Emerging Treatment Options in the Management of Neuroendocrine Tumors Moderator: Martyn Caplin, MD...
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Transcript of Emerging Treatment Options in the Management of Neuroendocrine Tumors Moderator: Martyn Caplin, MD...
NETs: A Clinical Challenge
• Heterogeneous group of cancers derived from hormone-producing cells of the diffuse endocrine system
• Increasing incidence over past 3 decades• Reported prevalence up to 35 per 100,000• Frequently diagnosed at advanced stage
• Early detection improves chance of surgical cure or prolonged palliation with therapy
Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.
NETs: neuroendocrine tumors
Treatment Options in NETs
PRRT: peptide receptor radionuclide therapy
Multidisciplinary Treatment for NETs
• Multimodality treatment is optimal‒ Medical oncologists, surgeons, gastroenterologists,
endocrinologists, interventional radiologists, nurses
• Surgery and other local modality treatments ‒ Includes radio-frequency ablation, liver-directed
embolization, hepatic artery embolization
• Systemic treatment‒ Includes SSAs, chemotherapy, biologic targeted agents
SSAs: somatostatin analogues
RADIANT-2: The Rationale for Combining Everolimus and Octreotide LAR
• mTOR: central regulator of growth, proliferation, metabolism, and angiogenesis [a-c]
• NETs linked to genetic alterations that activate the mTOR pathway [b,c]
• Everolimus inhibits mTOR [c]
• Octreotide downregulates IGF-1, an upstream activator of the PI3K/AKT/mTOR pathway [d]
• Everolimus + octreotide LAR showed activity in a phase-2 trial [e]
a. O’Reilly T, et al. Transl Oncol. 2010;3:65-79. b. Meric-Bernstam F, et al. J Clin Oncol. 2009;27:2278-2287. c. Faivre S, et al. Nat Rev Drug Disc. 2006;5:671-688. d. Susini C, et al. Ann Oncol. 2006;17:1733-1742. e. Yao JC, et al. J Clin Oncol. 2008;26:4311-4318.
LAR: long-acting release
RADIANT-2 Phase 3 Double-Blind, Placebo-Controlled Trial: Study Design
Everolimus 10 mg/d + octreotide LAR 30 mg/28 days
n = 216
Placebo + octreotide LAR 30 mg/28 days
n = 213
Treatment until disease
progression
Patients with advanced NET and
history of symptoms attributed to
carcinoid syndrome, N = 429
1:1
Multiphasic CT or MRI performed every 12 weeks
Crossover
Primary endpoint: • PFS (RECIST)
Secondary endpoints: • Tumor response, OS, biomarkers,
safety, PK
Enrollment January 2007–March 2008
CT: computed tomography; MRI: magnetic resonance imaging; OS: overall survival; PFS: progression-free survival; PK: pharmacokinetics; RECIST: Response Evaluation Criteria In Solid Tumors
Pavel M, et al. ESMO 2010; Abstract LBA 8.
RANDOMIZE
RADIANT-2: PFS by Central Review*
No. of patients still at riskE + OP + O
216213
202202
167155
129117
120106
102 84
8172
6965
6357
5650
5042
4235
3324
2218
1711
11 9
43
11
10
00
Kaplan-Meier median PFSEverolimus + octreotide LAR: 16.4 monthsPlacebo + octreotide LAR: 11.3 months
HR = 0.77; 95% CI (0.59–1.00) P = .026
Time (mo)
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
% E
vent
-fre
e
Total events = 223Censoring timesE + O (n/N = 103/216)P + O (n/N = 120/213)
Pavel M, et al. ESMO 2010; Abstract LBA 8.
*Independent adjudicated central review committee; P value obtained from one-sided log-rank test; HR obtained from unadjusted Cox model.
E + O: everolimus + octreotide LAR; HR: hazard ratio; P + O: placebo + octreotide LAR.
RADIANT-2: PFS by Local Investigator Review
P value obtained from the one-sided log-rank test.HR obtained from unadjusted Cox model.
Pavel M, et al. ESMO 2010; Abstract LBA 8.
No. of patients still at riskE + OP + O
216213
199201
167159
129121
119114
100 92
8175
7472
6864
6256
5150
4041
3227
2421
1811
1110
44
21
10
00
% E
vent
-fre
e
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Time (mo)
Kaplan-Meier median PFSEverolimus + octreotide LAR: 12.0 monthsPlacebo + octreotide LAR: 8.6 months
HR = 0.78; 95% CI (0.62–0.98)P = .018
Total events = 284Censoring times
E + O (n/N = 128/216)P + O (n/N = 156/213)
RADIANT-2: Summary
• Everolimus + octreotide LAR prolonged median PFS by 5.1 mo (HR = 0.77; P = .026)• Did not reach statistical significance (prespecified at
P = .0246)
• Everolimus + octreotide LAR demonstrated benefit across all subgroups
• Everolimus + octreotide LAR has an acceptable safety profile
HR: hazard ratio
RADIANT-3: Study Rationale
• mTOR: central regulator of growth, proliferation, cellular metabolism, and angiogenesis [a-c]
• mTOR pathway activation observed with genetic cancer syndromes associated with pNET [d]
• TSC2, NF1, VHL
• Dysregulation of mTOR pathway, PTEN, and TSC2, in sporadic pNET is associated with poor prognosis [e]
• Everolimus demonstrated antitumour activity in pNET in two phase-2 studies [f,g]
a. O’Reilly T, et al. Transl Oncol. 2010;3:65-79. b. Meric-Bernstam F, et al. J Clin Oncol. 2009;27:2278-2287. c. Faivre S, et al. Nat Rev Drug Disc. 2006;5:671-688. d. Yao JC, et al. Pancreatic Endocrine tumours. In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 8th Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:1702-1721. e. Missialgia E, et al. J Clin Oncol. 2010;28:245-255. f. Yao JC, et al. J Clin Oncol. 2008;26:4311-4318. g. Yao JC, et al. J Clin Oncol. 2010;28:69-76.
NF1: neurofibromatosis-1; pNET: pancreatic NET; TSC2: tuberous sclerosis-2; VHL: von Hippel–Lindau disease
RADIANT-3 Phase 3 Double-Blind, Placebo-Controlled Trial: Study Design
Everolimus 10 mg/d +BSC*
n = 207
Placebo +BSC*
n = 203
Treatment until disease
progression
Patients with advanced pNETN = 410
Stratified by:• WHO PS• Prior chemotherapy
1:1
Multi-phasic CT or MRI performed every 12 weeks
Crossover
Primary endpoint: PFS (RECIST)
Secondary endpoints: Response, OS, biomarkers, safety, and PK
RANDOMIZE
BSC: best supportive care; PS: performance status; WHO: World Health Organization Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.
Randomization August 2007–May 2009
RADIANT-3: PFS by Investigator Review
• P-value obtained from stratified one-sided log rank test• Hazard ratio is obtained from stratified unadjusted Cox model
No. of patients still at riskEverolimus
Placebo207203
189177
153 98
126 59
114 52
8024
4916
36 7
28 4
21 3
10 2
61
21
01
Kaplan-Meier median PFSEverolimus: 11.0 months
Placebo: 4.6 months
HR = 0.35; 95% CI [0.27-0.45]P < .0001
01
00
Time (mo)
100
80
% E
vent
-fre
e
Censoring TimesEverolimus (n/N = 109/207)Placebo (n/N = 165/203)
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain. Poster # O-0028.
Subgroups (n)HR
Median PFS (mo)
E PInvestigator review (410) 0.35 11.0 4.6Central review* (410) 0.34 11.4 5.4Prior chemotherapy Yes (89) 0.34 11.0 3.0 No (221) 0.41 11.1 5.5WHO Performance Status 0 (279) 0.39 13.8 5.4 1 or 2 (131) 0.30 8.3 3.0Age Group < 65 years (299) 0.39 11.0 4.5 ≥ 65 years (111) 0.36 11.1 4.9Gender Male (227) 0.41 11.0 4.6 Female (183) 0.33 11.0 3.3Race Caucasian (322) 0.41 10.8 4.6 Asian (74) 0.29 19.5 3.8Region America (185) 0.36 11.0 4.6 Europe (156) 0.47 10.8 4.6 Asia (69) 0.29 19.5 2.9Prior long-acting SSA Yes (203) 0.40 11.2 3.7 No (207) 0.36 10.8 4.9Tumor grade Well diff. (341) 0.41 10.9 4.6 Moderately diff.(65) 0.21 16.6 3.0
RADIANT-3: Subgroup PFS Analysis
Hazard Ratio
Favors Everolimus Favors Placebo
0 10.4 0.8
Yao J et al. 12th World Congress on Gastrointestinal Cancer; June 30–July 3, 2010; Barcelona, Spain. Poster # O-0028.
*Independent adjudicated central reviewE = Everolimus 10 mg PO daily; P = Placebo
RADIANT-3: Overall SurvivalEverolimus 10 mg
n = 207Placebo n = 203
Events: n (%) 51 (24.6%) 50 (24.6%)
HR = 1.05; 95% CI (0.71–1.55); P = .594
Censored: n (%) 156 (75.4%) 153 (75.4%)
Kaplan-Meier estimates (95% CI) at:
3 months 97.1 (93.6–98.7) 98.5 (95.5–99.5)
6 months 93.1 (88.7–95.9) 91.6 (86.8–94.7)
12 months 82.3 (76.0–87.0) 82.6 (76.5–87.3)
18 months 73.1 (65.1–79.6) 73.9 (66.1–80.2)
24 months 57.3 (43.0–69.2) 62.8 (51.1–72.4)
148 placebo patients crossed over to receive everolimus
Hazard ratio is obtained from the unadjusted stratified Cox modelP-value is obtained from the stratified one-sided log rank testYao J et al. 12th World Congress on Gastrointestinal Cancer; June 30-July 3, 2010; Barcelona, Spain.
Poster # O-0028.
RADIANT-3 Summary and Conclusions
• RADIANT-3: largest randomized controlled trial ever completed in advanced pNET
• Everolimus reduced risk of progression by 65% vs placebo (HR = 0.35, P < .0001)• Median PFS: 11.0 mo with everolimus vs 4.6 mo with placebo
• Acceptable safety profile: stomatitis, rash, infection, infrequent pneumonitis
• Everolimus should be considered a standard of care in advanced pNET
Progress in NET Treatment
PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors
PROMID: Octreotide LAR Slows Disease Progression in Midgut NETs
Octreotide LAR vs placebo P < .001HR: 0.34 (95% CI: 0.20–0.59)
Octreotide LAR (n = 42) Median 14.3 months
Placebo (n = 43) Median 6.0 months
Time (mo)
Prop
ortio
n w
ithou
t pro
gres
sion
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Based on conservative ITT analysis
Rinke A, et al. J Clin Oncol. 2009;27:4656-4663.
TTP in Midgut NET
HR: hazard ratio; ITT: intent-to-treat; TTP: time to progression
Placebo, n 79 25 6 1 0Sunitinib, n 74 32 14 2 0
1.0
Surv
ival
pro
babi
lity
0 5 10 15 20
Efficacy endpoint variable value (mo)
SunitinibPlacebo
Raymond E, et al. Presented at ESMO-GI 2009: Abstract 0013.
Phase 3 Trial: Sunitinib vs Placebo in Advanced pNET
Study halted prior to complete accrual due to treatment benefitUnplanned Kaplan-Meier PFS analysis
Sunitinib: PFS 11.1 mo
Placebo: PFS 5.5 mo
P < .001; HR: 0.397 (95% CI: 0.243 to 0.649)
0.8
0.6
0.4
0.2
0
Ongoing Issues in NET Treatment
• Predicting treatment efficacy/individualizing treatment
• Drug approvals and insurance: access to treatment options
• Combination regimens
• Balancing toxicity and efficacy
Ongoing Issues in NET Treatment, cont’d.
• Impact of treatment on quality of life• EORTC QOL questionnaire for NETs
• Treatment selection: monotherapies vs combination regimens
• Adjuvant therapy
EORTC: European Organization for Research and Treatment of Cancer
Conclusions
• NETs: A heterogeneous group of tumors for which multiple therapeutic options are available
• Treatment should be individualized by multidiscliplinary teams
• Exciting new trial data with octreotide LAR, everolimus, and sunitinib
• Ongoing clinical trial programs will provide additional clarity to treatment decisions