of therapy for each patient
? I/O+TKI
? I/O+TKI
?Cabozantinib

The Future is already here :European Association of Urology: Algorithm
for the Management of Metastatic, Clear-cell RCC- May 2019
Powles T, et al. Eur Urol 2018; 73:311-5.
INITIAL THERAPY SUBSEQUENT CHOICES

The Issue of Patient Drop Out/ Lost Opportunity on
Switching Lines of Therapy
Wells JC, et al. Eur Urol 2017;71:204‒209.
IMDC analysis of treatment patterns in 4824 mRCC patients at 25
cancer centres in 9 countries
4824
52.5%
21%
2534
1012
First-line
Second-
line
Third-
line
An important consideration in treatment choices ?

Biology of renal
cancer
Non-clear cell
What are emerging treatments and strategies for non-
clear cell disease?

Non-Clear Cell RCC
Other (~5%):
• Collecting Duct
• Unclassified
• Xp11.2Translocation
Sarcomatoid (10-15%)
Sarcomatoid variant is an aggressive form of RCC that can develop from any histology subtype

The Previous Approach
Lump into a single clinical trial
Sarcomatoid
Papillary
Chromophobe

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)
Randomization
Crossover
• 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

Everolimus vs. Sunitinib in
Patients with Metastatic Non-clear cell RCC
(ASPEN Trial): Randomized phase 2 trial
Armstrong A. et al Lancet Oncol 2016

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
They need you!

Treatment of non-clear cell RCC-
Conclusions
 nccRCCs are a clinically and genetically diverse group
of tumours
 Sunitinib/sorafenib and temsirolimus/everolimus have
shown some benefit in series and expanded-access
programs
 Randomised phase II / Meta-analyses studies suggest
sunitinib may be the agent of choice for first line
therapy in most nRCC patients
 Large randomized studies are lacking
 Further insights into the molecular basis of nccRCC
may provide new targets

Biology of renal
cancer
Non-clear cell
cell disease?
Adjuvant What are some emerging strategies for adjuvant
treatment?

• Patient at very high risk ofrecurrence
• Drug active on microscopic cancer
• Lowtoxicity
• Inexpensive
• Clinically meaningful outcome
The “Ideal” Adjuvant Therapy Setting
61

• ARISER - girentuximab -negative
• ASSURE – sunitinib vssorafenib vsplacebo -negative
• S-TRAC – adjuvant suntinib – ESMO2016
• PROTECT– adjuvant pazopanib– 2017
Recent Trials in Adjuvant Therapy for RCC
62

ASSURE : Adjuvant Sorafenib or Sunitinib for
Unfavorable REnal Carcinoma (ECOG 2805)
63
ccRCC or ncRCC
pT1b (G3-4)Pt2-4
pN+
R
A
N
D
O
M
I
Z
A
T
I
O
N
Placebo
Sunitib 50 mg POqd
(4/2 schedule) for 1year
641
641
1:1:1
Primary Endpoint:
DFS (Investigator Review)
Sorafenib 400 mg PObid
for 1year
641

Assure Results Disappointing
64
No improvement inDFS
TreatmentArm DFS(years)
Sunitinib 5.8
Sorafenib 6.1
Placebo 6.6y
Arms compared HazardRatio
Sunitinib vsPlacebo
1.02, 97.5%CI0.85-
1.23, p=0.8038
Sorafenib vsPlacebo
0.97, 97.5%CI0.80-
1.17, p=0.7184
No significantdifference
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
Disease-freesurvival(%)
Sunitinib
Sorafenib
Placebo

S-TRAC : Sunitinib TRial in Adjuvant Renal Cancer
65
ccRCC
pT3-4
pN+
ECOG0-2
R
A
N
D
O
M
I
Z
A
T
I
O
N
Placebo
Sunitinib 50 mg POqd
(4/2 schedule) for 1year
309
306
1:1
Primary Endpoint:
DFS (Independent Central Review)

S-TRAC: Results Disappointing
DISEASE-FREE SURVIVAL OVERALL SURVIVAL
67 Ravaud A et al. NEJM2016

PROTECT : A Study to Evaluate Pazopanib as an
Adjuvant Treatment for Localized Renal Cell
Carcinoma
71
ccRCC
pT2(G3-4)
pT3-4
pN+
R
A
N
D
O
M
I
Z
A
T
I
O
N
Placebo
Pazopanib
800 mg POqd for 1 year
750
750
1:1
Primary Endpoint:
DFS (Independent Central Review)

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)

IMD
C RF
No CNOS,mo
(n) CNOS,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

CARMENA: Cytoreductive Nephrectomy Followed by
Sunitinib vs Sunitinib Alone in Metastatic RCC
Investigators concluded that nephrectomy should no longer be part of
standard of care for patients with mRCC requiring medical treatment
• Sunitinib alone not inferior to cytoreductive nephrectomy followed by
sunitinib in patients with mRCC
• Median OS longer in sunitinib-alone arm for all patients and in
intermediate-risk and poor-risk subgroups
Does that mean we should not do cytoreductive
nephrectomy in the appropriately selected patient ?
• 40% of patients in the nephrectomy arm in CARMENA had poor
risk criteria

CARMENA: One versus two risk factors in IMDC
Intermediate Disease
Mejean et al ASCO2019

CARMENA: Impact of delayed Nephrectomy in
Sunitinib only treated Patients
Mejean et al ASCO2019
Delayed nephrectomy in good responders is associated
with improved OS and should be considered in selected
patients

Finally-Cytoreductive should mean cytoreductive!
• Potentially long-term disease control
• Prolongs PFS
May substantially delay targeted therapy
Barbastefano et al., BJUI 106(9):1266-1269, 2010

Biology of renal
cancer
Non-clear cell
cell disease?
Hint: Anyone in oncology better be fluid in I/O Therapy

Study name Interventions N
Primary
endpoint(s)
Projected
primary
completion date
Checkmate-9ER2
(NCT03141177)
Nivolumab + cabozantinib
vs. sunitinib
630 PFS Sept. 2019
CLEAR3
(NCT02811861)
Lenvatinib + everolimus vs.
lenvatinib +
pembrolizumab vs.
sunitinib
1,050 PFS Apr. 2020
CA0450024
(NCT03729245)
Nivolumab + NKTR-214 vs.
sunitinib or cabozantinib
600 ORR, OS Dec. 2021
Just a Few of the Ongoing Phase 3 Studies with Immuno-
oncology Therapies in Advanced RCC
ORR: objective response rate; OS: overall survival; PFS: progression-free survival; RCC: renal cell carcinoma

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.
• The Cabosun study suggested that Cabozanitib might be a
superior first line agent- ?PCODR approval 1st line

Conclusions – management of advanced RCC
• Checkpoint-inhibitor combination regimens are intensely
studied in the first-line space and are already challenging first
line TKI therapy based on numerous phase III trials.
• A number of options exist after first-line TKI including
Nivolumab, cabozantinib, axitinib, lenvatinib/everolimus
• If I/O therapy is used as first line-targeted agents
axitinib/cabozantinib appear very active after immunotherapy
• The treatment of non-clear cell RCC is steadily evolving
• There have been no home runs with adjuvant therapy yet-
although Sunitinib appears to improve DFS in high risk patients
• Even in the era of I/O and targeted therapies, there still maybe
a role for cytoreductive nephrectomy in certain patient
subgroups

? The “Diamond Age” of RCC Therapy-Potential
impact of new agents after 2025-From the Lancet
Are we entering the therapeutic diamond age?-you decide!!

NCCN 2019 RCC Metastatic Recommendations

A 2020 Renal Cancer update

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