La terapia radio recettoriale

(1)

On colog ia di precisione

Sessione VIII – Le nuove frontiere

- La terapia radio recettoriale Stefano Severi

SS Terapia Radiometabolica, Direttore Prof. Giovanni Paganelli

IRCCS - IRST MELDOLA Università di Ferrara

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THERAGNOSTIC

THERAPY

DIAGNOSIS

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PRRT: rationale basis

By Gray JA and Roth BL, Science 2002 Metastatic

gastrinomas

Lamberts SWJ, Hofland LJ. Endocr Rev 2003

Receptorial binding

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Radiology interventionist Psycologist Biologist

Nuclear Radiologist Data Manager Radiologist Palliatologist Endocrinologist

Pathologist Oncologist Nurse

Radioterapist Surgeon

Multidisciplinary Team of NENs

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Strosberg J, et al. N Engl J Med. 2017;376(2):125-135.

(6)

The NETTER Study: Trial Design 229 Patients With Midgut NETs

177

Lu-DOTATATE group, 116 patients

Control group, 113 patients

177

Lu-DOTATATE

7.4 GBq /8 weeks +

Octreotide LAR 30 mg/4 weeks

Octreotide LAR

60 /mg4 weeks

(7)

Objective Response After 4 Cycles of PRRT

Aug 2004 Nov 2004 Feb 2005 May 2005

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The NETTER Study: Results

PFS

Months Since Randomization Progression-Free Survival (% of Patients)

P<.001

PFS, progression-free survival

(9)

The NETTER Study: Results OS (Interim Analysis)

Months Since Randomization Overall Survival (% of Patients)

P = .004

OS, overall survival

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The NETTER Study: Adverse Events

Safety Population (Cont’d)

177Lu-DOTATATE Group (N = 111) Control Group (N = 110) P Value

Event Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 Any Grade

Blood disorders

Thrombocytopenia 28 (25) 2 (2) 1 (1) 0 <.001

Anemia 16 (14) 0 6 (5) 0 .04

Lymphopenia 20 (18) 10 (9) 2 (2) 0 <.001

Leukopenia 11 (10) 1 (1) 1 (1) 0 .005

Neutropenia 6 (5) 1 (1) 1 (1) 0 .12

Musculoskeletal pain 32 (29) 2 (2) 22 (20) 1 (1) .16

Decreased appetite 20 (18) 0 9 (8) 3 (3) .04

Headache 18 (16) 0 5 (5) 0 .007

Dizziness 12 (11) 0 6 (5) 0 .22

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ENETS Consensus Guidelines 2016: Midgut NEN

Pavel M, et al. Neuroendocrinology. 2016;103(2):172-185.

Therapeutic Algorithm for the Management of (Midgut) NEN With Advanced Locoregional Disease

CS, carcinoid syndrome; G, grade; LM, liver mestasis; NEN, neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; PD, disease progression; SD, stable disease; SSA, somatostatin analogue; SSTR, somatostatin receptor

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PRRT: the IEO-IRST experience

90

Y-DOTATOC:

Dosimetry - Phase I studies - Efficacy

177

Lu-DOTATATE

Dosimetry - Phase I-II study

177

LU- PRRT Safety and efficacy Renal and Bone Marrow Toxicity Phase II study in GEP-NETs

FDG-PET in GEP NETs Randomized studies

Prognostic factors oriented PRRT-Chemo associations

1997

… 2004

TODAY

2010 2008

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NENs

GRADING GEP-NETs

(ENETS - WHO)

G1≤2 mytosis /10hpf <3% Ki67 index

G2 3 - 20 mytosis / 10hpf 3%-20% Ki67 index

G3 >20 mytosis / 10hpf >20% Ki67 index

Histology

The 2017 WHO classification is based on tumor volume, localization, cell proliferation index, local or vascular invasivity, presence of metastases and biological active hormone production, TUMOR DIFFERENTIAION

well differentiated Ki67 ≤50% NET G3

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In patient with metastasized NET, planar scintigraphy image 4 h after injection of ¹¹¹In-DTPA- octreotide (A) and PET image 1 h after injection of ⁶⁸Ga-

DOTATATE (B). Images were obtained 3 wk apart. (D. Wild, University Hospital Freiburg.)

111

In-DTPA-octreotide Vs

68

Ga-DOTATATE

do you like to

win easily

68Ga dota-peptide PET

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68Ga PET Uptake

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[

¹⁷⁷

Lu-DOTA

⁰

-Tyr

³

]-octreotate (

¹⁷⁷

Lu-DOTATATE)

Affinity (IC₅₀, nM)

sst

₁ sst₂ sst₃ sst₄ sst₅

>10,000 1.6 ± 0.4 >1,000 523 ± 239 187 ± 50

HOOC

N

HOOC COOH

O

NH-D-Phe Cys Tyr

Cys Thr Lys

Thr (OH)

177Lu

N N

D-Trp

Radiopharmaceutical type

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

 



 

) ln (

1

₀

57 I t

t I



Co

Patient water equivalent thickness z for attenuation correction of projection image counts

1h 24h 48h

120h

Pre and Post injection images

I

0

I(z)

Trasmission

(⁵⁷Co) Blank (⁵⁷Co)

reni reni

S

reni

A

D  *

__

 A

altriOrgani

* S

_reni___altriOrgan_i

Conjugated projection method

Dosimetry

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diabetes, hypertension, previous chemotherapy, previous PRRT

Risk factors for kidney and bone marrow toxicity:

Toxicity

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Creatine Clearance % Decrease vs BED and Risk factors

BED threshold of 28 Gy in patients with Risk Factors BED threshold of 40 Gy in patients without Risk Factors

0 10 20 30 40 50 60

0 10 20 30 40 50 60 70

BED (Gy)

creatinine clearance loss %

pts

risk factors

(20)

Warburg Effect

Aggressiveness

(21)

FDG – PET with a prognostic purpose in NET

(22)

T. P. Ileal NET G2 Ki67 8%, FDG PET negative

Baseline 68Ga FDG PET 177Lu-Dotatate 1° TB

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31 patients had 25.5 GBq (range 20.7-27.8)

DCR 87%

Median PFS 46 mesi (26-69) Median OS nr

13%

51%

26% 10%

34 patients had 17.8 GBq (range 11.1-19.9)

DCR 85%

Median PFS 25 mesi (20-nr) Median OS 50 (28-nr)

62%

20% 3% 15%

5 years Follow up in 65 p-NET patients

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Median PFS according to FDG-PET in p-NET

0.00 0.20 0.40 0.60 0.80 1.00

PFS

0 12 24 36 48 60

months

PET- : 69m ( 46-69)

PET+ : 23m (19-29)

p < 0.0001

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IV cycle ¹⁷⁷Lu PRRT 6.4GBq 18/12/2012 I cycle ¹⁷⁷Lu PRRT

6.4GBq 19/6/2012

S.C. P-NET

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Toxicity Overall (%) FD Group (%) RD Group (%)

G1 G2 G3 G1 G2 G3 G1 G2 G3

WBC 10

(15)

5 (8)

0 2

(6)

5 (16)

0 8

(23)

0 0

PLT 12

(18)

1 (2)

0 5

(16)

0 0 7

(21)

1 (3)

0

HB 18

(28)

4 (6)

0 10

(32)

2 (6)

0 8

(23)

2 (6)

0

CREATININE 4 (6)

1 (2)

0 0 0 4

(12)

1 (3)

No major haematological toxicity. One G3

kidney toxicity in a patient with risk factors

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Fase II prospective Protocol: High Grade Ki67 GEP- NENs patients treated with 177Lu-Dotatate to evaluate

activity and toxicity

• 33 consecutive patients with Ki67 >15% treated with 4-5 cycles 177Lu dotatate therapy 6 ± 2 weeks apart

• Reduced dosage for patients with risk factors

• 22/29 (76%) patients had FDG PET positive

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pts n. DCR Median PFS

(95% CI) p Median OS

(95% CI) p

Overall 33 23 (70%) 23 m.

(14.9-31.0) - 52.9 m.

(17.1-68.9) - Ki67 15-35% 23 20 (87%) 26.3 m.

(18.4-37.7)

52.9 m

(26.3-68.9)

Ki67 >35% 10 3 (30%) 6.8 m.

(2.1-27.0) 0.005 12.6

(3.4-55.8) 0.012

33 High Ki67 Grade GEP-NENs patients

Median follow-up: 43 months (range 3-69)

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GEP-NENs SSTR2 Positive

Risk factor for FDG PET positivity

FDG PET (positive)

177

Lu 750 mCi in 5 cycles + metronomic capecitabine

vs ¹⁷⁷

Lu 750 mCi in 5 cycles

FDG PET (negative)

177

Lu 500 mCi in 5 cycles

Vs ¹⁷⁷

Lu 700 mCi in 7 cycles

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PFS OS

No. Pt. Events % Median PFS (m) p Events % Median OS (m) p Overall patients 43 35 59.8 (29.8-76.4) - 27 82.0 (64.0-125.6) - Administered activity

RA 18 14 59.8 (14.3-79.6) 13 71.0 (46.1-107.3)

FA 25 21 59.8 (23.3-82.0) 0.957 14 97.6 (64.3-nr) 0.195

PET-FDG results

FDG - 21 16 66.5 (36.8-97.6) 10 97.6 (66.5-nr)

FDG + 12 10 30.4 (9.0-69.0) 0.101 8 55.2 (18.6-nr) 0.152

Tumor burden

1 13 7 97.6 (79.6-nr) 4 nr

2 19 17 36.8 (16.1-64.0) 13 64.3 (39.6-nr)

3 11 11 16.3 (11.8-66.5) 0.0002 10 55.6 (16.2-76.4) 0.007

Hepatic lesions

No 7 3 nr 1 nr

< 6 18 14 78.0 (16.3-97.6) 13 81.9 (51.1-107.3)

≥ 6 18 18 30.4 (14.3-36.8) 0.0003 13 65.4 (35.6-125.6) 0.053

Histologic grade*

1 15 13 60.1 (23.3-76.4) 9 81.7 (50.8-125.6)

2 18 15 46.2 (16.1-83.7) 0.888 12 86.0 (51.1-107.3) 0.479

177Lu-PRRT in 43 GI-NETs: 10 Years Follow up

Tumour burden

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NET - TEST

(32)

G1 G2

G3 ≤ 55%

Positive

Prognostic Factors

G1 G2

G3 ≤ 35%

Negative

Prognostic Factors

Therapeutic Grading Meldola GEP-NENs

G3 > 55%

(33)

Precision Medicine in PRRT

1) Grading

2) Gallium PET positivity 3) Gallium intensity uptake 4) Radiopharmaceutical type 5) Dosimetry

6) Risk factors

7) FDG PET positivity 8) Prognostic factors

9) Liquid biopsy - Net Test

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Giovanni Paganelli, Severi Stefano, Silvia Nicolini, Maddalena Sansovini, Ilaria Grassi, Federica Matteucci, Paola Caroli, Anna

Sarnelli, Emilio Mezzenga, Vincenzo D’errico, David Bianchini, Valentina Di Iorio, Manuela Monti, Monica Golinucci e tanti altri!!