Transcript Slide 1

Advances in Treatment of
Renal Cell Carcinoma: Evolving Role
of mTOR Inhibitors
Gary R. Hudes MD
Fox Chase Cancer Center
Philadelphia, PA
Targeted Therapies for Treatment
of Advanced RCC
•
•
•
•
•
•
Bevacizumab +/- Interferon
Sorafenib
Sunitinib
Temsirolimus
Everolimus
Others in development
– Axitinib
– Pazopanib
IL-2 Highly Effective in Subset of Patients
• In meta-analysis (N=255)1
– Overall response rate (ORR) = 15%
– Complete response (CR) rate = 7%
– Median response duration, 54 mo (3 to >131)
• Duration among patients with CR, >80 mo
– Median OS, 16.3 mo
• 5- to 10-yr survival rate, 10%–20%
– Grade 3/4 toxicities with high-dose IL-2
• Hypotension (36%); malaise (21%); nausea/vomiting
(13%); oliguria (12%); CNS orientation (10%)
– Patient selection: most responders have clear cell
RCC, high tumor carbonic anhydrase IX
1. Fisher RJ et al. J Sci Am. 2000;6(S1):55
2. Yang JC et al. J Clin Oncol. 2003;21(16):3127
Sunitinib vs IFN-a in First-Line RCC:
Phase III Trial
Sunitinib
50 mg PO qd for 4 wk then 2 wk off for repeated
6-wk cycles
(n=375)
Patients with
untreated
metastatic RCC
(N=750)
Stratified based on performance status,
LDH level, prior nephrectomy
IFN-a
9 MU SC 3×/wk
(n=375)
Outcome
Sunitinib
IFN-a
P value
ORR,* %
39
8
<.000001
Median PFS,*
mo
11
5
<.000001
26.4
21.8
.051
Median OS, mo
HR (95% CI)
*By independent review
Figlin RA et al. J Clin Oncol. 2008;26. Abstract 5024
0.821 (0.673–1.001)
Bevacizumab + IFN-a vs IFN-a in
First-Line RCC: Phase III Trials
IFN-a + bevacizumab
IFN a-2a 9 MIU SC 3×/wk +
bevacizumab 10 mg/kg q 2 wk
Patients with untreated
metastatic RCC
IFN-a
9 MIU SC 3×/wk
(+ placebo on AVOREN trial)
AVOREN1 (N=649)
Outcome
ORR, %
Median PFS, %
HR (95% CI)
IFN-a +
Bevacizumab
(n=327)
IFN-a +
Placebo
(n=322)
31
10.2
CALGB 902062 (N=732)
P value
IFN-a +
Bevacizumab
(n=369)
IFN-a
(n=363)
P value
13
.0001
25.5
13.1
<.0001
5.4
.0001
8.5
5.2
<.0001
0.63 (0.52–0.75)
CALGB = Cancer And Leukemia Group B
1. Escudier B et al. Lancet. 2007;370(9605):2103
2. Rini BI et al. J Clin Oncol. 2008;26(33):5422
0.71 (0.61–0.83)
Temsirolimus in Poor-Risk,
Untreated Metastatic RCC: Phase III
Temsirolimus
25 mg IV qiw
(n=209)
Patients with previously
untreated, poor prognosis,
mRCC (N=626)
IFN-a
3–18 MU SC tiw
(n=207)
Temsirolimus 15 mg IV qw
+ IFN-a 6 MU SC tiw
(n=210)
Outcome
IFN-a
TEM
TEM + IFN-a
Median OS, mo
7.3
10.9
8.4
Median PFS, mo
1.9
3.8
3.7
ORR, %
4.8
8.6
8.1
Clinical benefit,* %
15.5
32.1†
28.1‡
*Clinical benefit = CR + PR + SD for ≥24 wk
†P<.001 vs IFN-a
‡P=.002 vs IFN-a
Hudes G et al. N Engl J Med. 2007;356(22):2271
SD = stable disease
Temsirolimus in Poor-Risk,
Untreated Metastatic RCC: Phase III
OS
Probability of Survival
1.00
0.75
Temsirolimus
0.50
Combination
IFN
0.25
0.00
0
5
10
20
15
25
30
Time (mo)
No. at Risk
IFN
207
126
80
42
15
3
0
Temsirolimus
209
159
110
56
19
3
0
Combination
210
135
93
50
17
7
2
Hudes G et al. N Engl J Med. 2007;356(22):2271
Poor-Risk Features for Eligibility in Phase
III Temsirolimus Trial
• Minimum of 3 of 6 poor-risk features required
– Lactose dehydrogenase: >1.5 x upper limit
of normal
– Hemoglobin: < lower limit of normal
– Corrected calcium: >10 mg/dL
– Time from RCC diagnosis to randomization:
<1 year
– Karnofsky performance status: 60-70
– Metastases in multiple organs
Hudes G et al. N Engl J Med. 2007;356:2271.
Efficacy of Targeted Agents After
First-Line Cytokines
Parameter
Sorafenib1
Sunitinib3
Bevacizumab4
Dose
400 mg BID
50 mg/day
4 wk on/2 wk off
10 mg/kg IV q 2 wk
Phase III
Phase II*
Phase II
No. of patients
receiving targeted
agent
451
168
39
ORR, %
10
45
10
Median PFS, mo
5.5
8.4
4.8
Median OS, mo
17.82
19.9
NR
Trial design
*Pooled data from 2 trials
NR = not reported
1. Escudier B et al. N Engl J Med. 2007;356(2):125
2. Bukowski RM et al. J Clin Oncol. 2007;25(18S). Abstract 5023
3. Rosenberg JE et al. J Clin Oncol. 2007;25(18S). Abstract 5095
4. Yang JC et al. N Engl J Med. 2003;349(5):427
Efficacy of Other Sequential Targeted
Agent Strategies
1st-Line Therapy 
2nd-Line Therapy
Study Design
Efficacy Outcomes
Antiangiogenic therapy  Sunitinib (n = 16)
or Sorafenib (n = 14)1
Retrospective
ORR 56% with sunitinib, 7% with sorafenib
Median TTP 10.4 mos
Sorafenib  Sunitinib (n = 51)2
Retrospective
PR 15%; SD 51%
Sunitinib  Sorafenib (n = 51)2
Retrospective
PR 9%; SD 55%
Bevacizumab  Sunitinib (N = 61)3
Prospective
PR 23%; SD 59%; tumor shrinkage 52%
VEGF-targeted therapy  Temsirolimus
(N = 15)4
Retrospective
SD 33%; PD 20%; too early to assess 47%
PD = progressive disease
1. Tamaskar I et al. J Urol. 2008;179:81.
2. Sablin MP et al. J Clin Oncol. 2007;25(18S):5038.
3. George DJ et al. J Clin Oncol. 2007;25(18S):5035.
4. Wood L et al. ASCO 2008 Genitourinary Cancers Symposium. Abstract 353.
Everolimus After First-Line
Targeted Agents (Phase III)
Everolimus 10 mg PO qd
+ best supportive care
(n=277)
Patients with metastatic
RCC progressing on
VEGFR TKI
(N=416)
Outcome
Stratified based on no. of prior TKIs
and MSKCC risk group
Crossover allowed upon
disease progression
Placebo
+ best supportive care
(n=139)
Everolimus
Placebo
P value
ORR, %
2
0
—
SD, %
67
32
—
Median PFS, mo
4.9
1.9
<.001
HR (95% CI)
Median OS,* mo
HR (95% CI)
0.33 (0.25–0.43)
14.8
14.4
.177
0.87 (0.65–1.17)
*112 of 139 placebo-treatment patients crossed over to everolimus
Kay A et al. Presented by Motzer at: ASCO Genitourinary Cancers Symposium. February 26-28, 2009; Orlando, FL. Abstract 278
RCC Treatment Algorithm: 2008
Regimen
Treatment-naive
patient
Treatment-refractory
patient (≥ 2nd-line)
Setting
Therapy
Options
MSK risk: good or
intermediate
Sunitinib
Bevacizumab
+ IFN-α
High-dose IL-2
MSK risk: poor
Temsirolimus
Sunitinib
Cytokine refractory
Sorafenib
Sunitinib
Bevacizumab
Refractory to
VEGF/VEGFR inhibitors
Everolimus
Sequential TKIs
or VEGF inhibitor
mTOR = mammalian target of rapamycin; TKI = tyrosine kinase inhibitor;
VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor
Bukowski RM. Presented at: 43rd ASCO Annual Meeting. June 1-5, 2007; Chicago, IL. Adapted from M Atkins
Case 1
Case 1: July 2008
• 61-yr-old man presents with abdominal bloating and
right upper quadrant abdominal pain
• KPS is 90, CBC is normal, creatinine and liver
functions are within normal range
• Ultrasound right abdomen: large right renal mass
• CT imaging:
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–
–
–
~17 cm right renal mass with IVC thrombus
Multiple bilateral lung lesions
Bilateral adrenal masses
Retroperitoneal adenopathy
• Bone scan, Brain MRI both negative
KPS = Karnofsky Performance Status
Patient Chart: July 20, 2008
• Patient undergoes right radical nephrectomy
and IVC tumor thrombectomy/IVC resection
• Pathology:
– 17 cm clear cell RCC, Furhman grade 4
– Tumor invades Gerota’s fascia, right renal vein,
and IVC
– Right hilar and paraaortic lymph nodes contain
metastatic tumor
– pT3bN1M1, stage IV
Patient Chart: September, 2008
• Post-operative evaluation:
– KPS = 90.
– Hgb, LDH, Calcium normal;
– Post-op CT imaging shows increasing pulmonary,
adrenal, and mediastinal and retroperitoneal nodal
metastases
What treatment do you recommend?
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•
•
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•
•
High-dose IL-2
Sunitinib
Sorafenib
Bevacizumab + Interferon alpha
Temsirolimus
Observation until symptoms of metastatic
disease develop
Patient Chart: September 9, 2008
• Patient starts sunitinib, 50 mg daily, 4/2
schedule
– AEs: Grade 1 fatigue and anorexia
– Best Response: Stable disease
• He is followed with serial CT imaging with
stable disease until 3/09
– Progression of lung, pleural, adrenal, and nodal
metastases after week 30 sunitinib
Case 1
Sept 2008, Pre-sunitinib
May 2009, week 30 sunitinib
What treatment do you recommend after the
patient’s tumor progresses on sunitinib?
•
•
•
•
•
•
High-dose IL-2
Sorafenib
Bevacizumab + Interferon alpha
Temsirolimus
Everolimus
Clinical trial of a new agent
Patient Chart, June 2009
• Patient begins everolimus, 10 mg PO daily
– AEs: diarrhea, stomatitis, fatigue all gr 1
– Triglyceride and cholesterol elevations, gr 1;
Anemia gr 2
• CT imaging after 8 weeks:
– Stable disease, with some reduction of pulmonary
and retroperitoneal node metastases
– Bilateral interstial “ground glass” infiltrates
– Pulmonary function tests
• DLCO 90% predicted
• Resting Room Air O2 Sat = 94%
Case 1
May 2009 Pre-everolimus
July 2009, Week 8 everolimus
Case 1
May 2009 Pre-everolimus
July 2009, Week 8 everolimus
What do you recommend for a patient with
asymptomatic everolimus-related pneumonitis?
• Continue everolimus at present dose
• Continue everolimus at reduced dose
• Continue everolimus at present dose, with
addition of prednisone
• Discontinue everolimus and begin
temsirolimus
• Discontinue everolimus and begin sorafenib
Case 2
Case 2: March 2006
• 64-yr-old woman presents with fever of unknown
etiology
• KPS is 90, Phys Exam negative for peripheral
adenopathy, organomegaly, or abdominal mass
• Diagnostic Evaluation:
– CBC and chemistries normal
– CT abdomen: 7.5 cm right renal mass and right renal hilar
adenopathy
– CT chest – no metastatic disease
– Bone scan: normal
KPS = Karnofsky Performance Status
Patient Chart: April 2006
• Patient undergoes right radical nephrectomy
and retroperitoneal tumor debulking
– Stage T2N2M0
– Histology: Clear cell carcinoma with papillary
features
– Grade: Fuhrman 4
Patient Chart, Sept 2006
• New symptoms of abdominal tightness and low back
pain; KPS = 70
• Physical findings:
– Decreased breath sounds right lung base
– Abdomen distended; ascites present
• Lab Data:
– Wbc 3.9, Hgb 11.5, platelets 259,000, creat 1.2, Calcium 9.7, LDH
629 (normal to 618 IU/L)
– Cytology (ascites): postive
• CT chest/abdomen:
– Retroperitoneal and mesenteric adenopathy
– Tumor on surface of right diaphragm
– Ascites, right pleural effusion
Prognostic Group
• Modified MSKCC prognostic factors in patients with
no prior systemic therapy:*
–
–
–
–
–
–
Karnofsky PS – 70
Time from diagnosis to need for systemic therapy < 1yr
LDH > 1.5 x ULN
Hemoglobin < ULN
Corrected serum calcium > 10mg/dL
Multiple organ sites of metastatic disease
• Presence of 3 or more factors places patient in the
poor prognosis group
*Mekhail TM et al, J Clin Oncol, 2005;23:832-41
What therapy would you recommend for a patient with
metastatic renal cell carcinoma and 3 or more adverse
prognostic factors?
•
•
•
•
•
High dose IL-2
Bevacizumab + Interferon
Sorafenib
Sunitinib
Temsirolimus
Patient Chart: Sept 2006
• Paracentesis performed to relieve distention and pain
• Patient begins temsirolimus 25 mg IV weekly
• Best Response: Stable disease x 24 weeks
– KPS improved, back pain resolved
– 20% reduction in size of retroperitoneal lymph nodes
– Decrease in ascites
• Adverse Effects:
– Grade 1 fatigue, stomatits, and skin rash
– Grade 2 hyperglycemia, grade 1 anemia
Safety of Targeted Agents
in First-Line RCC
Agent
Most Common Grade 3/4 Adverse Events
Sunitinib1
Hypertension (8%); fatigue (7%); hand-foot syndrome (5%);
diarrhea (5%); vomiting (4%); asthenia (4%)†
Bevacizumab2
Fatigue (37%); anorexia (17%); hypertension (10%);
dyspnea (9%); nausea (7%)
Temsirolimus3
Asthenia (11%); dyspnea (9%); infection (5%); pain (5%)
IFN-a (vs temsirolimus)3
Asthenia (26%); dyspnea (6%); infection (4%); fever (4%);
back pain (4%)
† All
grade 3; no grade 4 AEs observed in >1% of patients receiving sunitinib
1. Motzer RJ et al. N Engl J Med. 2007;356:115.
2. Rini BI et al. J Clin Oncol. 2008;26:5422.
3. Hudes G et al. N Engl J Med. 2007;356:2271.
Safety of Targeted Agents
in First-Line RCC
Most Common Grade 3/4
Laboratory Abnormalities
Agent
Sunitinib1
Increased lipase (16%); neutropenia (12%); lymphopenia (12%);
increased uric acid (12%); thrombocytopenia (8%); leukopenia (5%);
hypophosphatemia (5%); increased amylase (5%)
Bevacizumab2
Proteinuria (15%); neutropenia (9%); anemia (4%)
Temsirolimus3
Anemia (20%); hyperglycemia (11%); hyperlipidemia (3%)
IFN-a (vs
temsirolimus)3
Anemia (22%); neutropenia (7%); leukopenia (5%); increased
aspartate aminotransferase (4%)
† All
grade 3; no grade 4 AEs observed in >1% of patients receiving sunitinib
1. Motzer RJ et al. N Engl J Med. 2007;356:115.
2. Rini BI et al. J Clin Oncol. 2008;26:5422.
3. Hudes G et al. N Engl J Med. 2007;356:2271.
Planned Phase II Study of Bevacizumab,
Sorafenib, and Temsirolimus in mRCC
(ECOG 2804 “BeST” Trial)
Eligibility Criteria
• Confirmed clear cell RCC
• Measurable metastatic disease
• <25% of any other histology
(papillary, chromophobe, or
oncocytic)
• Primary or metastatic lesion
• Not curable by standard radiotherapy
or surgery
• Prior nephrectomy
* Expected enrollment
(N=360*)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Bevacizumab
IV over 30–90 min days 1–15
Temsirolimus
IV over 30 min +
days 1, 8, 15, 22
Bevacizumab
IV over
30–90 min
days 1–15
Bevacizumab
Sorafenib
IV over
+
bid PO, days 1–28
30–90 min
days 1–15
Sorafenib
Temsirolimus
IV over 30 min + PO bid,
days 1–28
days 1, 8, 15, 22
Primary end point: PFS
Available at: http://www.clinicaltrial.gov/ct2/show/NCT00378703?term=bevacizumab+and+sorafenib+and+temsirolimus&rank=1.
Accessed June 12, 2009
Advances in Treatment of
Renal Cell Carcinoma: Evolving Role
of mTOR Inhibitors
Gary R. Hudes MD
Fox Chase Cancer Center
Philadelphia, PA