CURRENT EVIDENCE TO DIAGNOSE AND TREAT GEP-NENS

Rocio Garcia-Carbonero

Medical Oncology Department

Hospital Universitario 12 de Octubre

Universidad Complutense de Madrid

rgcarbonero@gmail.com

MEDICAL ONCOLOGIST (METASTATIC DISEASE)

DISCLOSURE OF INTEREST

• Travel and educational support from Ipsen, Pfizer, Novartis, Roche, Merck.

• Advisory/Speaker honoraria from Ipsen, Pfizer, Novartis, AAA, Roche, Merck, MSD, Sanofi,

Bayer, Lilly, PharmaMar, BMS, Servier.

• Research support from Pfizer and BMS.

CLINICAL SCENARIO

✓ Stage: Advanced unresectable disease

✓ Proliferative index (Ki67): G2-G3 (Ki-67 3-100%)

✓ Therapeutic aim: Antiproliferative treatment/Tumor control

✓ Type of therapy: Systemic therapy (SSA, PRRT, CT, TT)

Baseline Assessment To Select an Optimal Therapeutic Strategy

Patient assessment

• Symptom assessment

• Performance status

• Age and comorbidities

• Family & social support

• Needs and aims

Tumor assessment

• Histological assessment

• Biochemistry

• CT / MR scan

• 68Ga PET / octreotide scan

Factors to consider

• Primary tumor site

• Tumor differentiation

• Proliferation rate (Ki-67)

• Tumor growth rate

• TNM stage

• Organs involved (liver

dominant disease?)

• Functional assessment

• Symptom & tumor burden

• Toxicity profiles

• Prior therapies

Treatment options

• Surgery

• Biological therapy

• Targeted therapy

• PRRT

• Chemotherapy

• Loco-regional therapy

Primary tumor site: prognostic and predictive implications

RectumAppendixStomachColonSmall intestineLungCecumPancreasLiver

Survival by Tumor Site

➢ PRRT: greater ORR in PNETs vs GI-NETs in non-controlled trials; RCT only conducted in midgut NETs

➢ Sunitinib: efficacy only demonstrated in PNETs (RCT)

➢ Chemotherapy: greater ORR in PNETs vs GI-NETs in non-controlled trials; greater ORR in G3 NECs vs NETs

Proliferation rate is really a continuous variable

Nuñez-Valdovinos B,..Garcia-Carbonero R. RGETNE. Oncologist 2018

Tumor differentiation and proliferation rates are related

but independent prognostic variables

Heetfeld et al, ERC 2015

Ki-67 values are generally lowerfor NETs vs NECsbut there is no absolute cutoffvalue to helpdiscriminate bothentities.

Ki-67 index in G3 NET vs NEC

NEC type A: NEC Ki-67>55%

NEC type B: NEC Ki-67 20-55%

NEC type C: NET Ki-67 20-55%

Milione et al, Neuroendocrinol 2017

Molecular features can help discriminate NET vs NEC

Coriat et al, The Oncologist 2016

Proliferation rate influences treatment response

NORDIC NEC Study

Sorbye et al, Ann Oncol 2013

✓ All CT-treated patients: ORR 31% OS 11 months (vs 1 month for BSC)

✓ Patients with Ki-67 < 55% had a lower response rate (15% vs 42%, P<.001), but better

survival (14 vs 10 months, p<.001) than patients with Ki-67>55%

✓ Negative prognostic factors for OS: poor PS, colorectal primary, platelets or LDH levels

Ki-67 < 55%

Ki-67 > 55%

Pancreatic

Colorectal

Tumor differentiation influences treatment response

Heetfeld et al, ERC 2015

Overall survival

✓NET G3: 99 months

✓NEC G3: 17 months

SSTR tumor expression

• Diagnostic implications: SSTR imaging (octreoscan, Ga68-PET)

✓ Localization of primary tumor

✓ Extent of disease

✓Confirms the NE nature of the tumor

• Prognostic significance: favorable

• Therapeutic implications:

✓ Selection of patients for treatment with “cold” SSA

✓ Selection of patients for treatment with PRRT (SSA-Radioisotope)

✓Assessment of response to PRRT

Other prognostic / predictive factors

TRASGU Study (nomogram to predict PFS in SSA-treated advanced NETs)

Garcia-Carbonero R, RGETNE, ESMO 2018

NOMOGRAM

http://www.iricom.es/prognostictools/Trasgu

Other prognostic / predictive factors

GI NEC Score

Lamarca et al, JNCI 2017

19.4 m vs 5.2 m

Drug- and treatment-related issues

Patient´s features: PS, age, comorbidity, preferences

Drug issues: safety profile, availability, convenience, cost

Therapeutic objective:

✓ induce tumor shrinkage

❖ to facilitate resection

❖ to control functional syndrome

❖ to control symptoms related to tumor burden

✓ slow tumor progression / improve survival?

✓ improve/maintain quality of life

But we should not forget…..

✓ Clinical judgement – our real patients are often far from the ideal patients of clinical

trials – don’t forget we are doctors !!

✓ Biology is complex – NEN is a very heterogenous family of diseases and we need to

understand them better

Endocrinol Metab Clin North Am. 2018;47:683

TAKE HOME MESSAGE

NET NEC

Ki-67 <10% 11-20% 21-55% 21-55% >55%

SSA ++

PRRT ++ ++ +

Sunitinib* ++ ++ +

Everolimus ++ ++ +

Tem-Cap + ++ +

Platinum-based ++ ++

* Pancreatic primary

✓ Include all factors in the equation – far beyond tumor diff and Ki-67

✓ Multidisciplinary expert care is key