Emerging Treatment Options in the Management of Neuroendocrine Tumors

1
Emerging Treatment Options in the Management of
Neuroendocrine Tumors
Moderator Martyn Caplin, MD Professor of
Gastroenterology University College
London Department of Gastroenterology Royal Free
Hospital London, United Kingdom Panel Eric Van
Cutsem, MD, PhD Professor of Internal
Medicine Digestive Oncology Department University
Hospital Gasthuisberg Leuven, Belgium
Panel (cont) Marianne Pavel, MD Department of
Gastroenterology, Hepatology, and
Endocrinology Charité Hospital Berlin, Germany
Simron Singh, MD Odette Cancer
Centre Sunnybrook Health Sciences Centre Toronto,
Canada
2
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

NETs neuroendocrine tumors
Yao JC, et al. J Clin Oncol. 2008263063-3072.
3
Treatment Options in NETs
PRRT peptide receptor radionuclide therapy
4
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
5
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

LAR long-acting release
a. OReilly T, et al. Transl Oncol. 2010365-79.
b. Meric-Bernstam F, et al. J Clin Oncol.
2009272278-2287. c. Faivre S, et al. Nat Rev
Drug Disc. 20065671-688. d. Susini C, et al.
Ann Oncol. 2006171733-1742. e. Yao JC, et al.
J Clin Oncol. 2008264311-4318.
6
RADIANT-2 Phase 3 Double-Blind,
Placebo-Controlled Trial Study Design
Enrollment January 2007March 2008
Everolimus 10 mg/d octreotide LAR 30 mg/28
days n 216
RANDOMIZE
Patients with advanced NET and history of
symptoms attributed to carcinoid syndrome, N
429
11
Treatment until disease progression
Crossover
Placebo octreotide LAR 30 mg/28 days n 213

• Primary endpoint
• PFS (RECIST)
• Secondary endpoints
• Tumor response, OS, biomarkers, safety, PK

Multiphasic CT or MRI performed every 12 weeks
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.
7
RADIANT-2 PFS by Central Review
Kaplan-Meier median PFSEverolimus octreotide
LAR 16.4 monthsPlacebo octreotide LAR 11.3
months HR 0.77 95 CI (0.591.00) P .026
No. of patients still at risk E O P O
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.
Pavel M, et al. ESMO 2010 Abstract LBA 8.
8
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.
9
RADIANT-2 Summary

• Everolimus octreotide LAR prolonged median PFS
  by 5.1 mo (HR 0.77 P .026)
• Did not reach statistical significance
  (prespecified atP .0246)
• Everolimus octreotide LAR demonstrated benefit
  across all subgroups
• Everolimus octreotide LAR has an acceptable
  safety profile

HR hazard ratio
10
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

NF1 neurofibromatosis-1 pNET pancreatic NET
TSC2 tuberous sclerosis-2 VHL von
HippelLindau disease
a. OReilly T, et al. Transl Oncol. 2010365-79.
b. Meric-Bernstam F, et al. J Clin Oncol.
2009272278-2287. c. Faivre S, et al. Nat Rev
Drug Disc. 20065671-688. 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 20081702-1721. e.
Missialgia E, et al. J Clin Oncol.
201028245-255. f. Yao JC, et al. J Clin Oncol.
2008264311-4318. g. Yao JC, et al. J Clin
Oncol. 20102869-76.
11
RADIANT-3 Phase 3 Double-Blind,
Placebo-Controlled Trial Study Design
Everolimus 10 mg/d BSC n 207
RANDOMIZE

• Patients with advanced pNETN 410
• Stratified by
• WHO PS
• Prior chemotherapy

11
Treatment until disease progression
Crossover
Placebo BSC n 203

• Primary endpoint PFS (RECIST)
• Secondary endpoints Response, OS, biomarkers,
  safety, and PK

Multi-phasic CT or MRI performed every 12 weeks
Randomization August 2007May 2009
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.
12
RADIANT-3 PFS by Investigator Review
Kaplan-Meier median PFS Everolimus 11.0
months Placebo 4.6 months HR 0.35 95 CI
0.27-0.45P lt .0001
100
80
60
Event-free
40
20
Censoring Times Everolimus (n/N
109/207) Placebo (n/N 165/203)
0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
Time (mo)
No. of patients still at risk
Everolimus Placebo
207 203
189 177
153 98
126 59
114 52
80 24
49 16
36 7
28 4
21 3
10 2
6 1
2 1
0 1
0 1
0 0

• P-value obtained from stratified one-sided log
  rank test
• Hazard ratio is obtained from stratified
  unadjusted Cox model

Yao J et al. 12th World Congress on
Gastrointestinal Cancer June 30-July 3, 2010
Barcelona, Spain. Poster O-0028.
13
RADIANT-3 Subgroup PFS Analysis
Subgroups (n) HR Median PFS (mo) Median PFS (mo)
Subgroups (n) HR E P
Investigator review (410) Investigator review (410) 0.35 11.0 4.6
Central review (410) Central review (410) 0.34 11.4 5.4
Prior chemotherapy Prior chemotherapy
Yes (89) Yes (89) 0.34 11.0 3.0
No (221) No (221) 0.41 11.1 5.5
WHO Performance Status WHO Performance Status
0 (279) 0 (279) 0.39 13.8 5.4
1 or 2 (131) 1 or 2 (131) 0.30 8.3 3.0
Age Group Age Group
lt 65 years (299) lt 65 years (299) 0.39 11.0 4.5
65 years (111) 65 years (111) 0.36 11.1 4.9
Gender Gender
Male (227) Male (227) 0.41 11.0 4.6
Female (183) Female (183) 0.33 11.0 3.3
Race Race
Caucasian (322) Caucasian (322) 0.41 10.8 4.6
Asian (74) Asian (74) 0.29 19.5 3.8
Region Region
America (185) America (185) 0.36 11.0 4.6
Europe (156) Europe (156) 0.47 10.8 4.6
Asia (69) Asia (69) 0.29 19.5 2.9
Prior long-acting SSA Prior long-acting SSA
Yes (203) Yes (203) 0.40 11.2 3.7
No (207) No (207) 0.36 10.8 4.9
Tumor grade Tumor grade
Well diff. (341) Well diff. (341) 0.41 10.9 4.6
Moderately diff.(65) Moderately diff.(65) 0.21 16.6 3.0
Favors Everolimus Favors Placebo
Independent adjudicated central review E
Everolimus 10 mg PO daily P Placebo
1
0
0.4
0.8
Hazard Ratio
Yao J et al. 12th World Congress on
Gastrointestinal Cancer June 30July 3, 2010
Barcelona, Spain. Poster O-0028.
14
RADIANT-3 Overall Survival
Everolimus 10 mg n 207 Placebo n 203
Events n () Events n () 51 (24.6) 50 (24.6)
HR 1.05 95 CI (0.711.55) P .594 HR 1.05 95 CI (0.711.55) P .594 HR 1.05 95 CI (0.711.55) P .594 HR 1.05 95 CI (0.711.55) P .594
Censored n () Censored n () 156 (75.4) 153 (75.4)
Kaplan-Meier estimates (95 CI) at Kaplan-Meier estimates (95 CI) at Kaplan-Meier estimates (95 CI) at Kaplan-Meier estimates (95 CI) at
3 months 97.1 (93.698.7) 98.5 (95.599.5)
6 months 93.1 (88.795.9) 91.6 (86.894.7)
12 months 82.3 (76.087.0) 82.6 (76.587.3)
18 months 73.1 (65.179.6) 73.9 (66.180.2)
24 months 57.3 (43.069.2) 62.8 (51.172.4)
148 placebo patients crossed over to receive
everolimus
Hazard ratio is obtained from the unadjusted
stratified Cox model P-value is obtained from the
stratified one-sided log rank test
Yao J et al. 12th World Congress on
Gastrointestinal Cancer June 30-July 3, 2010
Barcelona, Spain. Poster O-0028.
15
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 lt .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

16
Progress in NET Treatment
PROMID Placebo-controlled prospective Randomized
study on the antiproliferative efficacy of
Octreotide LAR in patients with metastatic
neuroendocrine MIDgut tumors
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PROMID Octreotide LAR Slows Disease Progression
in Midgut NETs
TTP in Midgut NET
Octreotide LAR vs placebo P lt .001 HR 0.34 (95
CI 0.200.59)
Based on conservative ITT analysis
HR hazard ratio ITT intent-to-treat TTP time
to progression
Rinke A, et al. J Clin Oncol. 2009274656-4663.
18
Phase 3 Trial Sunitinib vs Placebo in Advanced
pNET
Study halted prior to complete accrual due to
treatment benefit Unplanned Kaplan-Meier PFS
analysis
1.0
P lt .001 HR 0.397 (95 CI 0.243 to 0.649)
0.8
0.6
Sunitinib PFS 11.1 mo
Survival probability
0.4
Placebo PFS 5.5 mo
Sunitinib Placebo
0.2
0
0 5 10 15 20
Efficacy endpoint variable value (mo)
Placebo, n 79 25 6 1 0 Sunitinib, n 74 32 14 2 0
Raymond E, et al. Presented at ESMO-GI 2009
Abstract 0013.
19
Ongoing Issues in NET Treatment

• Predicting treatment efficacy/individualizing
  treatment
• Drug approvals and insurance access to treatment
  options
• Combination regimens
• Balancing toxicity and efficacy

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Ongoing Issues in NET Treatment, contd.

• 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
21
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