PRRT in Management of NETs - Human Health Campus · 2018. 5. 7. · EFFICACY: PFS/OS Trial...

PRRT in Management of NETs

Ioannis Karfis, MD PhD

Assistant Head of Clinic

Nuclear Medicine Dept

IJB, Brussels

Pavel M: Neuroendocrinology 2013;97:99-112

THERAPEUTIC TARGETS in NENs

locoregional treatments (surgery/RFA/TACE/TARE)

177Lu- / 90Y- PRRT

GRADE 2

SSAs

Chemo (STZ /

5FU / TMZ / CAP)

INF α-2b

sunitinib

(pNETs)

everolimus

GRADE 1

SSAs

INF α-2b

sunitinib

(pNETs)

everolimus

GRADE 3

Chemo

(cisplatin/etoposi

de,

temozolamide/ca

pecitabine,

topotecan, CAF)

THERAPEUTIC ARENA in NENs

KEY ROLE OF NM IN MGMT OF NETs

MOLECULAR IMAGING / DIAGNOSIS 68Gallium-DOTA-peptide (β+) [68Ga-DOTA-OCTREOTATE]

Receptor imaging

Staging/Sélection of patients (cold and hot SSAs)

Quantification

PEPTIDE RECEPTOR RADIONUCLIDE THERAPY 177Lutetium-DOTA-peptide (β-, γ) [177Lu-DOTA-OCTREOTATE]

Therapy

Dosimetry

CHELATOR PEPTIDE SS receptor

AGONIST

68Ga-DOTATATE PET MIP 177Lu-DOTATATE SPECT MIP

THERANOSTIC TWINS

WE SEE WHAT WE TREAT & WE TREAT WHAT WE SEE...

PRRT isotopes:

177Lu: third generation radionuclide

β-emission >>>>> therapy / reduced radiation dose to OaRs

γ-radiation >>>>> imaging / quantification / dosimetry

t1/2phys emissions energy

particule tissue

penetrationmax

111In 2,8d

γ

Auger e-

IC e-

0,5-25KeV

218-245KeV

0,02-10μm

200-550μm

90Y 2,7d β 2,2MeV 12mm

177Lu 6,7d γ β

497KeV

2mm

HISTORICAL BACKGROUND

Kwekkeboom DJ et al, Endocr-Rel Cancer 2010;17(1):R53-73

internalization

177Lu

Octr

90Y

Octr

Octr

111In

PRRT PRINCIPLE

Bodei L et al.: (joint IAEA/EANM/SNMMI guidelines). EJNMMI 2013

PRRT INDICATIONS


The ideal candidates are those with well-differentiated NET

G1/G2 (metastatic or inoperable NET with positive

expression of sstr2)

patients with gastroenteropancreatic/bronchial NETs, but also

patients with phaeochromocytoma, paraganglioma,

neuroblastoma or medullary thyroid carcinoma.

Bodei L et al.: (joint IAEA/EANM/SNMMI guidelines. EJNMMI 2013)

ABSOLUTE: Pregnancy

Acute/Severe concomitant disease

Acute psychiatric disease

RELATIVE: Lactation

Compromised renal fonction

[<60% NV adjusted for age]

Compromised bone marrow fonction

[WBC: <3,000/μL with neutros<1,000/μL]

PLT: <75,000/μL

RBC: <3,000,000/μL]

PRRT CONTRAINDICATIONS

Tx MODALITIES (177Lu-PRRT)

One injection iv every 6-12 weeks

Administered activity: 5.5-7.4GBq (150-200mCi)/cycle

Number of cycles: 3-5

0 1 2 3 4 5 6h

AA AE

177Lu

END AA START AA


HOSPITALISATION

Hospitalised in dedicated rooms / isolation

Duration according national regulations

Urine/faeces should be disposed to according national

regulations

Hydration/Urination as much as possible during the

process

POST-Tx RECOMMENDATIONS

Released if radiation rate <20µSv/h @1m

Oral/Written practical radioprotection instructions

Release Card to carry for up to 10x t1/2biol

Avoid close contacts (<1m) for up to 2 weeks

3 weeks if children <10y/pregnant women

Hydration as much as possible

0 5 10 15 20 25 30 35 40

Ezziddin et al, 2014 (Bonn)

Bodei et al, 2011 (Milan)

Garkavij et al, 2010 (Lund)

Sward et al, 2010 (Gothenberg)

Kweekeboom et al, 2008 (Rotterdam)

Pfeifer et al, 2011 (Copengahen)

Cwikla et al, 2010 (Warsaw)

Imhof et al, 2010 (Basel)

Valkema et al, 2006 -multicentric-

Bodei et al, 2004 (Milan)

Waldherr et al, 2002 (Basel)

Delpassand et al, 2012 (Houston)

Limouris et al, 2008 (Athens)

Anthony et al, 2002 (New Orleans)

Valkema et al, 2002 (Rotterdam)

111In-DTPAOC

90Y-DOTATOC

177Lu-DOTATATE

EFFICACY: OR(CR+PR)

%

EFFICACY: PFS/OS

Trial Therapeutic Agent pts PFS (m) OS (m)

Valkema et al, 2002 111In-DTPA-OC 32 - 12

Delpassand et al, 2012 111In-DTPA-OC 40 - 22

Valkema et al, 2006 90Y-DOTA-TOC 58 29 37

Bushnell et al, 2010 90Y-DOTA-TOC 90 16 27

Cwikla et al, 2010 90Y-DOTA-TOC 58 17 22

Pfeifer et al, 2011 90Y-DOTA-TOC 53 29 -

Kwekkeboom et al, 2008 177Lu-DOTATATE 310 33 46

Bodei et al, 2011 177Lu-DOTATATE 42 - 36

Ezziddin et al, 2014 177Lu-DOTATATE 74 26 55

Kouvaraki et al, 2004 STZ+5-FU+DOXORUBICIN 84 39 18/37

Kulke et al, 2009 TMZ 53 34 14/35

Chan et al, 2013 TMZ+BEVACIZUMAB 15 33 14/42

Chan et al, 2013 TMZ+EVEROLIMUS 43 40 15/-

Yao et al, 2011 EVEROLIMUS 207 5 11/-

Raymond et al, 2011 SUNITINIB 86 9 11/-

NETTER-1 multicentric (41 centers/8 countries), prospective,

randomized, phase III

sponsor: Advanced Accelerator Applications (Lutathera®)

unresectable progressive SSTR+ midgut NETs

Sandostatine LAR 60mg vs 177Lu-DOTATATE c.a.

229 patients were randomized on the 2 arms

study start date: 11/2012, estimated study completion

12/2019

Strosberg J et al.: NEJM 2017;376:125-35

RECIST 1.1 assessments every 12±1w from the first

treatment date until EOS

NETTER-1: DESIGN

NETTER-1: EFFICACY - PFS/OS (n: 229)

Octreotide LAR 60 mg

Median PFS: 8.4 m

177Lu-DOTATATE Median PFS: NR

trial has not yet reached the point at

which the mOS can be calculated

interim analysis results suggest a

longer mOS on the PRRT arm

mPFS has not been reached in the 177Lu-DOTATATE arm


PRRT (n=101) SSA (n=100)

Complete Response (n) 1 0

Partial Response (n) 18 3

Objective Response (n, %) 19% 3%

Progressive Disease (n, %) 5 (4%) 27 (24%)

Stable Disease (n, %) 77 (66%) 70 (62%)

NETTER-1: EFFICACY - OR (n: 229)


TOXICITY?

DOSE DEPENDENT

ACUTE

>nausea, vomiting

>fatigue (first 10d post-injection)

>abdominal pain/disconfort

>carcinoid crisis, <1% (6/479 pts)

SUBACUTE/CHRONIC

> G3/G4 hematological: <11% (BM: critical organ, nadir: 6-

8w PI)

> G1 alopecia: 65%

CHRONIC

> G4 renal: <3.5% (kidneys: critical organ)

de Keizer B et al.: EJNMMI 2008;35:749-55, Bodei L et al.: Sem NM 2016;46:225-238

Sabet A et al.: Nuclearmedizin 2014;53:54-59, Kwekkeboom DJ et al.: JCO 2008;26:2124-30

TOXICITY?

DOSE INDEPENDENT

MDS/AL

> rare: MDS (3%) / AL (1.1%)

> median interval btw last PRRT - MDS: 3.7y

> stochastic event: unidentified individual susceptibilities

> no correlation with administered activities

> consequence of mutational events induced by sequentional

cytotoxic therapies: prenious alkylating chemotherapy

>NETTER1: 1pt in the PRRT arm/229pts

>Kwekkeboom D et al: n: 504 MDS/ALL: 3

Sabet A et al: n: 203 MDS/ALL: 3

Bodei L et al: n: 807 MDS/ALL: 8

Strosberg J et al.: NEJM 2017;376:125-35, Bodei L et al.: EJNMMI 2015;42:5-19

Sabet A et al.: JNM 2013;54:1857-61, Kwekkeboom DJ et al.: JCO 2008;26:2124-30

PLACE OF PRRT (siNETs)?

Pavel M et al.: Neuroendocrinology 2016;103:172-185

PLACE OF PRRT (pNETs)?

Pavel M et al.: Neuroendocrinology 2016;103:172-185

PLACE OF PRRT? ideally, second line treatment, after failure of SSAs

outstanding results of NETTER1

effective treatments must be given earlier at the course of

the disease

IJB: one of the two PRRT centers in Belgium

63 pts: GEP-NETs: 46pts (1 insulinoma, 1 gastrinoma, 2

rectal)

mammary NET: 2pts

NET pulmonaire: 5 pt

paragangliome/pheochromocytome: 6pts

kidney NET: 1pt

CUPS: 3pts

186 injections iv so far

PRRT: THE IJB EXPERIENCE OF ~4y

LuMEn: ‘‘177Lu-octreotate treatment outcome prediction using

Multimodality imaging in refractory neuroEndocrine tumours’’

[NCT01842165]

ongoing φII, non-randomised trial

GEP-NETs

to be bicentric soon (+UZL)

objectives: evaluate the predictive value of the following imaging

biomarkers: 68Ga-DOTATATE and 18FDG uptake, tumor absorbed

dose > to identify non responding lesions / non responding patients.

endpoints: lb-TTP, pb-PFS, efficacy & safety


LuMEn: main inclusion criteria:

Disease progression defined as follows:

- Radiological progression (RECIST 1.1) over the last 12m

- Progression on SSTR imaging, over the last 12m

- Clinical progression + significant increase in tumoral markers

Adequate renal function:

GFR≥50 mL/min/1.73m2

Adequate bone marrow function:

Hg≥9 g/dL;

WBC≥2·103/μL;

PLTs≥100·103/μL.

Adequate liver function


UNMET NEEDS IN PRRT

REGISTRATION – APPROVAL UPON AUTHORITIES

ACCURATE DOSIMETRY TO GUIDE THERAPY

? cycles of PRRT

STANDARDISATION

optimal nephroprotection scheme

optimal interval between injections

optimal administered activity (cumulative, /cycle: standard vs tailored)

PREDICTIVE BIOMARKERS

PREDICTIVE BIOMARKERS?

OF RESPONSE:

High uptake on receptor imaging

[Rotterdam visual 5 scale: >liver uptake or ≥spleen uptake]

[68Ga-DOTA-peptide uptake correlates with sst2R expression]

OF NON RESPONSE:

Bulky hepatic metastases

Karnofsky performance score<70

Significant weight loss

Kwekkeboom DJ et al.: JCO 2008;26:2124-30

Boy C et al.: EJNMMI 2011;38:1224-36

STRATEGIES TO IMPROVE PRRT EFFICACY

combination with chemotherapy (5FU, Cap/Tem)

intra-arterial PRRT for liver only / dominant disease

α-emittors as novel therapeutic isotopes

re-Tx after progressive disease following PRRT

neo-adjuvant PRRT

Kashyap R et al.: EJNMMI 2014, Claringbold PG et al.: EJNMMI 2011, Limouris GS et al.: Clin Nucl Med

2016, Kratochwil C et al.: EJNMMI 2014, Sabet A et al.: EJNMMI 2014, van Vliet EI et al.: JNM 2015

TAKE HOME MESSAGES

PRRT IS EFFICIENT

high tumor response rates (80%: OR+SD)

PFS that may reach 40m according to NETTER1

SAFE PROFILE

excellent tolerance

mild acute AEs

<10% late AEs

ideally: second line Tx after failure of SSAs

MULTIDISCIPLINARITY IN NET MGMT

ENDOCRINO- LOGY

NUCLEAR MEDICINE

GASTRO- ENTEROLOGY

ONCOLOGY

RADIOLOGY

SURGERY

PATHOLOGY

PATIENT

10 novembre

THANK YOU

FOR YOUR

ATTENTION

PRRT in Management of NETs - Human Health Campus · 2018. 5. 7. · EFFICACY: PFS/OS Trial...

Documents

Transcript of PRRT in Management of NETs - Human Health Campus · 2018. 5. 7. · EFFICACY: PFS/OS Trial...