success story of m tor inhibitors in m rcc
TRANSCRIPT
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
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
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
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.
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:
Disease Overview:Angiogenesis:
Hallmark of Malignancy:
Proliferation Invasion Metastases
Treatment Failure
Apoptosis Resistance
VEGF ++
TK+
m-TOR
HIF=
VEGFR EGFRPDGFR
Sunitinib, Sorafenib, AG-013736
Sorafenib
Bevacizumab
RAF
Erlotinib
Kaelin WG. Nat Rev Cancer. 2002;2:673-682.
VEGF TGF-aPDGF
RAF
Sorafenib
TemsorilimusEverolimuspVHL
Disease Overview:Molecular Biology:
Disease Overview:Molecular Biology:
VEG
FR
PI3K AKT
Grb SOS
mTOR
Protein Synthesis
HIF-1@Metabolism
Growth
Angiogenesis
RAS
RAF
Mek
Erk
Cell Cycle Progression & Proliferation
PDG
F
EGFR
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 001Sorafinib
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
VEGFRPDGFR
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 VEGFRPDGFR
• Inhibits proliferation of endothelial cells and pericytes*
• Prevents VEGFR and PDGFR signaling
Pazopanib1,6
VEGFRPDGFRc-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
Disease Overview:Guidelines:
Regimen Setting Therapy Options
Treatment-naïve patient
MSKCC risk: Good or intermediate
SunitinibBevacizumab
+ IFN-αPazopanib
High-dose IL-2Sorafenib
Clinical trialObservation
MSKCC risk: Poor Temsirolimus SunitinibClinical trial
Treatment-refractorypatient(≥second line)
Cytokine refractory
Sorafenib BevacizumabSunitinib
Pazopanib
TKIrefractory
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.
• 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
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.
Different MOAe.g. Everolimus
Similar MOAe.g. other TKI
Disease Progression
Sunitinib
Disease Overview:Overcoming Resistance:
Resistance
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:
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:
• 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:
Disease Overview:Overcoming Resistance:
TKI/Bevacizumab mTOR
RANDOMIZATION
2:1
Crossoverupon
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
SurvivalFollow-
up:15 Nov
08
Studyunblinded
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:
No. of Patients at Risk
100
80
60
40
20
0
0 2 4 6 8 10 14
Pro
bab
ilit
y, %
Everolimus (n=277)Median, 4.9 moPlacebo (n=139)Median, 1.9 mo
Time, mo
2 0 0 026 10 1 0Everolimus
Placebo
12
139 47 15 6277 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:
nHR P value
Investigator review
FavourableMSKCC risk
Intermediate
Previous treatment
Sunitinib only
Sorafenib only
Both
Poor
< 65 years
Sex 65 years
Male
Age
Region
EuropeUSA and Canada
Japan and Australia
Female
In favour of everolimus
Central review
In favour of placebo
35
416416
12023561
124184108
263153
32294
130251
0.18
0.330.32
0.310.320.44
0.250.340.32
0.340.33
0.320.39
0.290.38
< .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:
Disease Overview:Overcoming Resistance: RECORD1:
0
Time, months
30
40
50
60
70
80
90
100
Pro
bab
ilit
y, %
Everolimus
Placebo
Reconstructed placebo
202 4 6 8 10 12 14 16 18 22
Kaplan-Meier median OSEverolimus: 14.8 moPlacebo: 14.4 moReconstructed 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.
Disease Overview:Overcoming Resistance: RECORD1:
Everolimus(n=274)
Placebo (n=137)
Event, % All Grades Grade 3/4 All Grades Grade 3/4Stomatitis 44 4/<1 8 0/0Asthenia 33 3/<1 23 4/0Fatigue 31 5/0 27 3/<1Rash 29 1/0 16 0/0Diarrhea 30 1/0 7 0/0Nausea 26 1/0 19 0/0Mucosal inflammation 19 1/0 1 0/0Edema peripheral 25 <1/0 8 <1/0Infections (total) 37 7/3 18 1/0Dyspnea 24 6/1 15 3/0Pneumonitis 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.
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
Disease Overview:Overcoming Resistance: Indirect Comparison:
• 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:
Trial ORR PFS OS
Di Lorenzo phase IISunitinib → Sorafenib 9.6% 3.7 mo (TTP) 7.4 mo
Garcia phase IISunitinib → Sorafenib NR 4.4 mo NR
RECORD-1TKI → 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:
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
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.
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