2. Update: Neuroendocrine Tumors
- Chief of Clinical Research
- Assistant Oncologist
Instituto do Cancer do Estado de São Paulo

3. Therapeutic Options for Advanced well differentiated NETs
Surgery
Curative, debulking
Transplant
Locoregional
Radiofrequency ablation
Embolization / chemoembolization / radioembolization (degradable starch microspheres)
Systemic therapy
Chemotherapy
Biological targeted agent (Somatostatin analogs , IFN-α )
Targeted molecular therapy
PRRT

4. What is new with SSA?

5. Antitumor Effect of SSA in double-blind placebo-controlled trials:
PROMID and CLARINET
mTTP 6 vs 14 mo w/ Octreotide
mPFS 18mo vs NR w/ Lanreotide
Rinke. JCO 2009; Caplin M, NEJM 2014

7. Phase II trial of pasireotide LAR in patients with metastatic neuroendocrine tumors
N= 29, Tx -naïve G1/2 GEP-NETs
Pasireotide LAR 60 mg q4 wks
Primary endpoint PFS
RESULTS:
mPFS was 11 months
RR: 4%
79% any grade hyperglycemia (14% G3)
Cives. Endocr Relat Cancer 2015.

8. A randomized, open-label, phase II study evaluating the efficacy and safety of combination of PAS and EVE or EVE alone in patients with advanced pNET
Best % change from baseline (measurable lesions)
EVE + PAS (n = 70)
EVE (n = 74)
***** **
Percentage of event-free survival
Time, months
100 80 60 40 20 2 4 6 8 10 12 14 16 18 22 24 26 28 30 32
Censoring Times
EVE + PAS: (n/N = 40/79)
EVE (n/N = 41/81)
HRb [95% CI] = [0.636, 1.543]
Kaplan Meier medians
EVE + PAS: months
EVE: months
Log rank P valuec = 0.488
Kulke M. ENETS 2015

9. UPDATES ON TARGETED AGENTS

10. Gain of appx 6 mo in median PFS
Targeted drugs in WD pancreatic NET: phase III placebo-controlled trials
SUNITINIB EVEROLIMUS
Gain of appx 6 mo in median PFS .
Raymond E, et al. N Engl J Med. 2011;364:
Yao J, et al. N Engl J Med. 2011;364:

11. Efficacy of everolimus or sunitinib by prior therapy
Drug
EVEROLIMUS2,3
HR vs placebo
SUNITINIB1
Prior chemo
Yes No
0.34
0.41 -
Prior SSA
0.40
0.36
0.43
Any Prior Therapy
0.33
0.61
Raymond E, et al. N Engl J Med. 2011;364:
Yao J, et al. N Engl J Med. 2011;364:
Lombard-Bohas C. Pancreas (2)
1. Raymond E, et al. N Engl J Med. 2011;364:
2. Yao J, et al. N Engl J Med. 2011;364:

12. RADIANT3: Final OS by Treatment arms20 40 60 80
100
Percentage of overall survival 4 8 12 16 24 28 32 36 44 48 52 56 64 68 72 76
Censoring Times
Everolimus (n/N = 126/207)
Placebo (n/N = 130/203)
Kaplan-Meier medians
Everolimus: months
Placebo: months
Hazard ratio = 0.94 (95% CI [ ])
Log-rank P-value = (significance boundary )
Time (months)
No. of patients still at risk
Everolimus
207
194
181
163
152
142
130
122
112
105 97 93 87 77 67 39 22 10 2
Placebo
203
195
175
162
150
140
123
113
104 96 91 81 68 64 45 25 6 1
Cutoff date: March 05, 2014
Adjusted HR was 0.90 (95% CI, )
Adjusted for pre-specified baseline covariates (age, gender, region, and prior SSA use)
85% in placebo group crossed over to open-label everolimus
Yao JC. Annals of Oncology (2014) 25 (suppl_4): iv394-iv /annonc/mdu345

13. Phase II Trial of Temsirolimus and Bevacizumab in pNETs
WD pNETs progressing within 7 mo
Primary endpoint: RR and PFS
N= 58 (52 naïve or prior octreotide)
RESULTS:
RR: 41%, mPFS 13.2 mo
82% required dose reduction of TEM
25% interrupted bevacizumab
30% discontinued
Hobday TJ. JCO 2014

14. CALGB 80701: Randomized Phase II of Everolimus ± Bevacizumab in Advanced pNET
Everolimus 10 mg daily + octreotide LAR
Randomize
N= 183
Everolimus 10 mg daily + octreotide LAR + bevacizumab 10 mg/kg q 2 wks
Primary endpoint: PFS
Accrual complete
NCT

15. What is new about functioning NETs?

16. RADIANT-2: phase III placebo-controlled trial of octreotide +/- everolimus in progressive functioning GEPNET
N=429, PFS primary endpoint
PROBLEMS: Unbalanced groups + lots informative censoring  lost power
Central Radiology Assessment
Investigator Assessment
Pavel M. Lancet 2012

17. Telotristat etiprate (TE), oral inhibitor of peripheral serotonin synthesis in carcinoid syndrome refractory to
Phase II:1 dose-escalating 12-week,
N= 14 pts: ≥4 bowel movements/day. SSA use was allowed.
RESULTS:
All reduced BM/day (mean decrease 43.5%)
74.2% mean reduction in u5-HIAA
Randomized placebo-controlled phase II of scalating doses of TE:2
Placebo: TE  1:3 or 1:6
N= 23 pts ≥4 bowel movements/day despite stable- dose octreotide LAR
RESULTS:
28% reduced ≥30% BM for ≥2 wks
56% ≥50% reduction in 24h u5- HIAA at wk 2 or 4
1- Kulke MH.Endocr Rel Cancer. 2014
2- Pavel M. J Clin Endocrinol Metab. 2015

18. SILENT NETs

19. Everolimus in silent NETs
N=26, 21 colorectal,
RR: 11%, median dur. 6.4m
mPFS: 17 mo
N= 58, mPFS 6mo
Unknown= 11m
Lung= 6.7 m
GI= 6.2
Do-Youn Oh. Cancer 2012
Pavel M. ESMO 2012

20. RADIANT-4: phase III, double-blind study of everolimus + BSC versus placebo + BSC in advanced GI or lung nonfunctional NET
Everolimus 10mg/daily + BSC
Randomize 2:1
Matched placebo + BSC
Primary endpoint= PFS

21. Baseline Demographics of RADIANT-4
Baseline characteristic
Full Analysis Set
n = 302 (%)
Age
Median (years) 63
Age < 65
159 (53)
Age ≥ 65
143 (47)
Sex
Males
142 (47)
Females
160 (53)
Race
Caucasians
230 (76)
Asians
50 (17)
Blacks
15 (5)
WHO PS#
219 (73) 1
82 (27)
Primary tumor site
Lung
90 (30)
Ileum
71 (24)
Rectum
40 (13)
CUP 
36 (12)
Jejunum
22 (7)
Stomach
11 (4)
Duodenum
10 (3)
302 pts were included in the study and randomized
At the time of data cut-off (September 16, 2013)
173 (57.3%) patients were on treatment
127 (42.1%) discontinued treatment
2 (0.7%) were not treated
Disease progression (24.2%), adverse events (10.6%), and withdrawal of consent (5.3%) were the most common reasons for treatment discontinuation
Patients were stratified to balance for potential prognostic factors and included prior treatment with SSA, WHO PS and tumor origin
Yao. JC. ASCO GI abst# 276 21

22. CHEMOTHERAPY

23. Capecitabine+ temozolamide (CAPTEM) in NET
NET; N = 28
Parameter
Patients, %
Tumor stabilization 54
Tumor shrinkage 43
Tumor response in patients progressing on high-dose octreotide LAR 95
Type of tumor n
SD, %
PR, %
CR, %
PFS, months
OS, months
Carcinoid 12 58 33 8
> 23.9
> 31.5
Pituitary 3 67
> 41.6
pNET 11 55 36
> 20.0
> 24.4
Medullary thyroid 2
100
> 22.8
> 27.7
Overall 28 54 32
> 22.2
> 29.1
Fine RL, et al. Presented at: 2014 Gastrointestinal Cancers Symposium (Presscast); January 14, Abstract 179.

25. BETTER trial: single arm phase II trial of capecitabine + bevacizumab in progressive, WD GI-NETs
N= 49 progressive GI NETs, ki67 < 15%, Tx naïve
82% midgut
Primary endpoint: PFS
RESULTS:
RR: 18%, mPFS 23.4 months [95% CI: 13.2; NR]
Mitry E. EJC 2014.

26. PRRT

27. First US experience w/ PRRT
Phase II design of Lu177
N= 37 progressive GEPNET G1/2
Cycles of 200 mCi until cumulative dose of 800 mCi
RR: 28%
Improvement in PS and quality of life
Delpassand ES. Pancreas 2014

28. Ongoing Trials of PRRT in NET
Study
Treatment
Reference
NETTER1
phase III trial
177Lutetium vs octreotide LAR 60mg
in progressive, SSTR-positive midgut carcinoid tumors
NCT

29. Conclusions about Advances on NET up to 2015
The knowledge on GEPNET continuous to evolve
phase III data!
Some are mature data!
But…there are numerous gaps:
The best sequence ? Likely the more lines, the better
Refractory carcinoid syndrome and lung remain a great challenge

30. Yao J. NEJM 2011