177lu-psma targeted radionuclide therapy€¦ · gaertner et al. uptake of psma-ligands in normal...

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177Lu-PSMA targeted Radionuclide Therapy Hojjat Ahmadzadehfar

Seite 2 Siegel R et al. CA Cancer J Clin 2013; 63:11-30

Prostate cancer Estimated new cases

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Prostate cancer Estimated deaths

Siegel R et al. CA Cancer J Clin 2013; 63:11-30

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Prostate cancer Five-year relative survival rate

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Prostate cancer PSMA

Prostate-specific membrane antigen

(PSMA) is highly expressed on prostate

epithelial cells and strongly upregulated in

prostate cancer.

Kahn et al. 111In-labeled 7E11 mAb (ProstaScint). Radioimmunoscintigraphy with 111indium labeled CYT-356 for the detection of occult prostate

cancer recurrence. J Urol. 1994;152:1490–1495

111In-labeled 7E11 mAb (ProstaScint)

Radiolabeled 7E11 antibody does not bind to

viable cells but only to intracellular part

of PSMA, which may be accessible only in dead

, dying,or apoptotic cells within tumor sites.

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Prostate cancer PSMA therapy using mAb

Charles B. Simone II and Stephen M. Hahn . Clin Cancer Res; 19(18) September 15, 2013

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177Lu-PSMA mAb Toxicity

Tagawa et al. Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant

prostate cancer. Clin Cancer Res. 2013 Sep 15;19(18):5182-91.

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PSMA therapy mAb vs peptide

mAb Peptide

elephant hummingbird

-poor permeability in solid tumours -slow clearance from the circulation

suboptimal tumour targeting and an increased absorbed dose to red marrow, narrowing the therapeutic window

177Lu-J591

7 Tage p.i.

177Lu-PSMA-617 7 Tage p.i.

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» Operation

» Hormone therapy

» Chemotherapy

» Radiation

» Radionuclides

mCRPC Therapy of mCRPC

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mCRPC Approved therapies

Drug Trial Disease state N Comparator Median OS (m) HR

Docetaxel TAX-321 1 Chemonaive 1006 Mitoxantron 18.9 vs. 16.5(p=0.009) 0.76

Carbazitaxel TROPIC 2 Post-Docetaxel 755 Mitoxantron 15.1 vs. 12.7 (p<0.0001) 0.70

Abiraterone COU-AA-3013 Post-Docetaxel

1195 Placebo+ Presnisone

14.8 vs. 10.9 (p<0.0001) 0.65

Abiraterone

COU-AA-302 4 Chemonaive 1088 Placebo+ Presnisone

27.2 vs. NR (p=0.01)

Ra-223 ALSYMPCA 5 Bone-metastaric mCRPC

922 Placebo + BSC

14.9 vs. 11.3 (p<0.001) 0.70

Enzalutamide AFFIRM 6 Post-Docetaxel

1199 Placebo 18.4 vs. 13.6 (p<0.001) 0.631

Enzalutamide

PREVAIL 7 Chemonaive

1717 Placebo 32.4 vs. 30.2 (p<0.0001) 0.706

1Tannock IF et al. NEJM 2004;35(15):1502-12, 2 deBono JS et al. Lancet 2010;376:1147-54; 3 deBono JS et al. NEJM 2011;364:1995-2005; 4 Ryan CJ et al.

NEJM 2013; 368:138-48; 5 Parker C et al. N Engl J Med 2013; 369:213-223; 6 Scher HI et al. NEJM 2012;367: 1187-97;7 Beer TM et al. ADCO GU 2014,

abstract LBA1; 8 Kantoff PW et al. NEJM 2010; 363: 411-22

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PSMA therapy As the last therapeutic option

Theranostics

Tx with 6.1 GBq 177Lu-PSMA

68Ga-PSMA PET

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Radioligand Therapy using 177Lu-PSMA-617

Inclusion criteria

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• WBC > 2 Tsd./µl.

• Hb > 8 g/dl, in the case of symptomatic anaemia a red-blood-cell transfusion should be preceded the therapy.

• Platelets > 75 x 109/l

• Creatinine < 2 mg/dl

• Rule out an obstructive renal disease by using Tc-MAG3 or Tc-DTPA

• ECOG <= 2

Radioligand Therapy Inclusion criteria

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Response

Ahmadzadehfar H & Rahbar K et al. EJNMMI Res. 2015 Dec;5(1):114

Die erste Studie: 10 Patienten

70 %: PSA-decline

50 %: PSA-decline>50%


Response

Rahbar K……Ahmadzadehfar H. J Nucl Med. 2016 Apr 7. pii: jnumed.116.173757

The first multicentre study: 82 patients, 1 cycle

64 %: PSA-decline 31 %: PSA-decline>50%

Ga-PSMA-PET Lu-PSMA-GK


Response

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Rahbar & Ahmadzadehfar et al. J Nucl Med. 2017 Jan;58(1):85-90

45 % > 50 %-PSA-decline

145 patients :248 cycles


Response

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40 patients, one cycle


Predictive factors of response

Seite 19 Ferdinandus J, …….. Ahmadzadehfar H.,

parameters p-value

p-value

multivariate analysis

Activity (MBq)/weight (kg) 0.62

Abiretarone 0.69

Enzalutamide 0.87

Chemotherapy 0.57

Ra-223 0.27

Bisphosphonate or denosumab 0.80

Number of bone metastases 0.75

Extent of lymph node

metastases

0.38

Existence of liver metastases 0.90

ECOG performance status 0.19

AST 0.23

ALT 0.21

GGT (> 100) 0.008 ns

ALP 0.15

LDH 0.04 ns

Creatinine 0.19

parameters p-value

p-value

multivariate analysis

Total bilirubin 0.18

Hb 0.04 ns

RBC 0.17

WBS 0.21

PSA level 0.15

SUV max (bone) 0.26

SUV max (lymph node) 0.30

SUV max bone/liver 0.09

SUV max bone/spleen 0.06

SUV max lymph node/liver 0.16

SUV max lymph node/spleen 0.22

Plt (>300) 0.02 0.01

CRP (>20) 0.009 ns

Age (< 65) 0.01 ns

Gleason score (=10) 0.01 ns

Regular need for pain medication 0.005 0.0018



40 patients, one cycle

Seite 20 Ferdinandus J, …….. Ahmadzadehfar H.,



» Regarding a PSA decline >

50%, only a Gleason score of 10 and

regular need for pain medication

had a negative impact on the

therapeutic response in the

univariate analysis

in the multivariate analysis, only the

regular need for pain medication

was significant.

PSA-decline > 50 %

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Hematotoxicity

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Hematotoxicity


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23



Hematotoxicity

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Hematotoxicity

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49 hormone refractory mPC patients with distant metastases and progressive

disease


Hematotoxicity

Ahmadzadehfar et al. Oncotarget 2017

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Hematotoxicity


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Hematotoxicity

49 patients Hematotoxicity according to common toxicity criteria (version 4.0) in all patients prior to and after 3 cycles of RLT


low hematotoxicity

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Hematotoxicity

Group 1 (Hx of Ra-223) Group 2

CTC 0°

(%)

CTC 1°

(%)

CTC 2°

(%)

CTC 3°

(%)

CTC 0°

(%)

CTC 1°

(%)

CTC 2°

(%)

CTC 3°

(%)

p-value

WBC 15 (75) 3 (15) 2 (10) 0 (0)

27

(93.1) 2 (6.9) 0 (0) 0 (0)

0.12

Hb 8 (40) 1 (05) 10 (50) 1 (05)

22

(75.8) 2 (6.9) 2 (6.9) 3 (10.4)

0.008

Plt 16 (93.8) 2 (10) 1 (5.0) 1 (5.0)*

21

(72.4) 5 (17.2) 1 (3.4) 2 (7.0)+

0.88


Lu-PSMA Tx after therapy with Ra-223 is

feasible and safe

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Nephrototoxicity

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Nephrototoxicity


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Renal toxicity

Yordanova ………. Ahmadzadehfar. EJNMMI 2017

55 patients

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Renal toxicity


» Twenty patients were treated with

more than 3 cycles 177Lu-PSMA-

therapy. Eleven, six and three

patients with 4, 5 and 6 cycles,

respectively. Again, there was no

significant radiation induced

impairment of the renal function (CTC

3° or 4°)

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Renal toxicity


low nephrototoxicity

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Dosimetry

» a mean of 192.6±11.0 MBq.

» 2-cc blood samples were withdrawn in short variable

times (3, 15, 30, 60, and 180 min and 24, 48,and 120

h) after injection.

» Whole-body images were obtained at 4, 24, 48, and

120 h post-injection (p.i.).

» The geometric mean of anterior and posterior counts

was determined through region of interest (ROI)

analysis.

» The OLINDA/EXM dosimetry program was used for

curve fitting, residence time calculation, and absorbed

dose calculations.

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Dosimetry

Kabasakal et al. Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA)

inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015 Dec;42(13):1976-83

https://www.ncbi.nlm.nih.gov/pubmed/26227531


Seite 36 Kabasakal et al. Pre-therapeutic dosimetry of normal organs and tissues of (177)Lu-PSMA-617 prostate-specific membrane antigen (PSMA)

inhibitor in patients with castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2015 Dec;42(13):1976-83


Dosimetry



» Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients

(mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after

administration of 3.6 GBq (range 3.4 to 3.9 GBq) 177Lu-DKFZ-PSMA-617

Seite 37 Delker et al. Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol

Imaging. 2016 Jan;43(1):42-51


Dosimetry




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Dosimetry

Delker et al. Dosimetry for (177)Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer. Eur J Nucl Med Mol

Imaging. 2016 Jan;43(1):42-51




» 135 patients

» SUV was measured in the lacrimal and salivary glands, brain, heart,

liver, spleen, kidneys, muscle and bone

» SUV was correlated with visual tumor load, total tracer retention and

PSA

Seite 39 Gaertner et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget, 2017, Vol. 8, (No. 33), pp:

55094-55103


Dosimetry

Seite 40


Dosimetry

Gaertner et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget, 2017, Vol. 8, (No. 33), pp:

55094-55103

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Dosimetry

Gaertner et al. Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. Oncotarget, 2017, Vol. 8, (No. 33), pp:

55094-55103

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Amount of the activity

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• Accoriding to retrospective studies 6-7.4 GBq activity is safe

Radioligand Therapy Amount of activity

Rathke et al. Repeated Lu-177-PSMA-617 radioligand therapy using treatment activities up to 9.3 GBq. JNM 2017

10 pat 10 pat 10 pat 10 pat

4 GBq 6 GBq 7.4 GBq 9.3 GBq

Initial PSA response presented no correlation to treatment activity 21 patients completed 3 cycles of PSMA therapies

2/10, 4/10, 4/10 and 7/10 patients with doses of 4, 6, 7.4 and 9.3 GBq were in partial remission 8 weeks after completing all 3 cycles

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Radioligand Therapy Amount of activity

Rathke et al. Repeated Lu-177-PSMA-617 radioligand therapy using treatment activities up to 9.3 GBq. JNM 2017

WBC (/nl)

platelet count

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Overall Survival

Rahbar K. Clin Nucl Med. 2016 Jul;41(7):522-8. doi: 10.1097

PSMA-patients


Overall-Survival

Rahbar K. Clin Nucl Med. 2016 Jul;41(7):522-8. doi: 10.1097

Historical collective


Overall-Survival

Seite 48 Rahbar K. Clin Nucl Med. 2016 Jul;41(7):522-8. doi: 10.1097


Overall-Survival

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Overall-Survival

Ahmadzadehfar et al. EJNMMI 2017

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Overall-Survival


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Overall-Survival

Median OS: 60 weeks


Seite 52 Bräuer et al. EJNMMI 2017


Overall-Survival

Median OS: 32 weeks

48 % of patients had an ECOG 2/3

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Overall-Survival

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Inclusion criteria •patients with mCRPC •patients with a history of therapy with either abiraterone or enzalutamide or both •patients treated with at least 3 cycles of RLT, or patients with 1 – 2 cycles of RLT who died before the third cycle, did not receive the third cycle because of significant worsening of their general condition or because of an excellent response to the first or second cycle •patient follow-up of at least two months after the last cycle or the patient died •complete documentation.

150 patients were evaluated

100 patients were eligible

Ahmadzadehfar et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand

therapy. Oncotarget 2017


Overall-Survival

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100 patients (347 cylces; median: 3 cycles; 1-8 cycles)


Overall-Survival



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Median OS

All patients: 60 weeks

Responder to the first cycle: 71 weeks

Non-responder to the first cycle: 29 weeks

P<0.0001


Overall-Survival



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Median OS

noe CTx: 63 weeks (49.1-76.9)

Hx of CTx: 57 weeks (40.2-73.8)

P=0.40


Overall-Survival



Seite 58 Ahmadzadehfar et al.


Overall-Survival

Parameters p-value

Median OS

reported in

weeks (95 % CI)

Multivariate

analysis

p-value

Number of bone

metastases

29 patients ≤ 20 met

45 patients > 20 met

24 patients : super scan

or

diffuse bone/bone

marrow met

0.02

94 (60.7–127.3)

55 (38.8–71.2)

37 (12.7–61.3)

ns

Existence of liver

metastases

13 patients: yes

87 patients: no

0.04

28 (18.6–37.4)

60 (47.3–72.7)

0.02

HR: 3.2 (95% CI:

1.5 - 7.1)

ECOG performance status

(0/1 vs 2/3)

77patients: 0–1

23 patients: 2–3

<0.000

1

71 (43.7–98.3)

33 (24.7–41.3)

ns

Blood transfusion prior to

the first cycle

16 patients: yes

84 patients: no

0.04

36 (28.3–43.7)

63 (49.5–76.5)

ns

Albumin (cut-off: 38.6 g/l)

49 patients ≤ 38.6

51 patients > 38.6

0.0003

38 (26.0–50.0)

95 (47.3–142.7)

0.01

HR: 0.9 (95% CI:

0.8 - 0.95)

AST (cut-off: 24 U/l))

56 patients ≤ 24

44 patients > 24

0.0002

88 (61.1–114.9)

36 (16.8–55.2)

0.04

HR: 2.5 (95% CI:

1.3 - 4.8)

GGT (cut-off: 31 U/l)

42 patients ≤ 31

58 patients > 31

0.0001

88 (63.4–112.6)

47 (31.5–62.5)

ns

ALP (cut-off: 140 U/l)

52 patients ≤ 140

48 patients > 140

0.0003

71 (45.9–96.0)

42 (24.0–60.0)

ns

ALP (cut-off: 220 U/l)

65 patients ≤ 220

35 patients > 220

0.019

70 (56.9–83.1)

37 (17.7–56.2)

ns

LDH (cut-off: 225 U/l)

36 patients < 225

64 patients ≥ 225

<0.000

1

not reached

46 (29.6–62.4)

ns

Hb (cut-off: 10.4 g/dl)

33 patients <10.4

67 patients ≥10.4

0.0001

36 (24.5–47.5)

88 (60.7–115.3)

<0.0001

HR: 0.5 (95% CI:

0.2 - 0.9)

CRP (cut-off: 16 mg/l)

65 patients ≤ 16

35 patients > 16

0.0001

71 (46.8–95.2)

33 (25.2–40.8)

ns

Regular need for analgesics

39 patients: yes

61 patients: no

0.007

36 (24.7–47.3)

70 (56.1–83.9)

ns

Regular need for opioids

35 patients: yes

65 patients: no

0.0002

33 ( 24.9–41.1)

88 (48.0–127.9)

ns

PSA percent change (cut-off: -

14%)

62 patients: decline > 14 %

38: no PSA decline or decline

≤14%

<0.0001

88 (58.3–117.7)

29 (20.1–37.8)

<0.0001

HR: 6.9 (95% CI:

3.6 - 13.3)

PSA any decline

69 patients: yes

31 patients: no

<0.0001

71 (45.4–96.6)

29 (20.5–37.5)

ns

PSA decline ≥ 50%

38 patients: yes

62 patients: no

0.009

70 (39.5–100.5)

49 (30.2–67.8)

ns

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Overall-Survival

Rahbar et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A

retrospective analysis of overall survival in the “real life”. EJNMMI 2017

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Overall-Survival



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N = 104 Estimated Median OS 56 Weeks [95%CI: 50.5 – 61.5]

N = 104 log rank P = 0.004 Hazard ratio: 0.38 [95%CI: 0.19 – 0.75] P = 0.005

any initial PSA decline N = 70 Estimated: 62.9 weeks [95%CI: 51.4 – 74.2]

no PSA decline N = 34 estimated: 47 weeks [95%CI: 39.4 – 54.5]



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Overall-Survival



Seite 63

Case Reports

3. Tx

4.8 GBq

08.2015

PSA: 9

ALP: 69

LDH: 208

ECOG:0

Seite 64

Case Reports

• 81 y patient, Gleason Score:7,

• Known bone & Ln met

• Under GNRH

• Hx of abiraterone and enzalutamide

• ECOG : 0

Seite 65

Case Reports

Wie X, …….. Ahmadzadehfar H., CNM 2016

PSA: 1030 ng/ml PSA: 5.5 ng/ml

Seite 66

Case Reports

Seite 66 Prior to the 1. cycle Prior to the 3. cylce After the 4. cycle

PSA:195 PSA:2.4

About 70-80 % of patients with mCRPC show a good response to RLT

Patients with a positive response (any PSA-decline) have a longer OS

PSMA therapy has low toxicity profile

Performing repeated cycles of Lu-PSMA-617 after 223Ra seems to

be safe, with a very small probability of hematotoxicity

Time for prospective studies

Seite 67

Conclusion

Hojjat Ahmadzadehfar, MD, MSc

Associate Professor

Head of the therapy section

Department of Nuclear Medicine

University Hospital Bonn

177lu-psma targeted radionuclide therapy€¦ · gaertner et al. uptake of psma-ligands in normal...

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