Part III – Renal Cell Carcinoma Thursday, September 13, 2012 7:30 PM – 8:30 PM ET
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Transcript of Part III – Renal Cell Carcinoma Thursday, September 13, 2012 7:30 PM – 8:30 PM ET
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Part III – Renal Cell CarcinomaThursday, September 13, 20127:30 PM – 8:30 PM ET
RTP TV: A Live CME Webcast Series Focused on Emerging Data Sets and Novel Therapeutic Strategies in the Management of Common Cancers
Thomas E Hutson, DO, PharmDDirector, GU Oncology ProgramCo-Director, GU Center of Excellence, Texas Oncology, PACharles A Sammons Cancer Center and Baylor University Medical CenterProfessor of Medicine, Texas A&M Health Science Center College of MedicineCo-Chair of GU Research, US OncologyDallas, Texas
Robert J Motzer, MD Medical Oncologist Memorial Sloan-Kettering Cancer Center New York, New York
Neil Love, MDResearch To PracticeMiami, Florida
Agenda — Renal Cell Carcinoma
• New Developments in mRCC
– Anti-PD-1
– Tivozanib
– Axitinib
– Cabozantinib
– Pazopanib
• Algorithm for Selecting Systemic Therapy
• Management of Toxicities with Novel Agents
– mTOR inhibitors
– TKIs
New Developments in mRCC
At this time, there is no known tissue or serum predictor of response to anti-PD-1.
Blockade of T-Cell Signaling in Tumor Immunotherapy
Ribas A et al. N Engl J Med 2012;366(26):2517-9.
Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with previously treated metastatic renal cell carcinoma (mRCC)McDermott DF et al. Proc ASCO 2012;Abstract 4505.
Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer
Topalian SL et al. N Engl J Med 2012;366(26):2443-54.
Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer
Brahmer JR et al. N Engl J Med 2012;366(26):2455-65.
Phase I Studies of Anti-PD-1/PD-L1 Agents: Advanced RCC Patient Subgroup
Clinical parameter
Anti-PD-1a
Anti-PD-L1b
10 mg/kg
(n = 17)
1 mg/kg
(n = 17)
10 mg/kg
(n = 16)
Objective response rate
4 (24%) 5 (31%) 2 (12%)
Stable disease at ≥24 weeks
4 (24%) 5 (31%) 7 (41%)
Duration of response (range)
5.6 - >17.5 mo 8.4 - >22.3 mo 4 - 17 mo
PFS rate at 24 weeks 47% 67% 53%
a Topalian SL et al. N Engl J Med 2012;366(26):2443-54. b Brahmer JR et al. N Engl J Med 2012; 366(26):2455-65.
Anti-PD-1 Treatment-Related Adverse Events: Advanced RCC Patient Subgroup (n = 34)
Adverse event (AE)* All grades Grades 3-4†
Any adverse event 82% 18%
Fatigue 38% 0%
Rash 24% 0%
Pruritis 18% 3%
Diarrhea 15% 0%
Decreased appetite 9% 0%
Nausea 6% 0%
McDermott DF et al. Proc ASCO 2012;Abstract 4505.
* All doses of anti-PD-1† Most common Grade 3-4 AEs were respiratory system disorders (2 pts) and hypophosphatemia (2 pts).
AgentIC50 (nM)
VEGFR-1 VEGFR-2 VEGFR-3
Tivozanib 0.21 0.16 0.24
Axitinib 1.2 0.25 0.29
Sunitinib 2 10 17
Pazopanib 10 47 30
Dovitinib 10 13 8
Sorafenib Not reported 90 20
Eskens FALM et al. Proc AACR 2008;Abstract LB-201; Nakamura K et al. Cancer Res 2006;66:9134-42; Chow LQ et al. J Clin Oncol 2007;25:884-96; Lee SH et al. Clin Cancer Res 2005;11:3633-41.
Relative Potencies of TKIs
Tivozanib is associated with fewer side effects and is more tolerable than sorafenib.
Tivozanib: Summary of Key Attributes
• Potent pan-VEGFR inhibitor
• Highly selective TKI for the VEGF receptors
• Favorable pharmacokinetic profile that enables
once-daily dosing
• Oral administration
Chow LQ et al. J Clin Oncol 2007;25:884-96. Eskens FALM et al. Proc AACR 2008;LB-201.
Tivozanib versus Sorafenib as Initial Targeted Therapy for Patients with Advanced Renal Cell Carcinoma: Results from a Phase III Randomized, Open-Label, Multicenter Trial
Motzer RJ et al. Proc ASCO 2012;Abstract 4501.
• Primary endpoint: Progression-free survival superiority of tivozanib
TIVO-1: A Phase III Trial of First-Line Tivozanib versus Sorafenib in Advanced RCC
Tivozanib(n = 260)Tivozanib(n = 260)
R
Advanced RCCClear cell histologyPrior nephrectomyNo prior VEGF or mTOR therapy
Sorafenib(n = 257)Sorafenib(n = 257)
Crossover to tivozanib via separate protocol
Progression
Motzer RJ et al. Proc ASCO 2012;Abstract 4501.
TIVO-1: Progression-Free Survival
With permission from Motzer RJ et al. Proc ASCO 2012;Abstract 4501.
Time (months)
Pro
bab
ility
of
PF
S
N Median PFS HR p-value
Tivozanib 260 11.9 mo0.797 0.042
Sorafenib 257 9.1 mo
TIVO-1: Treatment-Emergent Adverse Events
Adverse event, %
Tivozanib
(n = 259)
Sorafenib
(n = 257)
All grade Grade 3 (4) All grade Grade 3 (4)
Diarrhea 22 2 32 6
Hand-foot syndrome 13 2 54 17
Alopecia 2 0 21 0
Hypertension 44 24 (2) 34 17 (<1)
Dysphonia 21 0 5 0
Motzer RJ et al. Proc ASCO 2012;Abstract 4501.
Fewer dose interruptions and reductions and treatment discontinuations occurred on the tivozanib arm.
Sorafenib: Reported Progression-FreeSurvival Values Over Time
With permission from Eisen T. ASCO 2012 Discussant
Japan (PH2)RDD (PH2)
Target (PH3)
6.7
7.4
5.5 5.7
8.3
6.5
6.6
8.4
9.0
9.2
NA-ARCCS(Expanded
Access)
Sorafenib vs IFN
(PH2)
AXIS/Prior
Cytokine(PH3)
EU-ARCCS Overall (Expanded Access)
Italian Clinical Experience
AMG 386 (PH2) and Japan CI. Exp.
EU-ARCCS ECOG-0 (Expanded Access)
Yellow = includes treatment naïve patientsGray = prior treatment with cytokine therapy and/or selective therapy targeting the angiogenesis pathway
Publication Year
Rep
ort
ed
Med
ian
PFS
(M
on
ths)
Sorafenib Studies Safety
TARGET Ph III AMG 386 TIVO-1
Hypertension(Grade 3-4) % 17 (4) 46 (14) 34 (17)
Fatigue(Grade 3-4) %
37 (5) 22 (0)16 (4)
HFS(Grade 3-4) % 30 (6) 54 (28) 54 (17)
Diarrhea(Grade 3-4) % 43 (2) 56 (8) 32 (6)
Overall AEs(Grade 3-4) % 95 (38) 100 (86) NR
Dose reduction/ interruption %
13 DR21 DI
35 DR61 DI
43 DR35 DI
Eisen T. ASCO 2012 Discussant
• Primary endpoint: Patient preference for tivozanib or sunitinib after having received both in sequence
• Secondary endpoints: Safety, frequency of dose modifications and quality of life
TAURUS: A Phase II Crossover-Controlled Study of First-Line Tivozanib versus Sunitinib in Advanced RCC
TivozanibTivozanib SunitinibSunitinib
RUntreated, advanced RCC
Target Accrual: 160 (Open)
1:1TivozanibTivozanibSunitinibSunitinib
www.clinicaltrials.gov. Accessed September 2012.
Primary outcome measures:
•Correlation of predefined biomarkers for tivozanib activity present in blood and tumor tissue with clinical activity and/or treatment-related toxicity
•Progression-free survival rate at 6 months
BATON: A Phase II Biomarker Assessment of Tivozanib in Oncology Trial in Patients with Advanced RCC
TivozanibTivozanib
Unresectable locally recurrent or metastatic RCC
Prior nephrectomy
≤1 prior systemic therapy (no prior VEGF- or mTOR-targeted therapy)
Trial Identifier: NCT01297244 Target Accrual: 105 (Closed)
Hutson TE et al. Proc ASCO 2012;Abstract TPS4686.
There is a significant association between the development of hypertension and the antitumor benefit with axitinib.
Comparative Effectiveness of Axitinib versus Sorafenib in Advanced Renal Cell Carcinoma (AXIS): A Randomised Phase 3 TrialRini B et al. Lancet 2011;378(9807):1931-9.
AXIS: Progression-Free Survival in Patients with RCC Receiving Second-Line Axitinib or Sorafenib
Rini B et al. Lancet 2011;378(9807):1931-9.
Axitinib Sorafenib
Median PFS 6.7 mo 4.7 mo
Stratified hazard ratio 0.665
p-value <0.0001
Axitinib for First-Line Metastatic RCC: Overall Efficacy and Pharmacokinetic Analyses from a Randomized Phase II Study
Rini BI et al. Proc ASCO 2012;Abstract 4503.
Clinical Outcome According to Diastolic Blood Pressure on Cycle 1 Day 15
Rini BI et al. Proc ASCO 2012;Abstract 4503.
Blood pressure parameter mPFS ORR
AUC12
ng.h/mLa
ΔdBP≥10 mmHg, n = 39
<10 mmHg, n = 22
16.7 mo
8.3 mo
59%
45%
176
63
ΔdBP≥15 mmHg, n = 20
<15 mmHg, n = 41
19.3 mo
11.1 mo
60%
51%
235
93
ΔdBP≥90 mmHg, n = 17
<90 mmHg, n = 46
22.5 mo
13.7 mo
65%
50%
195
110
a Geometric meandBP = diastolic blood pressure (per ambulatory blood pressure monitoring); ΔdBP = change in dBP from baseline
Cabozantinib has resulted in bone scan and symptom improvements in prostate cancer but no other solid tumor.
Efficacy of Cabozantinib (XL184) in Patients with Metastatic, Refractory Renal Cell Carcinoma
Choueiri TK et al. Proc ASCO 2012;Abstract 4504.
Partial Bone Scan Resolution and Pain Relief in a Symptomatic Patient with Bone Metastases
With permission from Choueiri TK et al. Proc ASCO 2012;Abstract 4504.
• Patient substantially reduced narcotic use by 7 weeks; continued on reduced narcotics until week 25
• Another patient with bone metastases and pain at baseline reported complete resolution of pain by 4 weeks- Pain free 90+ weeks on
study
Prior therapies include sorafenib, everolimus, and sunitinib
Baseline 7-week follow-up
Cabozantinib Efficacy Summary
Clinical parameter
Cabozantinib
(N = 25)
Objective response rate, n (%)
Confirmed partial response
Stable disease
7 (28%)
13 (52%)
DCR at 16 weeks 18 (72%)
Median duration of response Not yet estimable
Median PFS 14.7 mo
Median OS Not reached
DCR = disease control rate defined as partial response + stable disease at 16 weeks
Choueiri TK et al. Proc ASCO 2012;Abstract 4504.
Pazopanib has about the same efficacy as sunitinib as first-line treatment but is strongly preferred by patients.
Patient Preference between Pazopanib (Paz) and Sunitinib (Sun): Results of a Randomized Double-Blind, Placebo-Controlled, Cross-Over Study in Patients with Metastatic Renal Cell Carcinoma (mRCC) — PISCES Study, NCT 01064310
Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.
Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.
Study Design
Pazopanib800 mg OD Pazopanib
800 mg OD
Sunitinib50 mg 4/2a
Sunitinib50 mg 4/2a
Sunitinib50 mg 4/2a
Sunitinib50 mg 4/2a
Patient preference for further treatment
Patient preference for further treatment
10 weeks 2-weekwashout
End of study
Time (weeks)Stratification factors:• ECOG PS (0 vs 1)• Metastatic sites (1 vs ≥2)
R
10 weeks
Period 1 Period 2
Pazopanib800 mg OD Pazopanib
800 mg OD
Double-blind phase
1:1
N = 169
2212100
a 4 weeks on treatment 2 weeks matching placebo 4 weeks on treatment.ECOG PS, Eastern Cooperative Oncology Group performance status
Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.
Study Design
Pazopanib Pazopanib
SunitinibSunitinib
SunitinibSunitinib
Patient preference for further treatment
Patient preference for further treatment
R
Period 1 Period 2
PazopanibPazopanib
1:1
N = 169
Week 0 2 4 6 8 10 12 14 16 18 20 22
Patient preference
EQ-5D
FACIT-F
SQLQ
CT CT* CT
* Could occur earlier if the patient crossed over early due to AE
Primary Endpoint: Patient PreferencePrimary Analysis Population
With permission from Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.
70%
22%8%
Pe
rce
nt o
f Pa
tien
ts
Difference (pazopanib vs sunitinib) 49.3%
90% CI for difference 37.0% - 61.5%
p-value <0.001
With permission from Escudier BJ et al. Proc ASCO 2012;Abstract CRA4502.
Which Reasons Influenced Their ChoicePrimary Analysis Population• Patients were able to select >1 option
Number of Patients
• Primary endpoint: Progression-free survival
COMPARZ: A Phase III Trial of Pazopanib versus Sunitinib in Locally Advanced or Metastatic RCC
PazopanibPazopanib
R
Untreated, advanced or metastatic RCC
Clear cell component histology
SunitinibSunitinib
Trial Identifier: NCT00720941 Target Accrual: 927 (Closed)
1:1
www.clinicaltrials.gov. Accessed September 2012.
Algorithm for Selecting Systemic Therapy
For patients with asymptomatic primary RCC and symptomatic mets, do you generally recommend nephrectomy?
What is your likely initial systemic treatment for RCC in a younger (age 55), otherwise healthy patient with low-volume asymptomatic mets?
What is your likely initial systemic treatment for RCC in an elderly (age 78), otherwise healthy patient with low-volume asymptomatic mets?
Management of Toxicities with Novel Agents
A patient about to receive sunitinib asks what the chance is that the drug will need to be held or stopped due to toxicity?
A patient about to receive everolimus asks what the chance is that the drug will need to be held or stopped due to toxicity?
An International Expanded-Access Programme of Everolimus: Addressing Safety and Efficacy in Patients with Metastatic Renal Cell Carcinoma Who Progress After Initial Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor TherapyGrünwald V et al. REACT Study Group.Eur J Cancer 2012;48(3):324-32.
REACT: Efficacy and Safety of Everolimus
Everolimus
(n = 1,367)
Partial response 1.7%
Stable disease 51.6%
Grade 3 or 4 adverse event
Anemia 13.4%
Fatigue 6.7%
Dyspnea 6.5%
Hyperglycemia 5.5%
Stomatitis 5.4%
Pneumonia 4.2%
Pneumonitis 2.7%
Grünwald V et al. Eur J Cancer 2012;48(3):324-32.
• In the REACT study, safety findings and tumor responses were consistent with those observed in RECORD-1.
Dabydeen DA et al. Eur J Cancer 2012;48:1519-24.
Best Response with Everolimus/Temsirolimus in Relation to Pneumonitis
No. of patients
Stable Disease
Progressive Disease
Pneumonitis 14 85.7% 14.3%
No Pneumonitis
32 43.8% 56.3%
• Primary endpoint: Progression-free survival after first-line therapy (noninferiority)
RECORD-3: A Phase II Study of Everolimus as First- and Second-Line Treatments for Metastatic RCC
EverolimusEverolimus
RMetastatic RCC
SunitinibSunitinib
Trial Identifier: NCT00903175 Target Accrual: 460 (Closed)
www.clinicaltrials.gov. Accessed September 2012.
SunitinibSunitinib
EverolimusEverolimus
• Primary endpoint: Overall survival
• Secondary endpoint: Progression-free survival, objective response rate, toxicity
CALGB 90802: A Phase III Trial of Everolimus with or without Bevacizumab for Advanced RCC
Everolimus +BevacizumabEverolimus +Bevacizumab
Metastatic, unresectable RCC, some clear cell histology
Treated with ≥1 prior VEGF TKI,progressed/intolerant to therapy
No active brain metastases
Metastatic, unresectable RCC, some clear cell histology
Treated with ≥1 prior VEGF TKI,progressed/intolerant to therapy
No active brain metastases Everolimus +Placebo
Everolimus +Placebo
Trial Identifier: NCT01198158Target Accrual: 700 (Open)
R
www.clinicaltrials.gov. Accessed September 2012.
Faculty Case: Dr Motzer
• A 70-year-old man
• 2008: Nephrectomy: conventional clear cell type RCC
– pT3b tumor grossly extended into renal vein(s) or vena cava
– Mets: right adrenal, left psoas muscle, left inguinal nodes
• Sunitinib: PR 18 months
– Dose reduction to 37.5 mg for fatigue and hand-foot reaction
• At progression: Everolimus: SD 6 months
– Grade 1 fatigue, weight loss, dyspnea on exertion, rash, chills, nausea, vomiting, bleeding gums and myalgias
– Bilateral pulmonary infiltrates but no respiratory symptoms
Faculty Case: Dr Hutson
• A 67-year-old man s/p sunitinib, tivozanib (trial)• On Phase II trial of everolimus for 11 months
Faculty Case: Dr Motzer
• A 43-year-old woman
• 2008: Laparoscopic radical nephrectomy with lymph node dissection
– Type II papillary RCC
• 2009: Subphrenic, peritoneal and hepatic nodules
– Biopsy: RCC
– Rx: Sunitinib 50 mg (4 weeks on/2 weeks off)
• Progression after 2 cycles
• Temsirolimus for 2 years – stable disease
– Grade 1 nausea, fatigue, headache, cough, mucositis, hypercholesterolemia, epistaxis, bilateral pedal edema and skin rash
Faculty Cases: TKIs
• Dr Hutson: 57-year-old man treated with tivozanib
• Dr Motzer: 70-year-old man treated with tivozanib
• Dr Hutson: 65-year-old man treated with axitinib
• Dr Motzer: 64-year-old man treated with axitinib
• Dr Hutson: 65-year-old woman treated with sunitinib
Faculty Case: Dr Hutson
• A 57-year-old man with metastatic clear cell RCC
– On tivozanib for 13 months
Faculty Case: Dr Motzer
• A 70-year-old man
• 2004: Right radical nephrectomy for clear cell RCC
• CT/MRI: Bilateral adrenal metastases
• RCC confirmed by needle biopsy
• Tivozanib (trial): PR for 30 months then progressed
– Tolerated tivozanib well (mild abdominal pain and myalgia)
Faculty Case: Dr Hutson
• A 65-year-old man with mRCC
• On front-line Phase III trial:
– Axitinib 2 mg po BID (dose reduced due to toxicity)
– Near CR at 20 months on therapy
Faculty Case: Dr Motzer
• A 64-year-old man
• 2007: Left nephrectomy clear cell RCC
– Mets to lung
– Hypertension; on 1 antihypertensive
– Sunitinib for 2 years: Dose reduction because of hand-foot syndrome
– Progression in lung and bone
• Axitinib (trial)
– PR: 23 four-week cycles
– Hypertension worse
– Required dose reduction for Grade 3 diarrhea
Faculty Case: Dr Hutson
• A 65-year-old woman with hematuria
– 10-cm renal mass with renal vein involvement
– Pulmonary metastases too numerous to count
– Retroperitoneal nodes, liver metastases
• Sunitinib: Cytopenias, hospitalizations (neutropenia, thrombocytopenia)
Schedule of Events
Thursday, October 11Advanced Prostate CancerChristopher J Logothetis, MD A Oliver Sartor, MD