Renal Cell Carcinoma: Renal Cell Carcinoma: A New Standard of Care A New Standard of Care Roberto Pili M.D. Associate Professor of Oncology and Urology The Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 6th Advancing Cancer Care in the Elderly Conference Taking Aim with Targeted Therapies: Are We Hitting the Right Marks?
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Renal Cell Carcinoma: Renal Cell Carcinoma: A New Standard of CareA New Standard of Care
Roberto Pili M.D.
Associate Professor of Oncology and Urology The Sydney Kimmel Comprehensive Cancer Center at
Johns Hopkins Baltimore MD
6th Advancing Cancer Care in the Elderly Conference Taking Aim with Targeted Therapies: Are We Hitting the Right Marks?
DisclosureDisclosure
• Research funding: Pfizer, Cephalon, Celgene
• Consultant: Active Biotech, Locus, Novartis, Genentech
ObjectivesObjectives
• To review the biological and clinical features of renal cell carcinoma
• To summarize the clinical activity & toxicity profiles of antiangiogenesis agents in renal cell carcinoma
• To describe the future development of anti angiogenesis therapies for renal cell carcinoma
Renal Cell CarcinomaRenal Cell Carcinoma• In the United States in 2008:
– 54,390 estimated new cases of RCC– 13,010 estimated deaths
• Risk factors:– Male sex (3:2), Cigarette smoking (2:1), Hypertension,
MSKCC Risk Factor Model in mRCC-MSKCC Risk Factor Model in mRCC-IFN daysIFN days
0 risk factors (n=80 patients)
1 or 2 risk factors (n=269 patients)
3, 4, or 5 risk factors (n=88 patients)
Risk factors associated with worse prognosis
• KPS <80
• Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F)
• High corrected calcium (10 mg/dL)
• High LDH (300 U/L)
• Time from Dx to IFN-α <1 yr
Time From Start of IFN-α (years)
Pro
po
rtio
n S
urv
ivin
g
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 1614131195436 151210876
MS:20 mo10 mo4 mo
Targets in RCCTargets in RCC
Adapted from Brugarolas J NEJM 2007
Bevacizumab
VEGF-Trap
Vorinostat
LBH589Everolimus
AxitinibPazopanib
Everolimus
Temsirolimus
Cell division AngiogenesisCell proliferation
Angiogenesis
Rational Targets in RCCRational Targets in RCC
• IL-2
- immune response FDA approved for RCC 1992
• Sorafenib FDA approved for RCC 12/05
– VEGFR, PDGFR, RAF
• Sunitinib FDA approved for RCC 1/06
– VEGFR, PDGFR
• Temsirolimus - mTor FDA approved for RCC 5/07
• Everolimus - mTor
• Bevacizumab -VEGF
• VEGF-Trap -VEGF
• Erlotinib - EGFR
EGFR=epidermal growth factor receptor.
RCC: Current NCCN Treatment ParadigmRCC: Current NCCN Treatment Paradigm
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: kidney cancer. V.1.2008. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed 01/14/2008.
*Category 1†Selected patients‡ Category 1 following cytokine therapy and category 2A following TKI§ Category 2A following cytokine therapy and category 2B following TKI¶Category 2B.
CRN = cytoreductive nephrectomy; IL-2 = interleukin-2; NCCN = National Comprehensive Cancer Network; TKI = tyrosine kinase inhibitor.
First LineClinical trial
Sunitinib*Temsirolimus
(poor prognosis patients)*
Bevacizumab + IFN High-
dose IL-2†
Sorafenib†
Best supportive care
Nephrectomy + metastasectomy or
CRN (if unresectable,
proceed to first-line systemic therapy)
Observation or consider adjuvant therapy in a clinical trial
Relapse
Stage I/II/IIISurgical excision
Second LineClinical trialSorafenib‡
Sunitinib‡
Temsirolimus§
IFN¶
High-dose IL-2¶
Low-dose IL-2 ± IFN¶
Bevacizumab¶
Best supportive care
Stage IV (metastatic)
Sorafenib for mRCC:Sorafenib for mRCC:Phase III Study Design (TARGET)Phase III Study Design (TARGET)
Sorafenib, 400 mg bid (n=451)
• 1° end point: OS• 2° end points: ORR, PFS, safety, HR-QoL• Demographics
– MSKCC good or intermediate risk patients(57/41)
– Clear-cell carcinoma
Unresectable and/or mRCC,
1 prior systemic Tx in last 8 months, ECOG PS 0/1
(N=903*) Placebo (n=452)
Escudier, NEJM 2007
Sorafenib for mRCC:Sorafenib for mRCC:Response Rate* (TARGET)Response Rate* (TARGET)
38 (8)18 (4)Missing
167 (37) 56 (12)Progressive disease
239 (53)333 (74)Stable disease
8 (2) 43 (10)Partial response
— 1 (<1)Complete response
Placebo (n=452)
n (%)
Sorafenib (n=451)n (%)Best Response by RECIST
Escudier, NEJM 2007
5.5
2.8
Sorafenib
Placebo0.51Hazard ratio
Median (months)PFS
Time From Randomization (months)
Pro
po
rtio
n o
f P
atie
nts
Pro
gre
ssio
n F
ree
0
0.25
0.50
0.75
1.00
0 4 10 202 6 8 12 14 16 18
Sorafenib for mRCC: Sorafenib for mRCC: Progression-Free Survival* (TARGETProgression-Free Survival* (TARGET)
Placebo (n=452)
Sorafenib (n=451)
Escudier, NEJM 2007
Sorafenib: Phase III TARGETs—Sorafenib: Phase III TARGETs—Summary of OS AnalysisSummary of OS Analysis
n/a
0.01
0.74
14.3 months
19.3 months
OS 6 Months Post-Crossover
With Placebo Censored2
13.5%30%39%Increase in OS
17.8 months19.3 monthsNot reachedSorafenib med. OS
15.2 months15.9 months14.7 monthsPlacebo median OS
Final OS 16 Months
Post-Crossover3
OS 6 Months Post-
Crossover1*
OS at Crossover1
*At the time of analysis, 216/452 (48%) of patients in the placebo group had crossed over to receive Sorafenib.1. Escudier B et al. New Engl J Med. 2007;356:125-134.2. Eisen T et al. Presented at: ASCO 20063. Adapted from: Escudier B et al. 2007
• In the final OS analysis, 62% of total patient-years of exposure to study drug in the placebo arm corresponded to Sorafenib
Sorafenib vs IFN-Sorafenib vs IFN-αα : Randomized Phase II : Randomized Phase II
PFS by Independent ReviewPFS by Independent Review
97 75 30 16 492 57 34 24 7
SorafenibInterferon
Patients at risk Time From Randomization (months)
Pro
po
rtio
n o
f P
atie
nts
Pro
gre
ssio
n-F
ree
0 151 2 3 4 5 6 7 8 9 10 11 12 13 14
1.00
0.25
0
0.50
Median PFS
Sorafenib=5.7 months
Interferon=5.6 months
Hazard ratio=0.88 (95% Cl: 0.61-1.27)
P value (log-rank test)=0.504
0.75
Sorafenib
IFN-αα
Adapted from Escudier B et al. Presented at: 5th Intl Symposium on TAT; March 8-10, 2007; Amsterdam, The Netherlands.
Sunitinib vs IFN-Sunitinib vs IFN-αα for mRCC: for mRCC:Phase III Study DesignPhase III Study Design
Sunitinib, 50 mg qd (n=375)
• 1° end point: PFS• 2° end points: RR, OS, safety, patient reported outcomes• Demographics
– MSKCC good or intermediate risk patients(34/47)– Clear-cell carcinoma
Efficacy of Sequencing Antiangiogenic Efficacy of Sequencing Antiangiogenic Agents in Resistant RCCAgents in Resistant RCC
Sorafenib (Phase III;
IFN-Resistant) 1
(n=451)
Sunitinib (Ph II: Bevacizumab -
Resistant) (n=61)2
Axitinib (Phase II: IFN-
Resistant) (n=52)3
Axitinib (Phase II; Soraf-/Sunit-Resistant)
(n=62)4
Pazopanib (Phase II; First -Line/Interferon -
Resistant) (n=225)5
Median PFS, months
5.5 23.6* NR 7.4/6.1
(n=62/14**) NR
ORR, % 10 16 46 21 26/30
(n=154/71)
Stable Disease, %
53 61 40 34 45/48 (n=154/71)
*TTP **Patients received both sorafenib and sunitinib 1. Escudier B, et al. N Engl J Med 2007; 356:125 -34 2. Rini BI, et al. ASCO 2006; # 4522 3. Rini BI, et al. ASCO 2005; #4509 4. Rini BI, et al. ASCO 2007; # 5032 5. Hutson TE, et al. ASCO 2007; abstract 5031
Everolimus After Progression on Everolimus After Progression on VEGFR-TKI: Study DesignVEGFR-TKI: Study Design
• 410 patients randomized between September 2006 and October 2007• Second interim analysis cutoff: October 15, 2007, based on 191 PFS events• Independent Data Monitoring Committee recommended termination of study
RRAANNDDOOMMIIZZAATTIIOONN
2:12:1
Upon Disease
Progression
Interim Analysis
Interim Analysis
N = 410
Stratification
Prior VEGFR-TKI: 1 or 2
MSKCC risk group: favorable, intermediate, or poor
=Final
Analysis
Everolimus + best supportive care
(n = 272)(n = 272)
Placebo + best supportive care
(n = 138)(n = 138)
Motzer RJ, et al. 2008 ASCO; Motzer RJ, Lancet 2008
Everolimus After Progression on Everolimus After Progression on VEGFR-TKI: Prior TherapiesVEGFR-TKI: Prior Therapies
*≥ 10% of everolimus patients and additional selected AEs.†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < .05) .
Motzer R et al. ASCO 2008
−100%
−75%
−50%
−25%
0%
25%
50%
75%
100%
Best Response n (%)
PR 3 (1) Stable 171 (63) PD 53 (20) NE 45 (16)
Best Response n (%)
PR 0 Stable 44 (32) PD 63 (46) NE 31 (22)
Maximum % Change in Target Lesions Maximum % Change in Target Lesions and Objective Response Rate*and Objective Response Rate*
EverolimusEverolimus PlaceboPlacebo
NE = not evaluable
* Central Radiology Review
Everolimus vs Placebo: PFS by Central Radiology
Review
Motzer RJ, et al. 2008 ASCO Annual Meeting; Abstract LBA5026.
100
80
60
40
20
0
0 2 4 6 8 10 12
PF
S P
rob
abili
ty (
%)
Everolimus (n = 272) Placebo (n = 138)
Hazard ratio = 0.30 95% CI (0.22, 0.40) Log-rank P<0.001 Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo
Months
Prospective Trials of Sequential Targeted Agents
4.0 months
3.8 months
7.4 months
7.1 months
PFS
1/50410Phase 3: RAD001 vs placebo in TKI-refractory
RAD0014
480Phase 3: Temsirolimus vs sorafenib in patients previously treated with sunitinib
Temsirolimus
540Phase 3: Axitinib vs sorafenib in previously treated patients
Sequential Approach: Phase II Study of Sequential Approach: Phase II Study of VEGF Trap in Metastatic RCC (ECOG 4805)VEGF Trap in Metastatic RCC (ECOG 4805)