Presentation on NETs

1. NETS – The evidence and
extrapolation beyond.
Hagen Kennecke, MD, MHA, FRCPC
Medical Oncology, Virginia Mason
Associate Professor, UBC
Virginia Mason Cancer Institute

2. Objectives
• Review classification and staging of NETs.
• Consider the major NET treatments:
– Surgery
– Liver Directed Therapy
– SSAs
– PRRT
– Small Molecule Therapy
– Chemotherapy
• Walk though a day of PRRT.
• Integrate PRRT with other NET treatment options.

3. Are NETs still rare?
Year Annual incidence rate
per 100,000
US prevalence count
estimate
2004 5.25 103,3121
2012 6.98
2014 171,3212
129-year limited duration prevalence. 220-year limited duration prevalence.
Yao et al (2008). J Clin Oncol 26(18) 3063-3072
Shen et al NANETS 2016
Daseri et al JAMA Oncology, 2017
Courtesy J Yao, ENETS
3800 in WA!

4. New 2017 WHO NET classification
Mitoses
(per 10
HPF)
Ki67
index
Morphology
G1 NET <2 <3% Well differentiated
G2 NET 2–20 3–20% Well differentiated
G3 pNET ONLY! >20 >20% Well differentiated
G3 NEC
• Small cell type
• Large cell type
>20 >20%
Poorly
differentiated
DAXX/ATRX/MEN1
p53/Rb1
PNETPathologic features1
(mutant genotype / loss
of nuclear labelling)
NET, neuroendocrine tumour; NEC, neuroendocrine carcinoma
1. Yachida et al. Am J Surg Pathol. 2012;36(2):173–84.
2. Tang et al. Clin Cancer Res. 2016;22(4):1011–7.
A. Perren, Session 3A: Aggressive NEN, March 9, 2017.
PNET

5. Presentation
• Mostly incidental diagnosis
• Frequency of secretory syndromes:
– Small Bowel NET: 40-50%, vasoactive amines
– PNET: 15%, peptides (insulin, gastrin, VIP, glucagon)
– Lung, Gastroduodenal: 20% secrete peptides
– Not prognostic, but influence management++

6. Diagnosis
• Colonoscopy
• Capsule Endoscopy
• CT
• MRI
• Gallium 68 Dotatate or NETSPOT®
• Octreoscan®

7. Octroscan
®️
CT
Octreoscan
Octrescan/CT
Ga-68
DOTATATE
PET
Ga-68
DOTATATE
PET/CT
Imaging for NETs

8. Lesions detected in 131 NETs, 45% PNETs
Ga-68 DOTATATE
PETCT
CT/MRI Octreoscan p- value
95% 45% 31% <.001
Management recommendations changed in 33%
Found primary in 4/14 Primary Unkown NET patients
Sadowski JCO 2016

9. Early Cancers
• Follow-up once all cancer has been removed?
– No need for Octreotide/Lanreotide
• Annual CT scan?
– Triphasic
– Minimum 5 years, 10 if node positive
• Blood tests or Urine tests?
– Chromogranin A: affected by kidney function and
medications.
– CONSIDER doing if elevated pre-surgery
– 24- Urine 5HIAA – if symptoms

10. Advanced NETs:
Therapeutic Options
–RESECTION – surgery, surgery, surgery!
–Octreotide, Lanreotide
– Intra-Arterial Therapy
– PRRT
– Chemo and small molecules

11. Hepatic Surgery
 Liver is dominant area of disease
 Meta-analysis hepatic surgery, 1469 NET patients
5 and 10 year Overall Survival was 70% and 42%
95% had symptom response, 57% complete
When not to do surgery?
High grade, extra-hepatic disease, can’t remove it all
Consider alternate therapies, unless symptomatic
Mayo Ann Surg Onc 2011, Saxena Surg Onc 2012

12. Role of liver directed therapy
Presented By Nitya Raj at 2018 ASCO Annual Meeting

13. Intra-Arterial Therapy
• Embolic: Bland = Chemoembolization
• Radioembolic: Y 90
• DEB: Drug Eluting Beads
• Used in patients with unresectable NETs
• Very good for control in sections of the liver

14. CAUTION Carcinoid crisis!
Hepatic Surgery and Ablation
Intra-Arterial Therapy
PRRT
Secretory tumors!!

15. ala gly lyscys asn phe phe
phe
trp
lys
thr
phethrsercys
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s
Human somatostatin
D-
phe
cys phe
lys
thrcys
D-
trp
thr
-ol
Octreotide acetate
D-
phe
cys tyr
lys
valcys
D-
trp
Thr
-NH2
Lanreotide
SSR2
Somatostatin Analogs are indicated for
symptom control and disease control.
SSR2,3,4

16. PROMID study design
Mo
nth
-1 0 3 6 9 1
2
1
5
1
8
Informed
consent
Randomization
1:1
Continuation of
treatment if no
progression
Octreotide LAR 30 mg i.m. every 4 weeks
Placebo i.m. every 4 weeks
Primary endpoint: time to tumor progression
• Treatment was continued until CT or MRI documented tumor progression (WHO)
• Follow-up until death
• CT and/or MRI was evaluated by a blinded central reader
• No observation period prior to treatment to judge spontaneous tumor growth
Rinke JCO 2009

17. PROMID: Octreotide LAR significantly
increases time to tumor progression
Octreotide LAR vs placebo P=0.000072
HR= 0.34 [95% CI: 0.20–0.59]
Octreotide LAR: 42 patients / 26 events
Median 14.3 months [95% CI: 11.0–28.8]
Placebo: 43 patients / 40 events
Median 6.0 months [95% CI: 3.7–9.4]
Time (months)
Proportionwithoutprogression
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Based on the conservative ITT analysis
Rinke JCO 2009

18. 18
CLARINET: R Ph III trial of Lanreotide vs Placebo in GEP-NETs
Ki 67 <10% or Mitotic count ≤ 2/10 hpf
Caplin ME, et al. N Engl J Med. 2014;371

19. Primary Endpoint:
Kulke JCO 2017

20. Peptide Receptor
Radionuclide Therapy
Radiation particle attached to protein that targets the
somatostatin receptor (SSR) on the cancer:
Lu-177 and Y-90
Octreotate higher SSR2 affinity
Single Institution: Response Rates 10-40%, Very long
survival of patients:
Rotterdam, Germany, Sweden, Australia, UK, Canada
Toxicity:
Kidney and Blood Cells/Hematologic
Risk of second cancer - much lower in modern studies
ENETS PRRT Guidelines Neuroendocrinology 2009,
Reubi Eur J Nucl Med 2000, Kwekkeboom Eur J Nucl Med 2001, Baum Eur J Nuclear Med 2000,
Kwekkeboom JCO 2008

21. NETTER -1 Study Objectives and Design
Presented by: Prof. Jonathan Strosberg
Aim
Design International, multicenter, randomized, comparator-controlled, parallel-group
Evaluate the efficacy and safety of 177Lu-Dotatate + SSAs (symptoms control) compared
to Octreotide LAR 60mg (off-label use)1 in patients with inoperable, somatostatin receptor
positive, midgut NET, progressive under Octreotide LAR 30mg (label use)
Baseline
and
Randomization
n = 115
5
Years
follow
upOctreotide LAR (high dose - 60mg every 4 weeks1)
n = 115
Dose 3Dose 1 Dose 2 Dose 4
4 administrations of 7.4 GBq of 177Lu-Dotatate
every 8 weeks + SSAs (symptoms control)
1 FDA and EMA recommendation
Treatment and Assessments
Progression free survival (RECIST criteria) every 12 weeks

22. Population Characteristics at Enrolment- Midgut NETS
(ITT population, N=229)
Presented by: Prof. Jonathan Strosberg
177Lu-Dotatate
(n=116)
Octreotide LAR 60mg
(n=113)
Ki67, n (%)
G1/G2 76/40 (66/34%) 81/32 (72/28%)
SRS, Krenning scale, n (%)*
Grade 2
Grade 3
Grade 4
13 (11%)
34 (29%)
69 (60%)
14 (12%)
32 (28%)
67 (59%)
Chromogranin A (µg/L), mean (SD) 649 (420) 670 (422)
5-HIAA (mg/24h), mean (SD)** 100 (183) 77 (83)
* highest grade
** only available in 98 patients

24. Objective Responses
(*) Exclude patients with no post-baseline scans or central response available
Presented by: Prof. Jonathan Strosberg
177-Lu-Dotatate
(n=101)*
Sandostatin LAR
60 mg (n=100)*
Complete Response (n) 1 0
Partial Response (n) 17 3
Objective Response Rate (*) 18% 3%
Confidence Interval (95%) 10% - 25% 0% - 6%
Statistical Significance p = 0.0008
All patients (n=116) (n=113)
Progressive Disease 6 (5%) 27 (24%)
Stable Disease 77 (66%) 70 (62%)

28. Grade 3-4 Hepatotoxicity
Presented by: Prof. Jonathan Strosberg
Lutathera
(N = 111)
Octreotide LAR
(N = 110)
AST increase 4% 0%
ALT increase 4% 0%
Bilirubin increase 2% 0%
GGT increase
(at inclusion respectively 11% and 9%)
18% 13%
(CTCAE V4.0; Safety Set)

29. Creatinine Clearance
Renal function remains stable over the 2-year observation period
Presented by: Prof. Jonathan Strosberg
Lutathera (N = 111) Octreotide LAR (N = 110)
Grade 3/4 Grade 3/4
Creatinine increased 0% 0%
0
20
40
60
80
100
120
 177Lu-Dotatate
 Octreotide 60 mg
n = 106/96 99/93 100/91 77/61 63/39 52/26 36/14 27/8 14/3 8/3
CreatinineClearance
mean(mL/min)

30. A Day of PRRT

31. PRRT @LIVE
8 AM Arrival
9 AM Start 2 IVs, IV Proteins and Nausea Meds
10 AM Nuc Med Team gives Lutetium 177
no visitors for that hour
11 AM Nuc Med Team FINISHED
1 PM GO HOME after 1 liters and bathroom +++

32. Chemotherapy Principles
• PNETs are generally chemosensitive, other NETs are not.
• Alkylating agents are active in PNETs.
• Platinum based chemo for NECs
• Ki 67% may serve as a guide to chemotherapy

33. E2211 Study Design
Presented By Pamela Kunz at 2018 ASCO Annual Meeting

34. Progression Free Survival
Presented By Pamela Kunz at 2018 ASCO Annual Meeting

35. Overall Survival
Presented By Pamela Kunz at 2018 ASCO Annual Meeting

36. Response Rates
Presented By Pamela Kunz at 2018 ASCO Annual Meeting

37. Targeted Therapy for NETs
PHASE III evidence:
• Sutent and Everolimus approved in PNETs
• Everolimus approved in NETs
• RADIANT-4 demonstrated benefit of
everolimus.

38. PNETs: Everolimus Efficacy Data from
RADIANT-3
• In patients with advanced, low-grade or intermediate-grade pNETs,
progression-free survival was significantly prolonged with everolimus
compared with placebo (11.0 vs. 4.6 months, P<0.001)
– Representing a 65% reduction in the estimated risk of progression or death
Months
Kaplan-Meier median
Everolimus, 11.0 mo
Placebo, 4.6 mo
Hazard ratio, 0.35 (95% CI, 0.27 - 0.45)
P<0.0001 by one-sided log-rank test
ProbabilityofProgression-Free
Survival(%)
0 2
0
20
40
60
80
100
4 6 8 10 12 14 16 18 20 22 24 26 28 30
Everolimus
Placebo
Censoring times
Yao et al. N Engl J Med. 2011; 364:514-523.

39. PNETs: Sunitinib Efficacy Data from a
Phase 3 Trial
In patients with advanced, well-differentiated pNETs, progression-free
survival was significantly prolonged with sunitinib compared with placebo
(11.4 vs. 5.5 months, P<0.001)
Raymond et al. N Engl J Med. 2011; 364:501-513.
Months since Randomization
No. at Risk
Sunitinib
Placebo
Sunitinib
Hazard ratio, 0.42 (95% CI, 0.26 - 0.66)
P<0.001
Placebo
86
85
39
28
19
7
4
2
0
1
0
0
ProbabilityofProgression-Free
Survival(%)
0
0 5 10 15 20 25
20
40
60
80
100

42. Octreotide
NEC
NET
PNET
Small Cell C
SYSTEMIC THERAPY- SUMMARY
PRRT
Everolimus
Sunitinib
Alkylating Agents
Platinum Agents

43. My conclusions:
extrapolate beyond the evidence!
• MultiD Conference
• Don’t treat unless you have to
• Surgery First!
• SSAs
• PRRT vs IAT vs Chemo & Small Molecule

44. TWO CASES

45. 68 y retired teacher
• 2013 screening endoscopy terminal ileum T2N0 in 0/25 G1,
mitosis in <1/10 hpf. Pre-op mild peripheral
neuropathy/neuralgia resolved post-op.
• 2015 re-emergence of peripheral neuropathy/neuralgia and
H/A, new solitary hepatic lesion on CT.
• 2016 RFA of hepatic lesions. Improvement of symptoms.
• 2017 Symptoms recurred, diagnostic Gallium 68 Dotatate.

46. Hepatic Metastases
46

47. Hepatic Metastases
47
2017 May Gallium 68 Dotatate:
Seg 8 (SUV 8.1), Segs 2 (6.6) and 5.

48. 2017 September MRI
Total 5 sub-cm lesions segs 2,6,8
Progression around RFA lesion
Segs 2,6 ablation lesions.
Questionable porta hepatis lesion

49. Therapy
• Octreotide LAR 30 mg IM monthly with
transient symptom improvement.
• Escalate to LAR 60 mg IM with little palliative
benefit.

50. Treatment options
• Everolimus
• PRRT
• Repeat bland embolization
• HIA Y90
• Chemotherapy: Cap-TMZ

51. PRRT

52. Treatment
• Ondansetron 16 mg IV
• Plenamine 15% AA in 2.5L @ 360-550 ml/hr
• Lutetium Lu 177 Dotatate 200 mCi/7.4 GBq slow
push
• In draped room with separate bathroom
• Est. 6 hours total

53. Early Outcome
• Day #3 mild fatigue, no nausea, “peeing a lot”
• Week 6 complete resolution of peripheral
neuropathy, headaches and fatigue, ECOG 0.
• “ I feel like a new man! “
• Dose #2 given week 8

54. KING TV Video

55. Questions
• How many doses would you offer for low
burden of disease?
• Would you re-start Octreotide after?

56. 71 y retired banker
• 2013 episodic cramping diarrhea.
• 2016 omental mass, Octreoscan avid, elevated 24◦ 5HIAA.,
resected jejunum and partial omentum. Diffuse
“innumeral” peritoneal and pelvic mets. T4aN1M1 jejunal
NET, Ki 67 1-2%, mitotic count 7/10 hpf G2
• PMHx 2007 Breast Cancer T1N0 triple neg breast cancer, DC
and mastectomy.
• Rx: Octreotide 30 mg IM

57. • 2017: Onset of mild generalized abdominal
ache and cramping in spite of Oct LAR.

58. Peritoneal Metastases

59. Peritoneal Metastases
59

60. Peritoneal Metastases

61. Therapy?
• Everolimus
• PRRT
• Peritoneal stripping
• HIA Y90
• Total abdominal irradiation

62. PRRT