Transcript Targeted Therapeutics in Urothelial Cancer: Early Results

Renal cell cancer: Integrating novel
agents into a therapeutic algorithm
Robert Dreicer, M.D., FACP
Chairman Department of Solid Tumor Oncology
Taussig Cancer Institute
Cleveland Clinic
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Metastatic Renal Cell Carcinoma:
Initial Therapy Considerations
Role of cytoreductive nephrectomy
 Sequential therapy
 Combination therapy
 Metastatic Kidney cancer as a
chronic disease?

Cytoreductive Nephrectomy: Current
Status
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
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Debulking nephrectomy has become a standard of
care in selected patients
Combined analysis of two prospective trials
demonstrated an overall survival (OS) advantage for
the nephrectomy group (mean survival, 13.6 v 7.8
months for the interferon alone arm)
Appropriate candidates:

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ECOG performance status of 0 or 1
Resectable primary tumor representing the majority of
tumor
No evidence of rapidly progressing extrarenal disease
No prohibitive medical comorbidities
Flanigan RC, et al. J Urol 171:1071 2004
Cytoreductive Nephrectomy: Current
Status

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Two randomized trials are ongoing
Metastatic RCC patients randomized to
upfront nephrectomy or not followed by
sunitinib for all patients
Second study is identical with the exception
of delayed nephrectomy in patients initially
randomly assigned to sunitinib
RCC (Clear Cell) Treatment Algorithm: 2012
Setting
Patients
Therapy
(level 1evidence)
Other Options
(≥ level 2)
Good/
Intermediate
risk
Sunitinib
Bevacizumab +
IFN
HD IL-2
Pazopanib
Sorafenib
Clinical trial
Observation
Poor risk
Temsirolimus
Sunitinib
Clinical trial
Cytokinerefractory
Sorafenib
Sunitinib
Bevacizumab
VEGF-R
refractory
Everolimus
Axitinib
Clinical trial
Sunitinib
Sorafenib
mTOR-refractory
Clinical trial
Clinical trial
Untreated
*Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007
Sequential Therapy

Developed as empiric necessity

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As drugs came on line, they were used as salvage
therapy i.e. sorafenib followed by sunitinib
Choice of initial therapy increasingly seen as
not as important given therapeutic paradigm


However, some patients have bad disease and
don’t get a second line therapy
The absence of data doesn’t mean it doesn’t matter
Sequential Therapy
Sequenced monotherapy has activity in RCC

Patients with the most favorable underlying biology will
have the greatest absolute overall survival as they will
receive multiple active treatments

Toxicity matters
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Significant numbers of patients long-term
responders
A consensus definition of ‘treatment-refractory’
RCC and identification of prognostic factors would
aid in the interpretation of clinical results
Sequential Therapy

A critical question for sequential therapy in
RCC is an understanding of the mechanism of
resistance which could guide the choice of next
treatment:
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Target a different pathway
Target the same pathway in a different way
Target the same target, but more potently
Take a drug holiday, then restart same drug
The spectrum and potency of VEGF-R inhibitors
is not identical
VEGF
R1
VEGF
R2
VEGF
R3
PDGFR
α
PDGFR
β
KIT
FLT3
RET
Sorafenib
NA
90
100
50-60
80
68
46
100-150
Sunitinib
10
4
10
5-10
10
13
1-10
100-200
Pazopanib
10
30
47
71
84
72
>1000
>1000
Axitinib
1.2
0.2
0.3
5
1.6
1.7
>1000
>1000
AV-951
0.21
0.16
0.24
1.7
1.6
BAY 73-4506
16
5
46
NR
74
7
440
1
3
3
35
31
48
13
ABT-869
* Inhibitory concentrations (kinase IC50 in nanomoles) for relevant targets
Selecting Salvage Therapy
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Level 1 evidence
Two phase III trials
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Everolimus
Axitinib
Everolimus Phase III
• Metastatic RCC
(clear cell component)
• Prior VEGF-R TKI with
RECIST PD ≤ 6
months:
sunitinib (50%),
sorafenib (25%)
or both (25%)
(other tx. permitted)
• MSKCC
favorable (30%),
intermediate (55%),
or poor risk (15%)
R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Everolimus 10 mg QD + BSC
(n = 272)
Disease
Progression
Placebo + BSC
(n = 138)
Hazard ratio = 0.30
95% CI [0.22, 0.40]
Median PFS
Everolimus: 4.0 mo
Placebo:
1.9 mo
Axitinib vs Sorafenib as Second-line Therapy for Metastatic Renal
Cell Carcinoma: Results of the Phase 3 AXIS Trial
Treatment-refractory
metastatic RCC
R
A
N
D
O
M
I
Z
E
Axitinib 5 mg BID†
Sorafenib 400 mg BID
1:1
Randomization stratified by ECOG PS and type of prior treatment
†Starting
dose 5 mg BID with option for dose titration to 10 mg BID
Rini B, et al. Lancet 2011 378:9807
Rini B, et al. Lancet 2011 378:9807
Management of Advanced RCC:
Current Status
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More than 5 years into the “novel agent”
paradigm in RCC, some sobering thoughts
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We don’t cure folks
Toxicity/cost are issues
Drug holidays
Timing of therapy ( does everyone need treatment
immediately)
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The treatment should not be worse than the disease
Accurate assessment of disease progression

Not always what the radiology report states
Disparity in Reporting of Progression in Metastatic Renal Cell
Carcinoma Patients Treated with Sunitinib According to Radiology
and Medical Oncology
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The medical records of a subset of mRCC
patients treated at the Cleveland Clinic who
had received sunitinib for > 6 months were
retrospectively reviewed
All Radiology reports from post-baseline
scans (every 2 cycles) were reviewed for text
in the body or conclusion of the Radiology
report consistent with disease progression
(specifically the terms ‘progressive’, ‘new’
and/or ‘interval enlargement/worsening’)
Ali H, et al. GU ASCO 2012
Disparity in Reporting of Progression in Metastatic Renal Cell
Carcinoma Patients Treated with Sunitinib According to Radiology
and Medical Oncology
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47 patients were identified with characteristics
typical of an mRCC population
The majority of patients were reported by Radiology
to have progression of existing metastatic sites only,
with 21% of patients having both existing site
progression and new metastatic disease
The median lag between Radiology’s report of PD
and Med Onc was 2.8 months (range 0-12.6+
months), with 5 patients not yet considered to have
progressed by Med Onc
In almost 50% of cases the Med Onc call was >3
months later than Radiology
Ali H, et al. GU ASCO 2012
Management of Advanced RCC:
Current Status
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Level 1 evidence to help drive decision making for
front-line and second line therapy is available
Optimal front line therapy for good/intermediate risk
patients remains unclear (some data is comingphase III pazopanib vs sunitinib)
Optimal therapy for non clear cell remains undefined
Combination therapy remains investigational: its
more toxic than you would think, don’t try this at
home
"It's not what you don't know
that hurts you; it's what you
know that just ain't so."
Satchel Paige