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