The Ever-Changing Landscape
Daniel Heng MD MPH FRCPC
University of Calgary
Outline
Staging
 Genetics behind RCC
 Treatment of metastatic disease

 Case
 Prognostic Factors
 Mechanisms of Resistance

Cytoreductive nephrectomy
Staging
Cohen et al NEJM 2004
Von Hippel Lindau
VHL
HIF1a
Ub
Ub
Ub
Ub
Proteosome
Degradation
Of HIF1a
Courtesy sppider.cchmc.org & www.bme.jhu.edu
Von Hippel Lindau
VHL
HIF1a
Transcription of Genes
Associated with
Angiogenesis and
Proliferation
Angiogenesis and Proliferation
VEGF
TGFa/B/
PDGF
VEGFR
EGFR
PDGFR
Angiogenesis
Cell Proliferation
Endothelial Stabilization
Cohen et al NEJM 2005
Von Hippel Lindau

75-80% of sporadic clear cell RCCs
have VHL defect:
 Frameshift / truncation mutation
 Deletion
 Promoter methylation
CH3
Promoter
Von Hippel Lindau Gene
Transcription
Cohen et al NEJM 2005
Targeted Therapies:
The Revolution
Courtesy AZ
Targeted Therapy in mRCC

VEGF inhibitors
 Sunitinib
 Sorafenib
 Bevacizumab
 Pazopanib
 Axitinib

mTOR inhibitors
 Temsirolimus
 Everolimus
Targets and Inhibitors
Rini et al JCO 2005, 2009
Treatment of mRCC: 2011
Setting
Untreated
Second-line
Patients
Therapy
Other Options
(level 1 evidence) (>level 1 evidence)
Good or
intermediate risk
Sunitinib
Bevacizumab+IFN
Pazopanib
HD IL-2
Sorafenib
Clinical Trial
Observation
Poor risk
Temsirolimus
Sunitinib
Clinical Trial
Cytokine
refractory
Axitinib
Sorafenib
Sunitinib
Bevacizumab+IFN
Prior VEGF
Axitinib
Everolimus
Clinical Trial
Targeted therapy
not previously used
Case I: JN
•
•
•
•
•
60F otherwise healthy
Had abdominal discomfort so abdominal
ultrasound was ordered
7x5 cm central mass in right kidney
incidentally detected
pT3a N0 M0 clear cell renal cell carcinoma
resected by laparoscopic right radical
nephrectomy
Staging CT scans revealed no other
metastases
Case I: JN

Standard of care would be CT scans of
the abdomen and pelvis with chest x-ray
 every 6 months for first 2 years
 yearly thereafter

Because of 50% chance of recurrence,
was offered adjuvant clinical trial
 REC2 clinical trial
○ One year of sunitinib, sorafenib, or placebo
Case I: JN

Consented to ASSURE clinical trial
 Had no side effects whatsoever … was she
on placebo?
 6 month CT scan clear
 12 month CT scan
○ Multiple pulmonary metastases bilaterally max
2 cm
○ Liver metastases
Case I: JN
Case I: JN
She now has metastatic disease
 Her calcium, LDH, neutrophils, platelets
are within normal range, ECOG 0
 Her hemoglobin is low at 100

What is her Prognostic Category?
1) Favorable risk – median OS 44 months
2) Intermediate risk – median OS 21 months
3) Poor risk – median OS 8 months
Intl mRCC Database Consortium:
Independent Predictors of Poor OS
KPS < 80
Dx to Tx Interval <1yr
Anemia
Hypercalcemia
Neutrophilia
Thrombocytosis
Heng et al JCO 2009
Prognostic Factors
If patient has 0 factors:
Favorable Prognosis
If patient has 1-2 factors:
Intermediate Prognosis
If patient has 3-6 factors:
Poor Prognosis
Overall Survival in the New Era
Favorable: 0 factors
(mOS 44 mos)
Intermediate: 1-2 factors
(mOS 21 mos)
p<0.0001
Heng et al
ASCO 2011
Poor: 3-6 factors
(mOS 8 mos)
Case I: JN

She has intermediate risk criteria due to
anemia
What first line targeted therapy would you
choose?
1)Sunitinib
2)Temsirolimus
3)Everolimus
4)Interferon
5)High dose IL-2
Sunitinib PFS
Motzer et al NEJM 2007
Pazopanib PFS
Sternberg et al..J Clin Oncol 2010; 28: 1061-1068.
Bevacizumab+IFN

AVOREN Phase III Trial
IFN-α2b SC
Met clear cell
RCC
Treatment naive
IFN-α2b SC +
Bevacizumab IV
Progression free survival benefit (10.2 vs. 5.4 months p<0.0001)
No OS benefit due to crossover
Temsirolimus
Overall Survival Benefit
TEMSR vs IFN log rank p=0.0069
PFS 3.7 vs. 1.9 months
mOS 10.9 vs. 7.3 months
Hudes et al NEJM 2007
Sorafenib
PFS
Progression-free
Survival
Probability of Being Progression-free
Improved with Sorafenib
1.00
Sorafenib (n = 451) = 5.5 months
Placebo (n = 452) = 2.8 months
0.75
Hazard ratio = 0.51; P < 0.001
0.50
0.25
0.00
0
2
4
6
8
10
12
14
16
18
20
Time from Randomization (Months)
* Based on investigator assessment
Escudier B, Eisen T, Stadler WM, et al. N Engl J Med. 2007;356:125-134.
47
Escudier et al NEJM 2007
Treatment of mRCC: 2011
Setting
Untreated
Second-line
Patients
Therapy
Other Options
(level 1 evidence) (>level 1 evidence)
Good or
intermediate risk
Sunitinib
Bevacizumab+IFN
Pazopanib
HD IL-2
Sorafenib
Clinical Trial
Observation
Poor risk
Temsirolimus
Sunitinib
Clinical Trial
Cytokine
refractory
Axitinib
Sorafenib
Sunitinib
Bevacizumab+IFN
Prior VEGF
Axitinib
Everolimus
Clinical Trial
Targeted therapy
not previously used
Case I: JN
•
She chooses to be on sunitinib
• She is dosed at the standard 50 mg 4
weeks on and 2 weeks off
• Her baseline assessments included
– CT scan of the chest, abdomen, pelvis
– Bone scan (normal)
– CBC, liver function tests, creatinine, baseline
TSH
– MUGA/echo only in patients with prior history of
cardiac disease or significant risk factors
Case I: JN
•
She is followed with CT scans every 3
months (every 2 cycles)
– 3 month CT: 19% tumor reduction
– 6 month CT: stable disease from previous
– 9 month CT: stable disease from previous
•
At 11 months:
–
–
–
–
She develops significant anemia (Hb 88)
She is tired, symptomatic of anemia
Had syncopal episode
She requires a transfusion of 2 units PRBC
Case I: JN
•
Sunitinib was held for 4 weeks but counts
did not recover, required blood transfusions
every 3 days
• Became neutropenic despite not being on
any drug
• Considered bone marrow infiltration of
RCC
– Bone marrow biopsy could not confirm this
(sampling error)
– Decided that this was progressive disease and
needed new line of therapy
Mechanisms of Resistance
Mechanisms of Resistance
1)
Angiogenic redundancy
–
2)
PDGF, FGF, PIGF
Intratumoral hypoxia induces redundancy
factors
Grepin R et al J Oncology 2010
Mechanisms of Resistance
3) Natural selection of more invasive tumor
cells
Grepin R et al J Oncology 2010
Mechanisms of Resistance
4) Recruitment of bone marrow derived
proangiogenic and inflammatory cells
– IL-6, GCSF recruitment
5) Targeted endothelial cells can recruit
pericytes to protect them and release
PDGF
6) Vessel cooption: smaller, new tumors
develop around normal blood vessels
Grepin R et al J Oncology 2010
Everolimus: Progression-Free Survival
Central Radiology Review
100
Hazard ratio = 0.30
80
Probability, %
95% CI [0.22, 0.40]
Median PFS
Everolimus: 4.0 mo
Placebo: 1.9 mo
60
40
Log rank P value <0.001
RAD001 (n=272)
Placebo (n=138)
20
0
0
Patients at Risk
Everolimus
Placebo
272
138
2
132
32
Motzer R, Escudier B, Oudard S et al. LBA 5026 ASCO 2008.
4
47
4
6
Months
8
1
8
2
0
12
10
0
0
0
0
Axitinib Progression-free Survival
Progression-Free Survival (probability)
(IRC Assessment)
mPFS, mo
1.0
Axitinib
Sorafenib
0.9
0.8
0.7
95% CI
6.7
4.7
6.3–8.6
4.6–5.6
P<0.0001 (log-rank)
Stratified HR 0.665
(95% CI 0.544–0.812)
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
20
6
10
3
1
1
0
0
Time (months)
Subjects at risk, n
Axitinib 361
Sorafenib 362
256
224
202
157
IRC = Independent Review Committee
145
100
96
51
64
28
38
12
Rini et al ASCO 2011
Treatment of mRCC: 2011
Setting
Untreated
Second-line
Patients
Therapy
Other Options
(level 1 evidence) (>level 1 evidence)
Good or
intermediate risk
Sunitinib
Bevacizumab+IFN
Pazopanib
HD IL-2
Sorafenib
Clinical Trial
Observation
Poor risk
Temsirolimus
Sunitinib
Clinical Trial
Cytokine
refractory
Axitinib
Sorafenib
Sunitinib
Bevacizumab+IFN
Prior VEGF
Axitinib
Everolimus
Clinical Trial
Targeted therapy
not previously used
Case I: JN
•
Began Everolimus 10mg/kg
– No longer required transfusions
– Feeling much better
– Minimal side effects
– Monitored with CT scans and Hb every 3 months
• 3 month CT: stable disease, Hb 135
– 6 months: symptomatic anemia again, Hb 88
• Did not recover with everolimus cessation
• Required transfusions every 3 days
• Deemed to have progressive disease
Case I: JN
What third-line targeted therapy would you
choose?
1)Sunitinib
2)Temsirolimus
3)Everolimus
4)Interferon
5)High dose IL-2
6)Pazopanib
7)Bevacizumab+IFN
8)Clinical Trial
Case I: JN
•
•
Patient chooses pazopanib as she had
third party insurance
Monitored patient with CT scans every 3
months
– 3 months: 18% decrease
– 6 months: slowly progressive liver disease,
lungs stable (15% increase)
– 9 months: progressive disease in liver (20%
increase)
Case I: JN
Screening for clinical trial of BMS PD-1
inhibitor
 Still slightly anemic

Lessons Learned

Targeted therapy extended her life
significantly
 “Thank you, this time last year I thought I
wouldn’t be here anymore”
Progression can come in different ways
and not just on CT scans
 Third line therapy is therapy that you
haven’t used before, if available

Background

Two prospective randomized trials1,2 with metastatic
RCC showed that the addition of cytoreductive
nephrectomy (CN) improves overall survival (OS) as
compared to interferon-alpha (IFN-a) alone (13.6
months vs. 7.8 months; Hazard ratio=0.69, p=0.001)

IFN-a is a historic standard of care.

Patients were enrolled between 1991-1998.

The role of debulking nephrectomy in the era of novel
VEGF-targeted agents remains poorly defined.
1. Flanigan RC et al. N Eng J Med. 2001;345:1655.
2. Mickisch GH et al. Lancet. 2001;358:966
RCC Consortium Database

Consecutive 645 patients with median follow up 25
months.

Metastatic RCC, any histology.

Treated with anti-VEGF agents:
○ Sunitinib
○ Sorafenib
○ Bevacizumab

No prior VEGF-targeted agents.

Data collected using uniform data collection software and
standardized definitions.

Excluded N=331 (s/p nephrectomy, but not cytoreductive).
Overall Survival on Univariable Analysis
mOS: 19.8 vs. 9.4 months
Hazard Ratio:0.44 (95% CI: 0.32-0.59)
p<0.001
Cytoreductive Nephrectomy

Cytoreductive nephrectomy in era of
targeted therapy may produce superior
OS when adjusted for known prognostic
factors
Adjusted Hazard Ratio 0.68 (95% CI: 0.46, 0.99)
Choueiri et al J Urol 2011
The impact of cytoreductive nephrectomy
by risk groups1

Favorable risk group (N=23):
 22/23 underwent CN

Intermediate risk group (N=143):
 HR: 0.46 (95% CI: 0.27-0.78, p=0.004)

Poor risk group (N=117):
 HR: 0.67 (95% CI: 0.44-1.01, p=0.056)
1. Heng et al. JCO 2009; 27: 5794-9
Cytoreductive Nephrectomy by KPS
-KPS>80: 23.9 vs. 14.5 months, p=0.003
-KPS<80: 10.1 vs. 6 months, p=0.077
Cytoreductive Nephrectomy
Cytoreductive Nephrectomy (CN) is
independently associated with an improved
overall survival in metastatic RCC patients
treated with VEGF-targeted agents
 Cytoreductive nephrectomy in era of
targeted therapy may produce superior OS
when adjusted for known prognostic factors
 The benefit seems to be marginal in
patients in the poor-risk group/poor KPS
 Prospective clinical trials in progress

Choueiri et al J Urol 2011
Conclusions

mRCC Treatment Revolution
 VEGF inhibitors
 mTOR inhibitors
 Clinical trials are important to find new drugs
Cytoreductive nephrectomy may be
helpful in certain patients
 Our patients are living much longer than
they used to … progress!!
