Role of Evirolimus in the management of Renal Call Carcinoma.

1. Success Story of m-TOR
Inhibitors in mRCC.
Mohamed Abdulla (M.D.)
Prof. of Clinical Oncology
Kasr Al-Aini School of Medicine
Cairo University
Oncology in Focus
Grand Hyatt, Cairo
16/05/2013

2. Disease Overview:
Natural History:
RCC
3% of all
Cancers
30%
Metastatic at
Presentation
30%
Metastatic
Later
High Symptom
Burden
Rapidly Fatal
Heterogeneous
Disease
RCC
Immunogenic
Highly
Vascular
Rosalie et al. Seminars in Cancer Biology 23 (2013)
38– 45

3. Disease Overview:
Chemo-Hormonal therapy:
Treatment OOR Impact on
PFS &OS
Chemo/Immunoth-
erapy
10 – 30% Not Demonstrated
Chemotherapy 0 – 10% Non
Hormonal Therapy 0 – 10% Non
Mignogna et al. BMC Cancer 2006;6:293

4. Disease Overview:
Immunotherapy:
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
Cochrane Review 2005.

5. BHD=Birt-Hogg-Dubé, FH=fumarate hydratase, VHL=von Hippel-Lindau.
Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.
RCC
Clear cell
75%
Type
Incidence
(%)
Associated
mutations
VHL
Papillary type 1
5%
c-Met
Papillary type 2
10%
FH
Chromophobe
5%
BHD
Oncocytoma
5%
BHD
Disease Overview:
Histologic Subtypes:

6. Disease Overview:
Angiogenesis:
Hallmark of Malignancy:
Proliferation Invasion Metastases
Treatment
Failure
Apoptosis
Resistance
VEGF +
+
TK
+
m-TOR

7. HIF=
VEGFR EGFRPDGFR
Sunitinib,
Sorafenib,
AG-013736
Sorafenib
Bevacizumab
RAF
Erlotinib
Kaelin WG. Nat Rev Cancer. 2002;2:673-682.
VEGF TGF-aPDGF
RAFSorafenib
Temsorilimus
EverolimuspVHL
Disease Overview:
Molecular Biology:

8. Disease Overview:
Molecular Biology:
VEGFR
AKT
Grb SOS
mTOR
Protein Synthesis
HIF-1@
Metabolism
Growth
Angiogenesis
RAS
RAF
Mek
Erk
Cell Cycle Progression &
Proliferation
1. Avastin [package insert]. South San Francisco, CA: Genentech; 2009. 2. Escudier B et al; TARGET Study Group. N Engl J
Med. 2007;356:125-134. 3. Escudier B et al. J Clin Oncol. 2009;27:3312-3318. 4. Nexavar [package insert]. Wayne, NJ: Bayer
Healthcare Pharmaceuticals; 2007.
Bevacizumab
RAD 001

9. Disease Overview:
Drug Specificity in mRCC:
Molecular
Target(s)
Downstream Effect(s)
Everolimus1,2 mTOR
• Inhibits cell growth and proliferation of tumor cells, fibroblasts,
endothelial cells, and pericytes
• Prevents production of HIF-1α, VEGF, and other angiogenic growth
factors
Temsirolimus1,3 mTOR
• Inhibits cell growth and proliferation of tumor cells, fibroblasts,
endothelial cells, and pericytes
• Prevents production of HIF-1α, VEGF, and other angiogenic growth
factors
Sorafenib1,4
VEGFR
PDGFR
Raf
• Inhibits proliferation of endothelial cells and pericytes*
• Prevents VEGFR and PDGFR signaling
• Blocks Ras/Raf pathway activation by growth factor receptor signaling
Sunitinib1,5 VEGFR
PDGFR
• Inhibits proliferation of endothelial cells and pericytes*
• Prevents VEGFR and PDGFR signaling
Pazopanib1,6
VEGFR
PDGFR
c-KIT
• Inhibits proliferation of endothelial cells and pericytes*
• Prevents VEGFR and PDGFR signaling
Bevacizumab1,7 VEGF • Inhibits proliferation of endothelial cells*
*May also inhibit VGFR-driven tumour cell proliferation
1. Ljungberg B, Hanbury DC, Kuczyk MA, et al. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed May 12, 2010. 2. Afinitor-
EMEA/499201/2009 EMEA/H/C/1038 3. Temsirolimus- EMEA/783677/2009 EMA/H/C/799 4. Sorafenib- EMEA/H/C/690 5. Sunitinib- EMEA/H/C/687 6. Pazopanib-
EMEA/123712/2010 EMEA/H/C/1141 7. Bevacizumab- EMEA/506050/2009 EMEA/H/C/582

10. Disease Overview:
Guidelines:
Regimen Setting Therapy Options
Treatment-naïve
patient
MSKCC risk:
Good or
intermediate
Sunitinib
Bevacizumab
+ IFN-α
Pazopanib
High-dose IL-2
Sorafenib
Clinical trial
Observation
MSKCC risk: Poor Temsirolimus Sunitinib
Clinical trial
Treatment-
refractory
patient
(≥second line)
Cytokine
refractory
Sorafenib Bevacizumab
Sunitinib
Pazopanib
TKI
refractory
Everolimus Clinical trials
MSKCC = Memorial Sloan-Kettering Cancer Center.
The RCC treatment algorithm is based on international treatment
guideline recommendations
Ljungberg B, et al. Eur Urol. 2010;58:398-406. Escudier B and Kataja V. Ann Oncol 2010;21(Suppl 5):V137-V139. de Reijke TM et al. Eur J Cancer
2009 45:765-773. National Comprehensive Cancer Network guidelines V1.2011. Available at
http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf.

11. • Complete & Durable Responses are Rare.
• Rapid Progression & High Fatality.
• Acquired Resistance.
• Toxicity Profiles.
Disease Overview:
Problems with Targeted Therapies:
1ry
Refractory
1ry
Responsive
Rini BI, Flaherty K. Clinical effect and future considerations for molecularly targeted therapy in renal cell carcinoma. Urologic
Oncology 2008;26: 543–9.
6 – 12 months

12. Disease Overview:
Developing Resistance:
Angiogenesis Angiogenic
Escape
1. Multiple Molecular Pathways.
2. Over-expression of Other
Growth Factors.
Sunitinib
TKI
RTK
1ry
Therapy
Lee AJ, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA, et al. Chromosomal instability confers intrinsic multidrug resistance.
Cancer Research 2011;71:1858–70.

13. Different MOA
e.g. Everolimus
Similar MOA
e.g. other TKI
Disease
Progression
Sunitinib
Disease Overview:
Overcoming Resistance:
Resistance

14. Sequence
Sablin, et al. 2009 Dudek, et al. 2009
No. of
Patients ORR* SD
No. of
Patients ORR* SD
Sorafenib 
sunitinib
68 15% 51% 29 21% 38%
Sunitinib 
sorafenib
22 9% 55% 20 5% 30%
– Data suggest anti-tumour activity of second agent
– No obvious correlation of response to first VEGFR-TKI
with response to second VEGFR-TKI
– Limited safety data available
Sablin, et al. J Urol. 2009;182:29-34; Dudek, et al. Cancer. 2009;115:61-67.
*After the second agent.
VEGFR = vascular endothelial growth factor
receptor.
Disease Overview:
Overcoming Resistance: Retrospective:

15. Disease Overview:
Overcoming Resistance: Prospective:
•Phase II study of sorafenib in sunitinib-refractory patients
•Primary endpoint
• ORR: 9.6% (95% CI: 5–17)
• Did not achieve endpoint for positive study: 15% ORR
•Secondary endpoints
• Median TTP was 4 months
• Median OS was 8 months
•Response to sunitinib did NOT predict for response to sorafenib
•The dose of sorafenib was reduced by 25% in 36 (33.0%) cycles and
by 50% in 18 (16.5%) cycles as a result of grade 2–4 toxicity
Cycle 1 Cycle 2
PR, n 0 5
SD, n 40 5
PD, n 12 42
Di Lorenzo, et al. J Clin Oncol. 2009;27:4469-4474.
TTP = time to progression.
Di Lorenzo Phase II Prospective Study:

16. • Limitations:
• Sorafenib was less active than the investigators
expected thus the response rate was initially over
estimated for the study design and statistical
analysis plan
• Conclusions:
• Sorafenib has manageable toxic effects and
limited efficacy in sunitinib-refractory mRCC.
Further clinical trials, specially comparing a TKI
with an mTOR inhibitor, will define the best
second-line treatment for patients who experience
treatment failure with first-line sunitinib.
Di Lorenzo, et al. J Clin Oncol. 2009;27:4469-4474.
Disease Overview:
Overcoming Resistance: Prospective:
Di Lorenzo Phase II Prospective Study:

17. Disease Overview:
Overcoming Resistance:
TKI/Bevacizumab mTOR

18. R
A
N
D
O
M
I
Z
A
T
I
O
N
2:1
Crossover
upon
disease
progression
Safety
Interim
Analysis
N=416
Stratification
 Prior VEGFR-
TKI: 1 or 2
 MSKCC risk
group:
Favorable,
intermediate,
or poor
2nd Interim
Analysis Data
Cutoff: 15 Oct
07
(N=410)
End of
Double- Blind
Analysis
Data Cutoff:
28 Feb 08
Survival
Follow-
up:
15 Nov
08
Study
unblinded
BSC = best supportive care; VEGFR = vascular
endothelial growth factor receptor; TKI =tyrosine
kinase inhibitors; MSKCC = Memorial Sloan-Kettering
Cancer Center.
Everolimus 10 mg/d + BSC
(n=277)
Placebo + BSC
(n=139)
Motzer RJ, et al. Cancer. 2010;116(18):4256-65.
Disease Overview:
Overcoming Resistance: RECORD1:

19. No. of Patients at Risk
100
80
60
40
20
0
0 2 4 6 8 10 14
Probability,%
Everolimus (n=277)
Median, 4.9 mo
Placebo (n=139)
Median, 1.9 mo
Time, mo
2 0 0 0
26 10 1 0Everolimus
Placebo
12
139 47 15 6
277 192 115 51
HR = 0.33 (95% CI: 0.25,
0.43)
Log-rank P <.001
ITT = intent-to-treat
Motzer RJ, et al. Cancer. 2010;116(18):4256-65.
More than
Double
PFS
Disease Overview:
Overcoming Resistance: RECORD1:

20. nHR P value
Investigator review
Favourable
MSKCC risk
Intermediat
e
Previous
treatment
Sunitinib
only
Sorafenib
only
Both
Poor
< 65 years
Sex
 65 years
Male
Age
Region
Europe
USA and
Canada
Japan and
Australia
Female
In favour of everolimus
Central review
In favour of placebo
35
416
416
120
235
61
124
184
108
263
153
322
94
130
251
0.18
0.33
0.32
0.31
0.32
0.44
0.25
0.34
0.32
0.34
0.33
0.32
0.39
0.29
0.38
< .001
< .001
< .001
< .001
< .001
.007
< .001
< .001
< .001
< .001
< .001
< .001
< .001
< .001
< .001
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Motzer RJ, et al. Cancer. 2010;116(18):4256-65. Bellmunt J. Sunday, 18 April 2010 (Novartis sponsored Symposium), 25th Annual EAU Congress, Barcelona, Spain.
Disease Overview:
Overcoming Resistance: RECORD1:

21. Disease Overview:
Overcoming Resistance: RECORD1:
0
Time, months
30
40
50
60
70
80
90
100
Probability,%
Everolimus
Placebo
Reconstructed placebo
202 4 6 8 10 12 14 16 18 22
Kaplan-Meier median OS
Everolimus: 14.8 mo
Placebo: 14.4 mo
Reconstructed placebo: 10.0 mo
• RPSFT estimate of survival with everolimus was 1.9×  (90% CI: 0.5
to 8.5) vs. placebo
• The “reconstructed” median OS for placebo was 10.0 months vs. the
uncorrected
value of 14.4 months
Rank preserving
structural failure
time (RPSFT)
analysis is a
statistical method
that allows
estimation of
survival time
gained by anyone
receiving active
treatment2
1. Motzer RJ, et al. Cancer. 2010;116(18):4256-65. 2. Robins JM, et al. Comm Stat Theory Meth. 1991;20:2609-2631.

22. Disease Overview:
Overcoming Resistance: RECORD1:
Everolimus
(n=274)
Placebo
(n=137)
Event, % All Grades Grade 3/4 All Grades Grade 3/4
Stomatitis 44 4/<1 8 0/0
Asthenia 33 3/<1 23 4/0
Fatigue 31 5/0 27 3/<1
Rash 29 1/0 16 0/0
Diarrhea 30 1/0 7 0/0
Nausea 26 1/0 19 0/0
Mucosal inflammation 19 1/0 1 0/0
Edema peripheral 25 <1/0 8 <1/0
Infections (total) 37 7/3 18 1/0
Dyspnea 24 6/1 15 3/0
Pneumonitis 14 4/0 0 0/0
4 treatment-related deaths: 1 each of candidal sepsis/ARDS, sepsis, acute respiratory failure,
and recurrent bronchopulmonary aspergillosis
Motzer RJ, et al. Cancer. 2010;116(18):4256-65.

23. Disease Overview:
Overcoming Resistance: JAC Trial:
• Phase II trial of everolimus in VEGFR-TKI–refractory
patients
Patients receiving everolimus after prior TKI (sunitinib or
sorafenib) had a PFS of 6.5 months and an OS of 16.3 months
Jac, et al. J Clin Oncol. 2008;26:ab5113.
Prior VEGFR-TKI
(N=26)
PR, n (%) 0 (0)
SD ≥3 mo, n (%) 22 (88)
PD or SD for <3 mo, n (%) 3 (12)
PFS, mo 6.5+
VEGFR = vascular endothelial growth factor receptor. TKI = Tyrosine Kinase Inhibitor

24. Disease Overview:
Overcoming Resistance:
Indirect Comparison:

25. • Everolimus resulted in a clinically meaningful increase in median
OS relative to sorafenib: 82.4 weeks (95% CI: 78–86) vs. 32.0
weeks (95% CI: 22–64).
• Everolimus resulted in a clinically meaningful increase in median
PFS relative to sorafenib: 32.0 weeks (95% CI: 31–38] vs. 16.0
weeks (95% CI: 8–40).
Conclusion:
Second-line treatment with everolimus in the sunitinib-refractory
patient population may have a potential added survival benefit when
compared with sorafenib.
Di Lorenzo G, Casciano R, Malagone E, et al. 35th Congress of the European Society for Medical Oncology (ESMO); October
8-12, 2010; Milan, Italy
Disease Overview:
Overcoming Resistance:
Indirect Comparison:

26. Trial ORR PFS OS
Di Lorenzo phase II
Sunitinib → Sorafenib
9.6% 3.7 mo (TTP) 7.4 mo
Garcia phase II
Sunitinib → Sorafenib
NR 4.4 mo NR
RECORD-1
TKI → Everolimus
2% 4.9 mo 14.8 mo
Jac Phase II
TKI → Everolimus 0% 6.5 mo 16.3 mo
Merchan Phase II
TKI → Temsirolimus + Bevacizumab 18% 5.3 mo (TTP) 14.5 mo
Di Lorenzo, et al. J Clin Oncol. 2009;27:1-6; Garcia JA, et al. Cancer 2010 Dec 1;116(23):5383-90; Motzer RJ, et al. Cancer 2010;116:4256–65;
Jac, et al. J Clin Oncol. 2008;26:ab5113; Merchan, et al. J Clin Oncol. 2009;27:ab5039.
NR = not reported; TTP = time to progression.
Disease Overview:
Overcoming Resistance:
Indirect Comparison:

27. RCC Guidelines Recommend
Everolimus as Second-line
Therapy
aCat 1 recommendation is based on high-level evidence and there is uniform NCCN consensus.
bBased on 1 good-quality RCT.
cBased on clinical studies of good quality and consistency addressing the specific recommendations and including at least 1 randomized trial.
Category 1 recommendation following TKIa
Everolimus can be recommended as second-line
treatment after failure of TKIs.
Grade A recommendationc
Standard of care after failure of a TKI.
Level 1b recommendationb
Recommended as second-line therapy after
TKI failure
Recommended as second-line therapy after TKIs

28. Conclusions:
• Unprecedented advances in the systemic treatment of advanced
RCC from 2003 to 2010 have changed our approach to RCC
• Resistance to VEGFR inhibitors develops at a median of 5-11
months and disease progression can be rapid especially if
treatment is stopped1-4
• Although retrospective studies suggest efficacy5-8, prospective
phase II studies do not support sequential use of sorafenib after
sunitinib failure9-10
• Sequential therapy that targets a different MOA (everolimus in
VEGFR-TKI–refractory mRCC) significantly improves PFS compared
with placebo
– Not changing MOA (i.e., TKI → TKI) has limited efficacy benefits in
prospective trials, with possible safety issues
• Everolimus is well tolerated and demonstrates a favourable risk-
benefit ratio
• Sequence of TKI → mTOR inhibitor → TKI is feasible, but needs
further evaluation
• Current level 1 guideline recommendations support changing MOA
(i.e., TKI → mTOR inhibitor) for second-line therapy after failure
of initial VEGF-targeted therapy
1. Rini BI, et al. Lancet. 2009;373(9669):1119-1132. 2. Escudier B, et al. N Engl J Med. 2007;356:125-134. 3. Motzer RJ, et al. N
Engl J Med. 2007;356:115-124. 4. Rini BI, et al. Lancet Oncol. 2009;10:992-1000. 5. Sablin, et al. J Urol. 2009;182:29-34. 6.
Dudek, et al. Cancer. 2009;115:61-73. 7. Choueiri, et al. Ann Oncol. 2008;19:ab593P. 8. Richter, et al. Onkologie. 2008;31:abV684.
9. Di Lorenzo, et al. J Clin Oncol. 2009;27:4469-4474. 10. Shepard, et al. J Clin Oncol. 2008;26:ab5123.

29. Thank You