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www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 2), pp: 3581-3590
Preliminary experience with dosimetry, response and patient
reported outcome after
177
Lu-PSMA-617 therapy for metastatic
castration-resistant prostate cancer
Wolfgang P. Fendler
1,2
, Svenja Reinhardt
1
, Harun Ilhan
1
, Andreas Delker
1
, Guido
Böning
1
, Franz J. Gildehaus
1
, Christian Stief
3,4
, Peter Bartenstein
1,4
, Christian
Gratzke
3,4
, Sebastian Lehner
1
and Axel Rominger
1
1
Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
2
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
3
Department of Urology, Ludwig-Maximilians-University of Munich, Munich, Germany
4
Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany
Correspondence to: Wolfgang P. Fendler, email: wolfgang.fendler@med.uni-muenchen.de
Keywords: mCRPC; PET; prostate cancer; PSMA; lutetium
Received: March 20, 2016 Accepted: September 19, 2016 Published: September 24, 2016
ABSTRACT
Prostate cancer can be targeted by ligands to the prostate-specic membrane
antigen (PSMA). We aimed to evaluate dosimetry, safety and efcacy of
177
Lu-
PSMA-617 radioligand therapy (RLT) in patients with metastatic castration-resistant
prostate cancer (mCRPC).
Fifteen patients each received two cycles of 3.7 GBq (n = 5) or 6.0 GBq (n =
10)
177
Lu-PSMA-617 at an eight to ten weeks interval. For safety monitoring, each
treatment was followed by dosimetry with serial quantitative SPECT as well as
inpatient and outpatient recording of adverse events. Response to RLT was primarily
determined by baseline to follow-up change in
68
Ga-PSMA PET/CT (RECIST1.1), as
well as change in prostate-specic antigen (PSA), quality of life (QoL, FACT-P scale),
and pain (Brief Pain Inventory) as secondary endpoints.
Radiation dose delivered to the tumor (6.1 Gy/GBq) was six to twelve-fold
higher than to critical organs (kidney left/right 0.5/0.6 Gy/GBq each, salivary glands
1.0 Gy/GBq). Total radiation dose per kidney did not exceed 23 Gy in any patient.
Three patients had sub-acute and latent grade 3 events, i.e. anemia, leukocytopenia,
and nausea. No acute events, grade ≥4 events or high grade events for salivary
gland or kidney function were observed. After two RLT cycles, 4 (27%) patients had
partial response, 6 (40%) had stable disease, and 5 (33%) had progressive disease
according to RECIST. Any PSA decline was observed in 12/15 (80%) patients during
RLT. Signicant pain relief was documented in 7/10 (70%) symptomatic patients and
QoL improved in 9/15 (60%) patients.
177
Lu-PSMA-617 therapy proved safe and indicated promising response rates for
both objective and patient-reported outcomes in our small group of mCRPC patients.
INTRODUCTION
After non-melanoma skin tumors, prostate cancer
(PCa) is the second most common malignancy in men, and
ultimately causes more than 250,000 deaths worldwide
each year [1]. Radionuclide therapy has become an
effective treatment option for metastatic disease with
the approval of bone seeking radiopharmaceuticals;
systemic application of the calcium ion mimetic
223
Ra
improves survival in patients with castration-resistant
PCa and symptomatic bone metastases [2]. However,
about one third of patients with metastatic castration-
resistant prostate cancer (mCRPC) present with lymph
node or visceral metastases, which are un-responsive
to bone-seeking agents [3]. Radiolabeled ligands to
the prostate-specic membrane antigen (PSMA) have
recently been developed to image and target systemic
disease. PSMA is over-expressed in PCa, and this over
expression increases further in cases of de-differentiated,
metastatic or hormone-refractory disease [4]. The
177
Lu
Clinical Research Paper
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labeled small molecule ligand DKFZ-PSMA-617 (
177
Lu-
PSMA-617) binds with high afnity to PSMA in vitro
and in vivo [5-6]. The potential of
177
Lu-PSMA-617 for
radioligand therapy (RLT) has been explored in several
preclinical and clinical studies, among which our previous
report on human dosimetry demonstrated favorable body
distribution and high tumor-to-organ uptake ratios [6].
Based on our dosimetry calculations, we identied kidney
as activity-limiting organ and recommended 6.0 GBq as an
appropriate activity for the initial
177
Lu-PSMA-617 RLT
cycle [6], giving high tumor dosing without excessive
irradiation of vulnerable healthy organs. Following upon
this result, we now aim to provide data on clinical safety
and efcacy of
177
Lu-PSMA-617 RLT in an expanded
patient cohort after a total of 30
177
Lu-PSMA-617 RLT
cycles. Efcacy was based both on objective endpoints
and patient-reported metrics, including pain intensity
and quality of life (QoL) scores. To complete dose
safety evaluation, we further aimed to perform accurate
dosimetry of salivary glands, the organ with highest
absorbed radiation dose.
RESULTS
Characteristics of the study cohort
Baseline clinical and demographic characteristics
are given in Table 1. All patients completed two cycles
of RLT. Five patients were unt for chemotherapy prior
to RLT. 14 of 15 (93%) patients underwent Abiraterone
Table 1: Baseline characteristics of the patients.
Characteristic (n = 15) Median (range) or total number (%)
Age 73 (54 - 81)
ECOG
0 5 (33%)
1 5 (33%)
2 5 (33%)
Gleason sum
7 1 (7%)
8 1 (7%)
9-10 13 (87%)
Sites of metastases
Bone 14 (93%)
Lymph node 12 (80%)
Liver 3 (20%)
Other 2 (13%)
Lung 1 (7%)
Mean pain intensity score at baseline (0-10)
0 5 (33%)
1-5 8 (53%)
6-10 2 (13%)
Biochemical values
Lactate dehydrogenase (U/L) 287 (167 - 1220)
Hemoglobin (g/dL) 12.3 (8.3 - 15.5)
Total alkaline phosphatase (U/L) 147 (49 - 420)
PSA (μg/L) 388 (3.2 - 10661)
No. of prior hormonal therapies
1 1 (7%)
2 4 (27%)
3 7 (47%)
≥4 3 (20%)
No. of prior chemotherapy regimens
0 5 (33%)
1 5 (33%)
≥2 5 (33%)
Prior
223
Ra 5 (33%)
Prior EBRT 9 (60%)
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; EBRT, External Beam Radiation Therapy.
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or Enzalutamide therapy before
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Lu-PSMA-617 RLT.
One patient did not tolerate second or third line hormonal
therapy. Patients had undergone a median of 3 (range,
1 to 5) courses of hormonal therapy prior to admission.
Patients with ongoing hormonal therapy at the start of RLT
continued their therapy until at least the nal follow-up
in the present study. None of the patients discontinued
gonadotropin-releasing hormone analogs within three
months before RLT.
Dosimetry
Mean±SD radiation dose by organ calculated
from serial quantitative SPECT and blood activity
concentrations is given in Table 2. The highest organ
radiation dose was observed for salivary glands (1.0±0.6
Gy/GBq) and kidneys (right/left 0.6±0.2/0.5±0.3 Gy/
GBq). The mean radiation dose to tumor lesions was
6.1±4.9 Gy/GBq resulting in a mean tumor-to-kidney
dose ratio of 11.1 and mean tumor-to-salivary-gland ratio
of 6.1. Liver, spleen and bone marrow all received doses ≤
0.1 Gy/GBq. Maximum cumulative kidney dose (10.3 Gy)
and salivary gland dose (16.5 Gy) were below the dose
range reported as critical (23 Gy for kidney [7]; 26-50 Gy
[8-9] for salivary glands).
Safety
No acute or grade ≥4 adverse events were observed.
Sub-acute and latent adverse events occurring in at least
one patient are listed in Table 3. Grade 1 and 2 adverse
events occurred almost equally often in patients with
3.7 versus 6.0 GBq RLT (3.4 events/patient versus 4.2
events/patient). During inpatient stay, one instance of
grade 3 anemia, and during follow-up one case of grade
3 leukocytopenia were noted in patients with 6.0 GBq
RLT; both conditions had improved at nal follow-up
without requiring transfusion or bone marrow stimulation.
No event for neutropenia was recorded. At intermediate
follow-up, grade 3 nausea was noted in one patient after
the second cycle of 3.7 GBq RLT, which responded well
to antiemetic medication. Mild or transient xerostomia
was reported both for patients with salivary gland dose
above (n = 4) versus below (n = 3) the median. One patient
Figure 1: Response after two cycles of 6.0 GBq
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Lu-PSMA-617 RLT. Axial
68
Ga-PSMA PET B. and D. and CT A. and C.
images of the abdomen before (A and B) and after (C and D) two RLT cycles. Lymph node metastases demonstrate a >30% baseline to
follow-up decrease in short axis diameter (A and C, arrows) and SUV
max
(B, arrows). Compression of the inferior vena cava by lymph node
metastases at baseline (A, double arrow) was resolved at follow-up (C, double arrow).
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presented with new onset of epigastric pain and markedly
elevated gamma-glutamyl transferase at nal follow-up.
PET/CT demonstrated progression of liver metastases with
inltration of hepatic veins and intrahepatic cholestasis.
The patient died six weeks later from acute liver failure
associated with progressive tumor inltration. In total,
four patients died from PCa-related events during the
observation period, at 24, 28, 36 and 42 weeks after start
of RLT.
Efcacy
Response after one cycle and two cycles of RLT
is given separately in Table 4. Ten (67%) patients had
measurable target lesions by RECIST1.1. According to
RECIST1.1, 4 (27%) patients had PR, 6 (40%) patients
had SD, and 5 (33%) patients had PD. Images from two
patients with partial response by CT criteria are shown in
Figures 1 and 2. Each 7 (47%) patients had biochemical
partial response by PSA level after the rst and second
cycle, respectively. Bone pain was completely resolved
in 3 (20%) and responded well in 4 (27%) symptomatic
patients after two RLT cycles. One and 3 (20%) patients
had increase in pain intensity after the rst and second
RLT cycle, respectively. QoL was improved in 8 (53%)
patients and 3 (20%) patients had a 30% or more increase
in QoL score after the second cycle.
Best response observed for PSA, pain score and
nal response by QoL score are shown for each patient
in Figure 3. Nine (60%) patients had a PSA decline of
50% or more during RLT. Response by baseline to follow-
up change in AP level or
68
Ga-PSMA uptake are given in
Supplemental Table 1.
Table 2: Radiation dose after 30 cycles of
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Lu-PSMA-617 RLT in 15 patients.
Organ (n = 30) Mean (Gy/GBq) SD
Dose limiting organs
Kidney left 0.5 0.3
Kidney right 0.6 0.2
Salivary glands* 1.0 0.6
Non-dose limiting organs
Liver 0.1 0.1
Spleen 0.1 0.1
Bone marrow 0.002 0.005
Tumor
‡
6.1 4.9
*determined in ten patients with 2x6.0 GBq
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Lu-PSMA-617 RLT, n = 20;
‡
up to three lesions with highest tracer uptake per
patient and cycle (n = 5 visceral metastases, n = 12 LN metastases, n = 22 bone metastases).
Table 3: Adverse events after 30 cycles of
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Lu-PSMA-617 RLT in 15 patients.
Adverse event Latent Sub-acute
All grades Grade 3 All grades Grade 3
Renal
Glomerular ltration rate (GFR) 8 (53%) 0 1 (7%) 0
Tubular extraction rate (TER) 2 (13%) 0 - -
Hyperkalemia 4 (27%) 0 0 0
Hematologic
Anemia 3 (20%) 0 9 (60%) 1 (7%)
Thrombocytopenia 2 (13%) 0 1 (7%) 0
Leukocytes 7 (47%) 1 (7%) 1 (7%) 0
Liver
Bilirubin 0 0 1 (7%) 0
AST/ALT 2 (13%) 0 1 (7%) 0
Other
Fatigue 5 (33%) 0 0 0
Dry mouth 7 (47%) 0 0 0
Nausea 5 (33%) 1 (7%) 0 0
Dysgeusia 3 (20%) 0 0 0
Absolute number of adverse events (%) are given.
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DISCUSSION
Dosimetry, safety and efcacy of
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Lu-PSMA-617
RLT were analyzed in 15 patients after a total of 30
applications. Treatment response was determined by
RECIST1.1 and a range of secondary endpoints, including
change in PSA and patient reported outcomes (pain,
quality of life). In general, we nd that
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Lu-PSMA-617
RLT was tolerated well for both activity regimens, i.e.
3.7 or 6.0 GBq per cycle. Dose limits for critical organs
(kidney, 23 Gy [7]; salivary glands, 26-50 Gy [8-9]) were
not exceeded in any patient. Eight to ten weeks after the
second application, tumor extent on CT had stabilized or
showed signicant reduction in 10 patients corresponding
to a disease control rate of 67%. Approximately half of
patients experienced pain relief and improvement in QoL
after RLT.
Endoradiotherapy using chelator-bound ligands
present several advantages over conventional therapy
for metastatic prostate cancer. Whereas the
68
Ga-labelled
compound provides pre-therapeutic staging and target
expression levels to PET, the corresponding
177
Lu-
labelled compound enables tumor irradiation through
focal beta emission, while also enabling imaging and
dosimetry through partial gamma emission. High efcacy
and safety of
177
Lu-based RLT was recently proven in a
phase III study of patients with advanced-stage mid-gut
neuroendocrine tumors (NET). In that study, somatostatin
analogue combination therapy with octreotide plus
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Lu-DOTATATE versus octreotide alone demonstrated
approximately 80% risk reduction for NET progression,
with few serious adverse events [10]. Chelating ligands
with high afnity to PSMA have been developed for
imaging (
68
Ga-HBED-PSMA) and RLT (
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Lu-PSMA-617)
Figure 2: Response after two cycles of 6.0 GBq
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Lu-PSMA-617 RLT. Axial
68
Ga-PSMA PET B., D., F., H. and CT A., C., E.,
G. images of the base of the skull and the pelvis before (A, B, C, D) and after (E, F, G, H) two RLT cycles. Brain metastasis (A, B, E, F,
arrow) and local recurrence (C, D, G, H, double arrow) demonstrate a >30% baseline to follow-up decrease in largest diameter and SUV
max
.
Inguinal lymph node metastasis (C, D, G, arrow) shows complete response on follow-up PET/CT.
Table 4: Response after two cycles
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Lu-PSMA-617 RLT.
n=15 Objective response Patient reported outcomes
RECIST* PSA Pain QoL
After one cycle
CR - 0 1 (7%) -
PR - 7 (47%)** 6 (40%) -
SD - 5 (33%) 2 (13%) -
PD - 3 (20%) 1 (7%) -
After two cycles
CR 0 0 3 (20%) 0
PR 4 (27%) 7 (47%)** 4 (27%) 3 (20%)
SD 6 (40%) 5 (33%) 0 11 (73%)
PD 5 (33%) 3 (20%) 3 (20%) 1 (7%)
*primary outcome, **≥30% decline in PSA; Abbreviations: RECIST, Response Evaluation Criteria in Solid Tumors; PSA,
Prostate-Specic Antigen; QoL, quality of life; SD, stable disease; PR, partial response; PD, progressive disease; CR, complete
response.