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Advances in Treatment ofRenal 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):552. Yang JC et al. J Clin Oncol. 2003;21(16):3127
Sunitinib vs IFN- in First-Line RCC: Phase III Trial
Sunitinib50 mg PO qd for 4 wk then 2 wk off for repeated
6-wk cycles (n=375)
IFN-9 MU SC 3×/wk
(n=375)
Patients with untreated
metastatic RCC (N=750)
Stratified based on performance status,LDH level, prior nephrectomy
Outcome Sunitinib IFN- P value
ORR,* % 39 8 <.000001
Median PFS,* mo
11 5 <.000001
Median OS, mo 26.4 21.8 .051
HR (95% CI) 0.821 (0.673–1.001)
Figlin RA et al. J Clin Oncol. 2008;26. Abstract 5024
*By independent review
Bevacizumab + IFN- vs IFN- in First-Line RCC: Phase III Trials
IFN- + bevacizumabIFN -2a 9 MIU SC 3×/wk +
bevacizumab 10 mg/kg q 2 wk
IFN-9 MIU SC 3×/wk
(+ placebo on AVOREN trial)
Patients with untreated metastatic RCC
Outcome
AVOREN1 (N=649) CALGB 902062 (N=732)
IFN- + Bevacizumab
(n=327)
IFN-+ Placebo (n=322) P value
IFN- + Bevacizumab
(n=369)IFN-(n=363) P value
ORR, % 31 13 .0001 25.5 13.1 <.0001
Median PFS, % 10.2 5.4 .0001 8.5 5.2 <.0001
HR (95% CI) 0.63 (0.52–0.75) 0.71 (0.61–0.83)
1. Escudier B et al. Lancet. 2007;370(9605):21032. Rini BI et al. J Clin Oncol. 2008;26(33):5422
CALGB = Cancer And Leukemia Group B
Temsirolimus in Poor-Risk,Untreated Metastatic RCC: Phase III
Outcome IFN- TEM TEM + IFN-
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-‡P=.002 vs IFN-
Temsirolimus25 mg IV qiw
(n=209)
IFN-3–18 MU SC tiw
(n=207)
Patients with previously untreated, poor prognosis,
mRCC (N=626)
Temsirolimus 15 mg IV qw+ IFN- 6 MU SC tiw
(n=210)
Hudes G et al. N Engl J Med. 2007;356(22):2271SD = stable disease
Temsirolimus in Poor-Risk,Untreated Metastatic RCC: Phase III
Hudes G et al. N Engl J Med. 2007;356(22):2271
Time (mo)
OS
Pro
ba
bil
ity
of
Su
rviv
al
Temsirolimus
IFN
Combination
1.00
0.75
0.50
0.25
0.00
0 5 10 15 20 25 30
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
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
1. Escudier B et al. N Engl J Med. 2007;356(2):1252. Bukowski RM et al. J Clin Oncol. 2007;25(18S). Abstract 50233. Rosenberg JE et al. J Clin Oncol. 2007;25(18S). Abstract 50954. Yang JC et al. N Engl J Med. 2003;349(5):427
Parameter Sorafenib1 Sunitinib3 Bevacizumab4
Dose 400 mg BID 50 mg/day 4 wk on/2 wk off
10 mg/kg IV q 2 wk
Trial design 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
*Pooled data from 2 trialsNR = not reported
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 sorafenibMedian 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%
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.
PD = progressive disease
Everolimus After First-Line Targeted Agents (Phase III)
Everolimus 10 mg PO qd + best supportive care
(n=277)
Placebo+ best supportive care
(n=139)
Patients with metastatic RCC progressing on
VEGFR TKI(N=416)
Stratified based on no. of prior TKIs and MSKCC risk group
Outcome Everolimus Placebo P value
ORR, % 2 0 —
SD, % 67 32 —
Median PFS, mo 4.9 1.9 <.001
HR (95% CI) 0.33 (0.25–0.43)
Median OS,* mo 14.8 14.4 .177
HR (95% CI) 0.87 (0.65–1.17)
Crossover allowed upon disease progression
Kay A et al. Presented by Motzer at: ASCO Genitourinary Cancers Symposium. February 26-28, 2009; Orlando, FL. Abstract 278
*112 of 139 placebo-treatment patients crossed over to everolimus
RCC Treatment Algorithm: 2008
Regimen Setting Therapy Options
Treatment-naivepatient
MSK risk: good or intermediate
SunitinibBevacizumab
+ IFN-α
High-dose IL-2
MSK risk: poor Temsirolimus Sunitinib
Treatment-refractory
patient (≥ 2nd-line)
Cytokine refractory Sorafenib SunitinibBevacizumab
Refractory to VEGF/VEGFR inhibitors
Everolimus Sequential TKIsor VEGF inhibitor
Bukowski RM. Presented at: 43rd ASCO Annual Meeting. June 1-5, 2007; Chicago, IL. Adapted from M Atkins
mTOR = mammalian target of rapamycin; TKI = tyrosine kinase inhibitor;VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor
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:
– ~17 cm right renal mass with IVC thrombus– Multiple bilateral lung lesions – Bilateral adrenal masses– Retroperitoneal adenopathy
• Bone scan, Brain MRI both negativeKPS = 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?
• 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- (vs temsirolimus)3 Asthenia (26%); dyspnea (6%); infection (4%); fever (4%);back pain (4%)
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.
† All grade 3; no grade 4 AEs observed in >1% of patients receiving sunitinib
Safety of Targeted Agents in First-Line RCC
AgentMost Common Grade 3/4 Laboratory Abnormalities
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- (vs temsirolimus)3
Anemia (22%); neutropenia (7%); leukopenia (5%); increased aspartate aminotransferase (4%)
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.
† All grade 3; no grade 4 AEs observed in >1% of patients receiving sunitinib
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
Bevacizumab IV over 30–90 min days 1–15
+TemsirolimusIV over 30 min
days 1, 8, 15, 22
Bevacizumab IV over
30–90 min days 1–15
Primary end point: PFS* Expected enrollment
(N=360*)
+Sorafenib
bid PO, days 1–28
Bevacizumab IV over
30–90 min days 1–15
+SorafenibPO bid,
days 1–28
TemsirolimusIV over 30 min
days 1, 8, 15, 22
RANDOMIZATION
Available at: http://www.clinicaltrial.gov/ct2/show/NCT00378703?term=bevacizumab+and+sorafenib+and+temsirolimus&rank=1.Accessed June 12, 2009
Advances in Treatment ofRenal Cell Carcinoma: Evolving Role
of mTOR Inhibitors
Gary R. Hudes MD
Fox Chase Cancer Center
Philadelphia, PA