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Management of mRCC
“Expanding The Landscape of Disease”
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Mansoura Cancer Congress
NOVARTIS Symposium
Fairmont Hotel & Tower
Thursday 27/04/2017
Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, Bayer.
• The content of this presentation does not relate to any product of a
commercial interest
Speaker Disclosures:
Increasing Incidence:
Pantuck, AJ, et al. J Urology 2001; 166:1612
Globocan 2010 (v1.1):
Incidence (ASR): 3.9/100000
Mortality: 1.6/100000
Globocan 2010 (v1.1):
8.5
2.8
2.5
1.3
0
5
10
Incidence Mortality
AgeStandardizedIncidence/100000
More Developed
Countries
Less Developed
Countries
Management of Stage IV RCC:
Treatment Outcome:
Treatment OOR Impact on
PFS &OS
IFN - Alpha 12 – 20% Superior to Cth.
SC IL-2 Alone 12 – 20% Not Demonstrated
SC IL – 2 + IFN @ 20 – 30% Not Demonstrated
High Dose IV IL-2 15 – 25% OS benefit only if CR
3 – 10%
Chemo/Immunotherapy 10 – 30% Not Demonstrated
Mignogna et al. BMC Cancer 2006;6:293
ORR= 14%
M rcc reempowering an old dogma
M rcc reempowering an old dogma
mRCC:
Survival Outcome:
20 months
10 months
4 months
mRCC:
Unmet Treatment Needs:
• Bad Prognosis: 5 – Year median Survival = 9%.
• Bad Therapeutic Outcome:
 Surgery is not the ideal goal for cure.
 Radio-Chemotherapy Trials  Ineffective.
 Immunotherapy: Early Trials  Limited Success.
NCI. SEER Cancer Statistics Fact Sheets: Kidney & Renal Pelvis. Accessed 2008.
mRCC:
Better Insight:
Renal Cell Carcinoma
Angiogenic Tumor Immunogenic Tumor
1. Spontaneous
Remission.
2. Prolonged
Stabilization.
3. TI-Lymph.
4. Durable responses
can be achieved with
cytokine therapy.
Coppin et al. Cochrane Systematic Reviews. (2005);(1): CD001423
mRCC:
Angiogenic Tumor:
VHL
Functional
E3
Ligase
P-VHL
HIF
Non -
Functional
HIF
Responsive
Element
VEGF PDGF
VEGFR PDGFR
Angiogenesis
GFR
Pi3k
AKT
mTOR
Cyclin
C-myc
Proliferation
Morais C. Journal of Kidney Cancer and VHL 2014;1(1):1-11
Bevacizumab
Sunitinib
Sorafenib
Pazobanib
Everolimus
Temsirolimus
Overview of VEGF-targeted agents in mRCC
VEGFR-1
VEGFR-2
VEGFR-3 PDGFR-β
PDGFR-α c-Kit Flt-3
Anti-angiogenesis
Bevacizumab
VEGF-A
VEGF-B
VEGF-C
VEGF-D
VEGF-E
Pazopanib Sorafenib
Raf
Sunitinib
Preclinical in vitro data need to be validated in a clinical setting
mRCC:
Bevacizumab/IFN@-CALGB 90206
Rini et al.J Clin Oncol. 2010 28:2137-2143.
mRCC:
Sorafinib:
05/2005
P = 0.02
11/2005
P = 0.02
Independent
P = 0.02
Investigators
P = 0.001
Escudier et al.N Engl J Med 2007;356:12534.
mRCC:
Temsirolimus: Poor Prognosis Patients:
Hudes et al. N Engl J Med 2007;356:2271-81.
VEGF-TKIs That Did Not Make It to First-Line:
Axitinib – PFS
*Does not meet the protocol-specified significance
boundary of  = .025.
Threshold was .025 instead of .05 because of multiple comparisons. Interim analysis identified that statistical power was low and
increased event number for primary endpoint; trial still failed to achieve significance.
19
Reprinted from Lancet Oncol, 14, Hutson T, et al, Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised
open-label phase 3 trial, 1287-1294, Copyright © 2013, with permission from Elsevier.
Management of Stage IV RCC:
Sunitinib as a 1st Line Therapy versus INF @:
Motzer et al. J Clin Oncol. 2009;27(22):3584-3590.
Management of Stage IV RCC:
Sunitinib as a 1st Line Therapy versus INF @:
Motzer et al. J Clin Oncol. 2009;27(22):3584-3590.
Management of Stage IV RCC:
Sunitinib as a 1st Line Therapy versus INF @:
Motzer et al. J Clin Oncol. 2009;27(22):3584-3590.
Management of Stage IV RCC:
Pazopanib as a 1st Line Therapy versus Placebo:
J Clin Oncol.2010.28:1061-1068.
Median OS
Pazopanib (n=290) 22.9 months
Placebo (n=145) 20.5 months
HR=0.91
(95% CI=0.71–1.16)
p=0.224
Pazopanib phase III study (VEG105192):
final OS results (all patients)1,2
1. Sternberg et al. ESMO 2010;Abstract LBA22 (presentation).
2. Sternberg et al. Eur J Cancer 2013;49:1287–96.
Number at risk
Pazopanib 290
Placebo 145
Time, months
0
0.2
0.4
0.6
0.8
1.0
0 10 20 30 40
Time of crossover:
OSprobability
213
93
147
71
95
53
25
9
Pazopanib phase III study
(VEG105192): ORR1
1. Sternberg et al. J Clin Oncol 2010;28:1061–8.
p<0.001
Pazopanib
Placebo
30
3 3
32
4
29
Overall population
(n=435)
Treatment-naive
(n=155)
Cytokine-pretreated
(n=78)
35
30
25
20
15
10
5
0
ORR,%
Management of Stage IV RCC:
Angiogenic Tumor:
Vazquez et al. Adv Ther (2012) 29(3):202-217.
Efficacy Data in Metastatic RCC Clinical Trials:
Management of Stage IV RCC:
Current Situation:
Management of Stage IV RCC:
NCCN Guidelines:
M rcc reempowering an old dogma
A New Scenario:
Maximising Efficacy as the Primary Goal in mRCC
Treatment
30
1. Escudier B, et al. Lancet. 2007;370:2103-2111; 2. Escudier B. Cancer J. 2008;14:325-329; 3. Motzer RJ, et al. J Clin
Oncol. 2009;27:3584-3590; 4. Motzer RJ, et al. N Engl J Med. 2007;356:115-124; 5. Heng DY, et al. Cancer. 2009;115:776-
783.
mRCC
Evolving Expectaions
Palliation
Efficacy
Outcome
+++ PFS
1. Motzer RJ, et al. N Engl J Med. 2013;369:722-731; 2. Motzer RJ, et al. N Engl J Med. 2014;370:1769-1780; 3. Escudier B, et al. J Clin Oncol. 2014:32:1412-1418.
Efficacy1,2
>2 years overall survival in clinical trials
PFS in real-world consistent with clinical
trials
Safety1,3
Well characterised
safety profiles
Treatment discontinuation due to
AEs <25%
Quality of Life3
Assessing QOL is becoming common in
clinical trials
Validation of tools to improve the
accuracy of PRO
31
Can we offer every patient with mRCC:
Critical Reviews in Oncology/Hematology 107 (2016) 44–53
Critical Reviews in Oncology/Hematology 107 (2016) 44–53
Critical Reviews in Oncology/Hematology 107 (2016) 44–53
COMPARZ (COMParing the efficacy, sAfety and
toleRability of paZopanib vs sunitinib)1
1. Motzer et al. N Engl J Med 2013;369:722–31.
Sunitinib 50 mg QD,
4 weeks on, 2 weeks off treatment
(n=553)
Pazopanib 800 mg QD,
continuous dosing
(n=557)
Key eligibility criteria
Advanced/mRCC, clear-cell histology
No prior systemic therapy
Measurable disease (RECIST 1.0)
KPS ≥70
Adequate organ function
R
A
N
D
O
M
I
S
A
T
I
O
N
n=1,110
Stratification
KPS 70/80 vs 90/100
Prior nephrectomy
Baseline LDH >1.5 vs
≤1.5 ×ULN
Primary endpoint
PFS (non-inferiority))
Secondary endpoints
OS
ORR
Medical resource
utilization
Safety
HRQoL
Management of Stage IV RCC:
Sunitinib versus Pazobanib:
Motzer et al. N Engl J Med 2013;369:722-31.
Item Pazobanib Sunitinib Significance
mPFS 8.4 m 9.5 m NS
PR 31% 24% 0.03
mOAS 28.4 m 29.3 m NS
Med.
Duration of
Therapy
8 m 7.6 m NS
Significant
Interruptions
44% 49% NS
LFTs.
Abnormalities
6% 1% NS
Pazobanib is Non Inferior to Sunitinib.
Management of Stage IV RCC:
Sunitinib versus Pazobanib:
Motzer et al. N Engl J Med 2013;369:722-31.
Management of Stage IV RCC:
Sunitinib versus Pazobanib:
Motzer et al. N Engl J Med 2013;369:722-31.
Management of Stage IV RCC:
Sunitinib versus Pazobanib:
Motzer et al. N Engl J Med 2013;369:722-31.
COMPARZ: Treatment modifications and
discontinuations due to AEs
44 2451 20
0
10
20
30
40
50
60
70
80
90
100
Dose reduction Treatment discontinuation due
to AEs
Percentpatients,%
Median duration of treatment
Pazopanib: 8.0 months (range 0–40)
Sunitinib: 7.6 months (range 0–38)
Sunitinib (n=548)
Pazopanib (n=553)
Pazopanib
Liver event (6%)*
Sunitinib
Cytopenia (3%)
Most common reasons for
discontinuation
*Patients who discontinued pazopanib
treatment due to a liver event returned to
baseline LFT levels.
Motzer RJ, et al. N Engl J Med
2013;369:722–731.
AE = adverse event.
COMPARZ: conclusions1
• This phase III trial demonstrated non-inferiority of pazopanib
vs sunitinib for PFS
• Pazopanib efficacy was supported by similar ORR and OS to
sunitinib
• The differentiated safety profile of pazopanib vs sunitinib
included:
– Lower incidence of hand–foot syndrome, fatigue and mucositis
– Higher incidence of liver function test abnormalities
• QoL assessments favoured pazopanib over sunitinib
1. Motzer et al. New Engl J Med 2013;369:722–31.
Traditional endpoints in oncology trials
Standardised assessments
RECIST1
• Measurable lesions defined by unidimensional measurement
• Tumour burden based on sum of diameters
• Categories of response: complete response (CR); partial response
(PR) (30% ), stable disease (SD); progressive disease (PD) (20% )
Common Terminology Criteria (CTC)2
• Descriptive terminology used for AE reporting
• If a patient experiences an AE, the highest grade (severity) is
recorded
How well do traditional endpoints and assessments reflect the symptom
burden as experienced by the patient?
Endpoint
Efficacy
• PFS
• OS
• Response rate
Safety
• Adverse events
• Dose modifications
1. Eisenhauer EA, et al. Eur J Cancer 2009;45:228−47;
2. Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03 (2010) available at
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed Aug
OS, overall survival;
PFS, progression-free survival;
RECIST, Response Evaluation Criteria in Solid Tumours.
PISCES (PazopanIb vs Sunitinib patient preferenCE Study in
treatment-naive advanced
or metastatic RCC)1, 2
1. Escudier et al. J Clin Oncol 2014;32:1412–8.
2. Escudier et al. J Clin Oncol 2012;30(Suppl):Abstract CRA4502
n=169*
Eligibility criteria:
Previously
untreated mRCC,
any histology
Measurable or non-
measurable disease
ECOG performance
status 0 or 1
Good or
intermediate
prognosis (MSKCC)
No brain metastases
Adequate cardiac
and renal function
R
A
N
D
O
M
I
S
A
T
I
O
N
Pazopanib
800 mg QD
(n=86)
Sunitinib 50 mg daily, 4
weeks on, 2 weeks off
treatment
Sunitinib 50 mg daily, 4
weeks on, 2 weeks off
treatment
(n=82)
Pazopanib
800 mg QD
Period 1
(10 weeks)
Period 2
(10 weeks)
2-week
washout
Off
study
Further
treatment
depending
on patient
preference
Drugs blinded by over-encapsulation; patients on sunitinib
received matching placebo during 2-week off period
*One patient was randomised in error;
therefore data are available on 168 patients
Pazopanib study (PISCES): Patient preference for
treatment
• Patients were still blinded when they stated their preference and before they were informed
of the final disease assessment
0
10
20
30
40
50
60
70
80
90
100
Preferred pazopanib Preferred sunitinib No preference
Patients,%
p<0.001*
70%
(n=80)
22%
(n=25)
8%
(n=9)
Escudier B, et al. J Clin Oncol 2014;32:1412–1418.
*Prescott’s test
Pazopanib study (PISCES): Physician and patient
preference
• Physicians were still blinded when they stated their preference
Physician/patientpreference,%
61%
(n=69)
70%
(n=80)
22%
(n=25)
22%
(n=25) 17%
(n=19)
8%
(n=9)
0
10
20
30
40
50
60
70
80
90
100
Preferred pazopanib Preferred sunitinib No preference
Physician preference
Patient preference
Escudier B, et al. J Clin Oncol 2014;32:1412–1418.
PISCES: Factors influencing patient choice
Patients expressing a preference (%)
0 10 20 30 40 50 60 70
Better quality of life
Less fatigue
Less taste change
Less mucositis/stomatitis
Less nausea/vomiting
Less hand-foot syndrome
Better appetite
Less stomach pain
Less diarrhoea
Less hair colour change
Not reported
Pazopanib preferred (n=80)
Sunitinib preferred (n=25)
Patients could select >1 reason
Escudier B, et al. J Clin Oncol 2014;32:1412–1418.
M rcc reempowering an old dogma
Significant Reduction of AEs with 2/1
Schedule: Retrospective:
Miyake et al. Med Oncol (2015) 32:78
Significant Reduction of AEs with 2/1
Schedule: Prospective:
mOAS 12.6 m 11.9 m NS
Najjar et al. European Journal of Cancer (2014) 50, 1084– 1089
M rcc reempowering an old dogma
Synergistic Survival:
A Link to Adverse Events:
Nagyivanyi et al. Clinical Genitourinary Cancer, 2015, Vol. 14, No. 4, 314-22
2nd Line Data
M rcc reempowering an old dogma
M rcc reempowering an old dogma
M rcc reempowering an old dogma
M rcc reempowering an old dogma
M rcc reempowering an old dogma
M rcc reempowering an old dogma
Management of Stage IV RCC:
NCCN Guidelines:
M rcc reempowering an old dogma
M rcc reempowering an old dogma
M rcc reempowering an old dogma
M rcc reempowering an old dogma
M rcc reempowering an old dogma
Toni et al. J Clin Oncol. 2016. 35:591-597.
CABOSUN: Efficacy Data:
mPFS = 8.2 vs 5.6 ms HR = 0.66 mOAS = 30.3 vs 21.8 ms HR = 0.80
Toni et al. J Clin Oncol. 2016. 35:591-597.
Immunotherapy:
M rcc reempowering an old dogma
M rcc reempowering an old dogma
Clear Takehome Message
First Line Second Line
Sunitinib Pazopanib Everolimus
M rcc reempowering an old dogma
M rcc reempowering an old dogma
Thank you

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M rcc reempowering an old dogma

  • 1. Management of mRCC “Expanding The Landscape of Disease” Mohamed Abdulla M.D. Prof. of Clinical Oncology Cairo University Mansoura Cancer Congress NOVARTIS Symposium Fairmont Hotel & Tower Thursday 27/04/2017
  • 2. Member of Advisory Board, Consultant, and Speaker for: • Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, Bayer. • The content of this presentation does not relate to any product of a commercial interest Speaker Disclosures:
  • 3. Increasing Incidence: Pantuck, AJ, et al. J Urology 2001; 166:1612
  • 4. Globocan 2010 (v1.1): Incidence (ASR): 3.9/100000 Mortality: 1.6/100000
  • 5. Globocan 2010 (v1.1): 8.5 2.8 2.5 1.3 0 5 10 Incidence Mortality AgeStandardizedIncidence/100000 More Developed Countries Less Developed Countries
  • 6. Management of Stage IV RCC: Treatment Outcome: Treatment OOR Impact on PFS &OS IFN - Alpha 12 – 20% Superior to Cth. SC IL-2 Alone 12 – 20% Not Demonstrated SC IL – 2 + IFN @ 20 – 30% Not Demonstrated High Dose IV IL-2 15 – 25% OS benefit only if CR 3 – 10% Chemo/Immunotherapy 10 – 30% Not Demonstrated Mignogna et al. BMC Cancer 2006;6:293
  • 11. mRCC: Unmet Treatment Needs: • Bad Prognosis: 5 – Year median Survival = 9%. • Bad Therapeutic Outcome:  Surgery is not the ideal goal for cure.  Radio-Chemotherapy Trials  Ineffective.  Immunotherapy: Early Trials  Limited Success. NCI. SEER Cancer Statistics Fact Sheets: Kidney & Renal Pelvis. Accessed 2008.
  • 12. mRCC: Better Insight: Renal Cell Carcinoma Angiogenic Tumor Immunogenic Tumor 1. Spontaneous Remission. 2. Prolonged Stabilization. 3. TI-Lymph. 4. Durable responses can be achieved with cytokine therapy. Coppin et al. Cochrane Systematic Reviews. (2005);(1): CD001423
  • 13. mRCC: Angiogenic Tumor: VHL Functional E3 Ligase P-VHL HIF Non - Functional HIF Responsive Element VEGF PDGF VEGFR PDGFR Angiogenesis GFR Pi3k AKT mTOR Cyclin C-myc Proliferation Morais C. Journal of Kidney Cancer and VHL 2014;1(1):1-11 Bevacizumab Sunitinib Sorafenib Pazobanib Everolimus Temsirolimus
  • 14. Overview of VEGF-targeted agents in mRCC VEGFR-1 VEGFR-2 VEGFR-3 PDGFR-β PDGFR-α c-Kit Flt-3 Anti-angiogenesis Bevacizumab VEGF-A VEGF-B VEGF-C VEGF-D VEGF-E Pazopanib Sorafenib Raf Sunitinib Preclinical in vitro data need to be validated in a clinical setting
  • 15. mRCC: Bevacizumab/IFN@-CALGB 90206 Rini et al.J Clin Oncol. 2010 28:2137-2143.
  • 16. mRCC: Sorafinib: 05/2005 P = 0.02 11/2005 P = 0.02 Independent P = 0.02 Investigators P = 0.001 Escudier et al.N Engl J Med 2007;356:12534.
  • 17. mRCC: Temsirolimus: Poor Prognosis Patients: Hudes et al. N Engl J Med 2007;356:2271-81.
  • 18. VEGF-TKIs That Did Not Make It to First-Line: Axitinib – PFS *Does not meet the protocol-specified significance boundary of  = .025. Threshold was .025 instead of .05 because of multiple comparisons. Interim analysis identified that statistical power was low and increased event number for primary endpoint; trial still failed to achieve significance. 19 Reprinted from Lancet Oncol, 14, Hutson T, et al, Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial, 1287-1294, Copyright © 2013, with permission from Elsevier.
  • 19. Management of Stage IV RCC: Sunitinib as a 1st Line Therapy versus INF @: Motzer et al. J Clin Oncol. 2009;27(22):3584-3590.
  • 20. Management of Stage IV RCC: Sunitinib as a 1st Line Therapy versus INF @: Motzer et al. J Clin Oncol. 2009;27(22):3584-3590.
  • 21. Management of Stage IV RCC: Sunitinib as a 1st Line Therapy versus INF @: Motzer et al. J Clin Oncol. 2009;27(22):3584-3590.
  • 22. Management of Stage IV RCC: Pazopanib as a 1st Line Therapy versus Placebo: J Clin Oncol.2010.28:1061-1068.
  • 23. Median OS Pazopanib (n=290) 22.9 months Placebo (n=145) 20.5 months HR=0.91 (95% CI=0.71–1.16) p=0.224 Pazopanib phase III study (VEG105192): final OS results (all patients)1,2 1. Sternberg et al. ESMO 2010;Abstract LBA22 (presentation). 2. Sternberg et al. Eur J Cancer 2013;49:1287–96. Number at risk Pazopanib 290 Placebo 145 Time, months 0 0.2 0.4 0.6 0.8 1.0 0 10 20 30 40 Time of crossover: OSprobability 213 93 147 71 95 53 25 9
  • 24. Pazopanib phase III study (VEG105192): ORR1 1. Sternberg et al. J Clin Oncol 2010;28:1061–8. p<0.001 Pazopanib Placebo 30 3 3 32 4 29 Overall population (n=435) Treatment-naive (n=155) Cytokine-pretreated (n=78) 35 30 25 20 15 10 5 0 ORR,%
  • 25. Management of Stage IV RCC: Angiogenic Tumor: Vazquez et al. Adv Ther (2012) 29(3):202-217. Efficacy Data in Metastatic RCC Clinical Trials:
  • 26. Management of Stage IV RCC: Current Situation:
  • 27. Management of Stage IV RCC: NCCN Guidelines:
  • 29. A New Scenario: Maximising Efficacy as the Primary Goal in mRCC Treatment 30 1. Escudier B, et al. Lancet. 2007;370:2103-2111; 2. Escudier B. Cancer J. 2008;14:325-329; 3. Motzer RJ, et al. J Clin Oncol. 2009;27:3584-3590; 4. Motzer RJ, et al. N Engl J Med. 2007;356:115-124; 5. Heng DY, et al. Cancer. 2009;115:776- 783. mRCC Evolving Expectaions Palliation Efficacy Outcome +++ PFS
  • 30. 1. Motzer RJ, et al. N Engl J Med. 2013;369:722-731; 2. Motzer RJ, et al. N Engl J Med. 2014;370:1769-1780; 3. Escudier B, et al. J Clin Oncol. 2014:32:1412-1418. Efficacy1,2 >2 years overall survival in clinical trials PFS in real-world consistent with clinical trials Safety1,3 Well characterised safety profiles Treatment discontinuation due to AEs <25% Quality of Life3 Assessing QOL is becoming common in clinical trials Validation of tools to improve the accuracy of PRO 31 Can we offer every patient with mRCC:
  • 31. Critical Reviews in Oncology/Hematology 107 (2016) 44–53
  • 32. Critical Reviews in Oncology/Hematology 107 (2016) 44–53
  • 33. Critical Reviews in Oncology/Hematology 107 (2016) 44–53
  • 34. COMPARZ (COMParing the efficacy, sAfety and toleRability of paZopanib vs sunitinib)1 1. Motzer et al. N Engl J Med 2013;369:722–31. Sunitinib 50 mg QD, 4 weeks on, 2 weeks off treatment (n=553) Pazopanib 800 mg QD, continuous dosing (n=557) Key eligibility criteria Advanced/mRCC, clear-cell histology No prior systemic therapy Measurable disease (RECIST 1.0) KPS ≥70 Adequate organ function R A N D O M I S A T I O N n=1,110 Stratification KPS 70/80 vs 90/100 Prior nephrectomy Baseline LDH >1.5 vs ≤1.5 ×ULN Primary endpoint PFS (non-inferiority)) Secondary endpoints OS ORR Medical resource utilization Safety HRQoL
  • 35. Management of Stage IV RCC: Sunitinib versus Pazobanib: Motzer et al. N Engl J Med 2013;369:722-31. Item Pazobanib Sunitinib Significance mPFS 8.4 m 9.5 m NS PR 31% 24% 0.03 mOAS 28.4 m 29.3 m NS Med. Duration of Therapy 8 m 7.6 m NS Significant Interruptions 44% 49% NS LFTs. Abnormalities 6% 1% NS Pazobanib is Non Inferior to Sunitinib.
  • 36. Management of Stage IV RCC: Sunitinib versus Pazobanib: Motzer et al. N Engl J Med 2013;369:722-31.
  • 37. Management of Stage IV RCC: Sunitinib versus Pazobanib: Motzer et al. N Engl J Med 2013;369:722-31.
  • 38. Management of Stage IV RCC: Sunitinib versus Pazobanib: Motzer et al. N Engl J Med 2013;369:722-31.
  • 39. COMPARZ: Treatment modifications and discontinuations due to AEs 44 2451 20 0 10 20 30 40 50 60 70 80 90 100 Dose reduction Treatment discontinuation due to AEs Percentpatients,% Median duration of treatment Pazopanib: 8.0 months (range 0–40) Sunitinib: 7.6 months (range 0–38) Sunitinib (n=548) Pazopanib (n=553) Pazopanib Liver event (6%)* Sunitinib Cytopenia (3%) Most common reasons for discontinuation *Patients who discontinued pazopanib treatment due to a liver event returned to baseline LFT levels. Motzer RJ, et al. N Engl J Med 2013;369:722–731. AE = adverse event.
  • 40. COMPARZ: conclusions1 • This phase III trial demonstrated non-inferiority of pazopanib vs sunitinib for PFS • Pazopanib efficacy was supported by similar ORR and OS to sunitinib • The differentiated safety profile of pazopanib vs sunitinib included: – Lower incidence of hand–foot syndrome, fatigue and mucositis – Higher incidence of liver function test abnormalities • QoL assessments favoured pazopanib over sunitinib 1. Motzer et al. New Engl J Med 2013;369:722–31.
  • 41. Traditional endpoints in oncology trials Standardised assessments RECIST1 • Measurable lesions defined by unidimensional measurement • Tumour burden based on sum of diameters • Categories of response: complete response (CR); partial response (PR) (30% ), stable disease (SD); progressive disease (PD) (20% ) Common Terminology Criteria (CTC)2 • Descriptive terminology used for AE reporting • If a patient experiences an AE, the highest grade (severity) is recorded How well do traditional endpoints and assessments reflect the symptom burden as experienced by the patient? Endpoint Efficacy • PFS • OS • Response rate Safety • Adverse events • Dose modifications 1. Eisenhauer EA, et al. Eur J Cancer 2009;45:228−47; 2. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (2010) available at http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed Aug OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumours.
  • 42. PISCES (PazopanIb vs Sunitinib patient preferenCE Study in treatment-naive advanced or metastatic RCC)1, 2 1. Escudier et al. J Clin Oncol 2014;32:1412–8. 2. Escudier et al. J Clin Oncol 2012;30(Suppl):Abstract CRA4502 n=169* Eligibility criteria: Previously untreated mRCC, any histology Measurable or non- measurable disease ECOG performance status 0 or 1 Good or intermediate prognosis (MSKCC) No brain metastases Adequate cardiac and renal function R A N D O M I S A T I O N Pazopanib 800 mg QD (n=86) Sunitinib 50 mg daily, 4 weeks on, 2 weeks off treatment Sunitinib 50 mg daily, 4 weeks on, 2 weeks off treatment (n=82) Pazopanib 800 mg QD Period 1 (10 weeks) Period 2 (10 weeks) 2-week washout Off study Further treatment depending on patient preference Drugs blinded by over-encapsulation; patients on sunitinib received matching placebo during 2-week off period *One patient was randomised in error; therefore data are available on 168 patients
  • 43. Pazopanib study (PISCES): Patient preference for treatment • Patients were still blinded when they stated their preference and before they were informed of the final disease assessment 0 10 20 30 40 50 60 70 80 90 100 Preferred pazopanib Preferred sunitinib No preference Patients,% p<0.001* 70% (n=80) 22% (n=25) 8% (n=9) Escudier B, et al. J Clin Oncol 2014;32:1412–1418. *Prescott’s test
  • 44. Pazopanib study (PISCES): Physician and patient preference • Physicians were still blinded when they stated their preference Physician/patientpreference,% 61% (n=69) 70% (n=80) 22% (n=25) 22% (n=25) 17% (n=19) 8% (n=9) 0 10 20 30 40 50 60 70 80 90 100 Preferred pazopanib Preferred sunitinib No preference Physician preference Patient preference Escudier B, et al. J Clin Oncol 2014;32:1412–1418.
  • 45. PISCES: Factors influencing patient choice Patients expressing a preference (%) 0 10 20 30 40 50 60 70 Better quality of life Less fatigue Less taste change Less mucositis/stomatitis Less nausea/vomiting Less hand-foot syndrome Better appetite Less stomach pain Less diarrhoea Less hair colour change Not reported Pazopanib preferred (n=80) Sunitinib preferred (n=25) Patients could select >1 reason Escudier B, et al. J Clin Oncol 2014;32:1412–1418.
  • 47. Significant Reduction of AEs with 2/1 Schedule: Retrospective: Miyake et al. Med Oncol (2015) 32:78
  • 48. Significant Reduction of AEs with 2/1 Schedule: Prospective: mOAS 12.6 m 11.9 m NS Najjar et al. European Journal of Cancer (2014) 50, 1084– 1089
  • 50. Synergistic Survival: A Link to Adverse Events: Nagyivanyi et al. Clinical Genitourinary Cancer, 2015, Vol. 14, No. 4, 314-22
  • 58. Management of Stage IV RCC: NCCN Guidelines:
  • 64. Toni et al. J Clin Oncol. 2016. 35:591-597.
  • 65. CABOSUN: Efficacy Data: mPFS = 8.2 vs 5.6 ms HR = 0.66 mOAS = 30.3 vs 21.8 ms HR = 0.80 Toni et al. J Clin Oncol. 2016. 35:591-597.
  • 69. Clear Takehome Message First Line Second Line Sunitinib Pazopanib Everolimus