Neuroendocrine tumor: an update on classification and targeted treatment Ming-Huang Chen MD, PhD Department of Oncology, Taipei Veterans General Hospital 2017/5/7 TJCC talk

Outlines New classification of pancreas NETs 2017 WHO classification Ethnic difference in pancreatic NETs Peptide Receptor Radiotherapy: experience sharing

Comparison of the WHO classifications of pancreatic NETs

WHO 2010 classification

WHO 2017 classification Ki67 at least 500 cells in higher nuclear labeling area, 50 HPF, show as per 10 HPF.

The changes 1. Ki67 cutoff level of grade 1 pancreatic NET

WHO 2017 classification <3 %

Grade 1 NET Cut of 3% Because this was always the intention of WHO 2010. That is Ki67 proliferative index were to be rounded up or down to nearest whole number. Ex: No ki67= 2.5%

The changes 1. Ki67 cutoff level of grade 1 pancreatic NET 2. Subdivision of tumors with Ki67>20% into - Well differentiated G3 NETs - Poorly differentiate G3 NECs

Increasing evidence suggests that G3 NEN are not a homogenous entity and can be further sub-classified into biologically relevant subgroups . A separation based on the proliferative index (Ki-67 >55%) was shown to have clinical implications regarding response to chemotherapy and prognosis.

2016 ENETS guideline for high grade NETs/NECs

Nodic NEC study Sorbye H et al. Cancer 2014; 2814-23

Nordic NEC study < 55% less responsive to platinum based chemotherapy >55% more responsive but worse survival However, pathology in this study is not well evaluated.

Well differentiated

Stem cells origin of GEP NETs

德國慕尼黑理工大學

Pancreatic neuroendocrine neoplasms with Ki67>20%

Pancreatic neuroendocrine neoplasms with Ki67>20%

Pancreatic neuroendocrine neoplasms with Ki67>20%

The distinction of NETs from NECs MEN1, DAXX, ATRX mutation P53, Rb1 mutations SSTR2A (+) SSTR2A (-) Recognisable as NETs Small cell or large cell types Often evolve from a recognisable low grade component No lower grade component No upper limit given, but usually Ki67<40 to 55% Mitotic count <20/10HPF Must have Ki67>20% no lower limit but usually> 55%

PNETs with Ki67>20% Strong evidence that not just Ki67/mitotic rate but also morphological differentiation is important Large cell, small cell NECs should be considered completely different entities to PNETS.

Pancreatic NET and Ki67 3%

WHO 2017 classification <3 %

The changes 1. Ki67 cutoff level of grade 1 pancreatic NET 2. Subdivision of tumors with Ki67>20% into - Well differentiated G3 NETs - Poorly differentiate G3 NECs 3. MANEC (mixed adenoneuroendocrine carcinoma) becomes MENEN/MINEN

WHO 2017 classification <3 %

Mixed endocrine non-endocrine neoplasms (MINEN) To qualify as MINEN each component must have at least 30%. (No change) Recognises that MINENs may occasional be well differentiated. (Not always poorly differentiated NECs) MINENs may have a non-endocrine component other than adenocarcinoma (SCC, acinar cell carcinoma)

Unsolved Problems How to treat well differentiated NET grade 3 ? - chemotherapy ? Which regimens? - Targeted therapy? - PRRT? - Hormone therapy? How to treat MINENS, especially well differentiated NET + SCC or adenocarcinoma or acinar cell carcinoma?

Outlines New classification of pancreas NETs 2017 WHO classification New 8th AJCC TNM staging of pancreatic NETs   Ethnic difference in pancreatic NETs Peptide Receptor Radiotherapy: experience sharing

AJCC 8th version of pancreatic NETs Primary tumor (T) TX Tumor cannot be assessed T1 Tumor limited to the pancreas, < 2 cm T2 Tumor limited to the pancreas, 2-4 cm T3 Tumor limited to the pancreas, > 4 cm or tumor invading the duodenum or bile duct T4 Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery) AJCC 7th version of pancreatic cancer AJCC 8th version of pancreatic neuroendocrine tumor

AJCC 8th version of pancreatic NETs Distance Metastasis (M) M0 No distant metastasis M1 Distant metastasis M1a Metastasis confined to liver M1b Metastsis in at least one extrahepatic site (e.g., lung, ovary, nonregional LN, peritoneum, bone) M1c Both hepatic and extrahepatic metastases AJCC 7th version of pancreatic cancer AJCC 8th version of pancreatic neuroendocrine tumor

AJCC 8th version of pancreatic NETs Stage T N M I T1 N0 M0 II T2 T3 III T4 Any T N1 IV Any N M1 AJCC 7th version of pancreatic cancer AJCC 8th version of pancreatic neuroendocrine tumor

Summary of Changes in AJCC8th version in PNETs New Chapter PNETS are staged using a TNM staging predominantly based on size The criteria of peripancreatic soft tissue invasion was eliminated. The Tis distinction was eliminated. M is subdivided to M1a, M1b and M1c

Outlines New classification of pancreas NETs 2017 WHO classification New 8th AJCC TNM staging of pancreatic NETs   Racial difference in NETs Ethnic difference in pancreatic NETs Peptide Receptor Radiotherapy: experience sharing

RADIANT3- Japan subgroup Jpn J Clin Oncol 2012;42:903–911

RADIANT3- Japan subgroup Overall population Japanese subgroup Overall population Japanese subgroup Everolimus Placebo RATIANT3 (Advanced progressive PNETs) Median PFS, mon 11.0 4.6 19.45 2.83 HR 0.35 0.19 Overall population Japanese subgroup Jpn J Clin Oncol 2012;42:903–911

RADIANT-4 Study Design Everolimus 10 mg/day N = 205 Placebo N = 97 Patients with well-differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N = 302) Absence of active or any history of carcinoid syndrome Pathologically confirmed advanced disease Enrolled within 6 months from radiologic progression Everolimus 10 mg/day N = 205 Treated until PD, intolerable AE, or consent withdrawal 2:1 RANDOMI ZE Placebo N = 97 Endpoints: Primary: PFS (central) Key Secondary: OS Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK Stratified by: Prior SSA treatment (yes vs. no) Tumor origin (stratum A vs. B)* WHO PS (0 vs. 1) Abbreviations: AE, adverse event; CgA, chromogranin A; DCR, disease control rate; FACT-G, functional assessment of cancer therapy-general; GI, gastrointestinal; HR, hazard ration; HRQOL, Health Related Quality of Life; NET, Neuroendocrine tumors; NSE, neuron-specific enolase; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, Pharmacokinetics; SSA, somatostatin analogues; WHO PS, World Health Organization performance status. *Based on prognostic level, grouped as: Stratum A (better prognosis)  appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worse prognosis)  lung, stomach, rectum, and colon except caecum. Crossover to open label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.

Primary Endpoint: PFS by Central Review 52% reduction in the relative risk of progression or death with everolimus vs placebo HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001 205 168 145 124 101 81 65 52 26 1 3 97 39 30 24 21 17 15 11 6 5 Placebo Everolimus No.of patients still at risk 2 4 8 10 12 18 27 Months 20 40 50 60 70 80 90 100 Probability of Progression-free Survival (%) Kaplan-Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43) Censoring Times Everolimus (n/N = 113/205) Placebo (n/N = 65/97) P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.

PFS HR by Pre-defined Subgroups All Age <65 ≥65 Sex Male Female Race Caucasian Asian Other Tumor grading Grade 1 Grade 2 302 159 143 142 160 230 50 22 194 107 Hazard Ratio (95% CI) No. Subgroups 0.56 (0.41-0.77) 0.55 (0.36-0.83) 0.59 (0.37-0.94) 0.78 (0.51-1.22) 0.39 (0.25-0.60) 0.83 (0.56-1.21) 0.19 (0.09-0.40) 0.26 (0.08-0.85) 0.57 (0.39-0.84) 0.49 (0.29-0.83) 0.1 0.4 1 10 Treatment naive* Y es No 17 185 0.65 (0.39-1.08) 0.51 (0.35-0.76) Prior chemotherapy Baseline CgA >2xULN ≤2xULN Baseline NSE >ULN ≤ULN 77 225 139 138 87 188 0.35 (0.19-0.64) 0.60 (0.42-0.86) 0.40 (0.25-0.62) 0.70 (0.45-1.11 0.77 (0.45-1.34) 0.44 (0.29-0.66) Everolimus Better Placebo Better *Defined as no prior chemotherapy or no SSA therapy continuously for ≥12 weeks any time before study. Hazard ratio is obtained from unstratified Cox model. CgA, chromogranin A; NSE, neuron-specific enolase; ULN, upper limit of normal.

Summary and conclusions In this East Asian subgroup analysis of the RADIANT -3 and -4 studies Everolimus demonstrated a clinically meaningful 8.1-month prolongation of PFS and an 82% reduction in risk of progression or death compared placebo in patients with advanced, progressive, nonfunctional NET of lung/GI origin consistent with the overall RADIANT-4 study population In patients with advanced PNET from the RADIANT-3 study, everolimus demonstrated a 7.7-month increase in PFS and a 66% reduction in risk of progression or death compared to placebo Safety profile was consistent for the East Asian subgroup with the known safety profile of everolimus and no new safety signals were observed Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of NET including those arising from the pancreas, lung, and GI tract NET, neuroendocrine tumors; GI, gastrointestinal; PNET, pancreatic NET

Ethnic and racial difference in pancreatic NETs RADIANT 3 East Asia Japan Taiwan Median PFS 11.0 months 14.1 months 19.5 months 18.9months Asia-Pacific Journal of Clinical Oncology 2016; 12: 396–402

Customized sequencing panel for 43 genes association with pNETs. N=40 pNETs. Customized sequencing panel for 43 genes association with pNETs. NGS of

Take Home Message New WHO 2017 classification of pancreatic NETs. New AJCC 8th classification of pancreatic NETs. Everolimus is effective in pancreatic NETs, lung NETs and GI NETs in Asia patients.

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