Renal and Multiorgan Safety of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer in the VISION Dosimetry Substudy

Ken Herrmann; Kambiz Rahbar; Matthias Eiber; Richard Sparks; Nicholas Baca; Bernd J. Krause; Michael Lassmann; Walter Jentzen; Jun Tang; Daniela Chicco; Patrick Klein; Lars Blumenstein; Jean-René Basque; Jens Kurth

doi:10.2967/jnumed.123.265448

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FIGURE 1.
Study design and assessments. Asterisk shows that blood pressure was measured before each electrocardiogram (ECG). Dagger symbol is blood pharmacokinetic (PK) samples that were collected after ECGs when time points overlapped. Double dagger shows whole urine collection that was required between end of dose and 2 h after dose before first image. HPLC = high-performance liquid chromatography.
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FIGURE 2.
Representative SPECT/CT images show kidneys of a patient at various times during cycle 1 of ¹⁷⁷Lu-PSMA-617 treatment. SPECT images (black/red/yellow scale) show uptake of ¹⁷⁷Lu-PSMA-617 in kidneys (axial and coronal orientations) at 2, 24, 48, and 168 h during cycle 1. Underlaid CT images (gray) are scaled equally. Both image types are maximum-intensity projections.
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FIGURE 3.
Predicted versus observed cumulative absorbed doses per cycle in at-risk organs. Injected activity: cycle 2, 14.8 GBq; cycle 3, 22.2 GBq; cycle 4, 29.6 GBq; cycle 5, 37.0 GBq; cycle 6, 44.4 GBq.

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TABLE 1.

Absorbed Doses per Unit Activity per Cycle

	Cycle 1^*		Cycles 2–6^*
Organ or tissue	Mean	SD	Mean	SD
Lacrimal glands	2.1 (1.2–3.2)	0.47	1.8 (0.70–3.9)	0.61
Salivary glands	0.63 (0.22–1.5)	0.36	0.63 (0.23–1.4)	0.30
Left colon	0.58 (0.33–1.0)	0.14	0.58 (0.32–0.73)	0.11
Rectum	0.56 (0.32–1.1)	0.14	0.55 (0.31–0.70)	0.10
Kidneys	0.43 (0.22–0.83)	0.16	0.44 (0.17–1.0)	0.21
Right colon	0.32 (0.18–0.60)	0.08	0.31 (0.18–0.40)	0.06
Urinary bladder wall	0.32 (0.29–0.43)	0.03	0.33 (0.29–0.43)	0.03
Thyroid	0.26 (0.09–1.69)	0.37	0.21 (0.06–1.6)	0.25
Heart wall	0.17 (0.03–0.52)	0.12	0.15 (0.05–0.37)	0.08
Lungs	0.11 (0.03–0.57)	0.11	0.06 (0.02–0.17)	0.03
Liver	0.090 (0.043–0.220)	0.044	0.11 (0.037–0.26)	0.054
Small intestine	0.071 (0.043–0.220)	0.031	0.065 (0.043–0.083)	0.010
Spleen	0.067 (0.031–0.140)	0.027	0.095 (0.028–0.32)	0.056
Osteogenic cells	0.036 (0.02–0.170)	0.028	0.030 (0.016–0.062)	0.009
Red marrow	0.035 (0.020–0.13)	0.020	0.031 (0.021–0.051)	0.007
Adrenal glands	0.033 (0.016–0.15)	0.025	0.028 (0.014–0.060)	0.009
Gallbladder wall	0.028 (0.013–0.15)	0.026	0.023 (0.012–0.055)	0.008
Pancreas	0.027 (0.012–0.15)	0.026	0.021 (0.008–0.051)	0.008
Prostate	0.027 (0.013–0.15)	0.026	0.021 (0.007–0.050)	0.008
Esophagus	0.025 (0.010–0.15)	0.026	0.019 (0.006–0.050)	0.008
Stomach wall	0.025 (0.011–0.15)	0.026	0.019 (0.006–0.050)	0.008
Thymus	0.025 (0.010–0.15)	0.026	0.018 (0.004–0.049)	0.008
Testes	0.023 (0.010–0.14)	0.025	0.017 (0.003–0.046)	0.008
Eyes	0.022 (0.009–0.14)	0.024	0.016 (0.003–0.045)	0.008
Brain	0.007 (0.002–0.025)	0.005	0.006 (0.003–0.028)	0.003
Whole body	0.037 (0.019–0.170)	0.027	0.031 (0.018–0.065)	0.009

↵* Dosimetry data were available for 29 patients at cycle 1, 21 patients at cycles 2 and 3, 19 patients at cycle 4, 13 patients at cycle 5, and 10 patients at cycle 6.
Bold font indicates organs considered to be at particular risk of radiotoxicity. Data are Gy/GBq.

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TABLE 2.

Cumulative Absorbed Doses Over 6 Cycles

	Predicted from cycle 1 data (n = 29)		Observed (n = 10)
Organ or tissue	Mean	SD	Mean	SD	Relative difference
Lacrimal glands	92 (54–140)	21	77 (53–115)	23	+19.5%
Salivary glands	28 (10–68)	16	30 (11–58)	15	−6.7%
Left colon	26 (15–45)	6.0	24 (14–29)	4.8	+8.3%
Rectum	25 (14–47)	6.2	23 (13–28)	4.6	+8.7%
Kidneys	19 (10–37)	7.3	15 (9.1–29)	5.8	+26.7%
Right colon	14 (8.1–27)	3.4	13 (8.0–16)	2.5	+7.7%
Urinary bladder wall	14 (13–19)	1.1	14 (13–15)	0.58	0.0%
Thyroid	11 (3.8–75)	16	9.8 (3.3–48)	14	+12.2%
Heart wall	7.8 (1.4–23)	5.2	5.7 (2.8–11)	3.0	+36.8%
Lungs	4.7 (1.3–25)	4.9	2.5 (1.2–5.4)	1.3	+88.0%
Liver	4.0 (1.9–9.6)	2.0	4.0 (2.1–9.3)	2.1	0.0%
Small intestine	3.1 (1.9–9.9)	1.4	2.7 (2.2–3.1)	0.36	+14.8%
Spleen	3.0 (1.4–6.0)	1.2	3.4 (1.4–8.0)	2.3	−11.8%
Osteogenic cells	1.6 (0.88–7.6)	1.3	1.3 (0.85–2.2)	0.44	+23.1%
Adrenal glands	1.5 (0.70–6.8)	1.1	1.1 (0.62–2.0)	0.41	+36.4%
Red marrow^*	1.5 (0.87–5.9)	0.9	1.3 (0.93–1.8)	0.33	+15.4%
Gallbladder wall	1.2 (0.56–6.7)	1.1	0.96 (0.52–1.8)	0.40	+25.0%
Pancreas	1.2 (0.55–6.7)	1.1	0.90 (0.50–1.8)	0.38	+33.3%
Prostate	1.2 (0.59–6.7)	1.1	0.91 (0.54–1.8)	0.36	+31.9%
Esophagus	1.1 (0.46–6.5)	1.1	0.81 (0.42–1.7)	0.39	+35.8%
Stomach wall	1.1 (0.48–6.6)	1.1	0.83 (0.44–1.7)	0.38	+32.5%
Thymus	1.1 (0.45–6.5)	1.1	0.78 (0.41–1.7)	0.39	+41.0%
Testes	1.0 (0.43–6.3)	1.1	0.74 (0.39–1.6)	0.36	+35.1%
Eyes	1.0 (0.40–6.1)	1.1	0.72 (0.36–1.6)	0.36	+38.9%
Brain	0.3 (0.08–1.1)	0.2	0.27 (0.17–0.41)	0.08	+11.1%
Whole body	1.6 (0.86–7.3)	1.2	1.3 (0.79–2.2)	0.42	+23.1%

↵* Cycles 2–6 observed data were based on blood samples and remainder-of-body activity from cycle 1 scaled according to respective imaging data. For cycle 6, total injected activity was 44.4 GBq.
Data are Gy. Bold font indicates organs considered to be at particular risk of radiotoxicity.

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TABLE 3.

TEAEs Grouped as Safety Topics of Interest in the Substudy

	¹⁷⁷Lu-PSMA-617 plus SoC (n = 30)
Safety topic	All grades	Grade ≥ 3 (%)
Bone marrow suppression	11 (36.7)	6 (20.0)
Nausea and vomiting	11 (36.7)	0 (0.0)
Fatigue	6 (20.0)	2 (6.7)
Dry mouth	5 (16.7)	0 (0.0)
Renal toxicity	5 (16.7)	0 (0.0)
Hepatotoxicity	2 (6.7)	0 (0.0)
Intracranial hemorrhage	0 (0.0)	0 (0.0)
QT prolongation	0 (0.0)	0 (0.0)
Reproductive toxicity	0 (0.0)	0 (0.0)
Second primary malignancies	0 (0.0)	0 (0.0)

Toxicity was assessed using CTCAE version 5.0. Safety topics occurred on or after start of treatment with ¹⁷⁷Lu-PSMA-617 plus standard of care (SoC) up to 30 d after last administration or before initiation of subsequent anticancer treatment. Patient with multiple grades for safety topic is counted only under maximum grade. Data in parentheses are percentages.