Somatostatin Receptor 2–Targeting Compounds

Daan A. Smit Duijzentkunst; Dik J. Kwekkeboom; Lisa Bodei

doi:10.2967/jnumed.117.191015

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Download powerpoint
FIGURE 1.
Structural formulae of DOTA⁰-Tyr³-octreotate (A), DOTA⁰-Tyr³-octreotide (B), and DTPA⁰-octreotide (C), also known as DOTATATE, DOTATOC, and DTPA-OC or pentetreotide, respectively.
Download figure
Open in new tab
Download powerpoint
FIGURE 2.
(A–D). Anterior (A and C) and posterior (B and D) planar whole-body scintigrams obtained 24 h after first (A and B) and fourth (C and D) treatments with [¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate in 43-y-old patient with grade 2 (Ki-67, 15%) rectal NET with metastases to liver. After treatment (C and D), physiologic uptake was more pronounced in pituitary gland, kidneys, spleen, and bowels. This decrease in tumor-to-organ ratio may indicate favorable outcome. (E and F) Contrast-enhanced CT of abdomen before (E) and 2 mo after (F) treatment. In addition to decrease in size after treatment, pretherapeutic arterial enhancement was lost and lesions became hypodense, indicating therapeutic efficacy.

Tables

Figures

View popup

TABLE 1

Characteristics of Radionuclides Used in PRRT (7,49,52)

Radionuclide	Half-life	Type	Decay energy	Maximum tissue penetration
¹¹¹In	2.8 d	Conversion	144–245 keV	0.2–0.55 mm
		Auger	0.5–25 keV	0.02–10 μm
		γ	171–245 keV
⁹⁰Y	2.7 d	β	2.3 MeV	12 mm
¹⁷⁷Lu	6.7 d	β	0.5 MeV	2 mm
		γ	113–208 keV
²¹³Bi	46 min	α	5.5–5.9 MeV	100 μm
		β	1.0–1.4 MeV
		γ	440 keV

View popup

TABLE 2

SSTR-2 Affinity (10)

Chemical	50% Inhibitory concentration (nM)^*	SEM
Octreotide	2.0	0.7
Indium-labeled DTPA-octreotide	22	3.6
Yttrium-labeled DOTA-Tyr³-octreotide	11	1.7
Yttrium-labeled DOTA-Tyr³-octeotate	1.6	0.4
Gallium-labeled DOTA-Tyr³-octreotide	2.5	0.5
Gallium-labeled DOTA-Tyr³-octreotate	0.2	0.04

↵* Lower values reflect greater affinity.

View popup

TABLE 3

Phase 2 Trials with Radiolabeled Somatostatin Analogs for Treatment of Advanced NETs

							Tumor response									Survival^‡
Study	Institution	Year	Radiopharmaceutical	Schedule	No. of patients	Tumor type	CR (%)	PR (%)	SD (%)	PD (%)	NA (%)	DCR (%)^*	Baseline PD (%)	Criterion	Follow-up (mo)^†	Overall	Progression-free
Anthony et al. (23)	Louisiana State University Medical Center	2002	[¹¹¹In-DTPA⁰-Tyr³]octreotide	6.6 GBq × (mean) 3 cycles (range, 1–7 cycles)	27	GEP	0	7	78	11	4	85	NA	Other	NA	18	NA
Waldherr et al. (53)	University Hospital Basel	2001	[⁹⁰Y-DOTA⁰-Tyr³]octreotide	6 GBq/m² × 4 cycles	41	NET	2	22	61	15	0	85	83	WHO	15	NR	NA
Waldherr et al. (54)	University Hospital Basel	2002	[⁹⁰Y-DOTA⁰-Tyr³]octreotide	7.4 GBq/m² × 4 cycles	39	NET	5	18	69	8	0	92	100	WHO	NA	NA	NA
Bushnell et al. (40)	Multiple centers	2010	[⁹⁰Y-DOTA⁰-Tyr³]octreotide	4.4 GBq × 3 cycles	90	GEP/B	0	4	70	12	14	74	100	SWOG	NA	27	16
Cwikla et al. (38)	CCHMIAA	2010	[⁹⁰Y-DOTA⁰-Tyr³]octreotide	3.7 GBq × 3 cycles	60	GEP	0	22	73	5	0	95	100	RECIST	NA	22	17
Savelli et al. (55)	Brescia Civic Hospital	2012	[⁹⁰Y-DOTA⁰-Tyr³]octreotide	2.56 GBq × 4 cycles	38	GEP	0	45	26	29	0	71	100	RECIST	NA	NA	22
Kwekkeboom et al. (36)	Erasmus University Medical Center	2008	[¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate	7.4 Gbq × 4 cycles	310	GEP	2	28	51	20	0	81	43	SWOG	19	46	33
Bodei et al. (37)	IEO	2011	[¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate	25.2–26.4 GBq × 4–6 cycles	51	SSTR+	2	27	53	18	0	82	76	RECIST	29	NR^§	NA
Sansovini et al. (41)	IRST-IRCCS	2013	[¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate	17.8–25.5 GBq × 5 cycles	51	Pancreas	8	21	52	19	0	81	100	SWOG	NA	NR	29
Paganelli et al. (56)	IRST-IRCCS	2014	[¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate	18.5–27.8 GBq × 5 cycles	43	GI	7	0	77	16	0	84	100	SWOG	38	NR	36
Delpassand et al. (57)	EDNOC	2014	[¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate	7.4 GBq × (mean) 3 cycles	37	GEP	0	24	38	24	14	62	100	RECIST	14^\|\|	NA	16
Baum et at. (42)	Zentralklinik Bad Berka	2016	[¹⁷⁷Lu-DOTA⁰-Tyr³]octreotide	7.0 GBq × 1–4 cycles	56	NET	16	18	32	34	0	66	100	RECIST	16^\|\|	34	17

↵* Disease control rates in studies of Anthony et al. (23), Bushnell et al. (40), and Delpassand et al. (57) were 88%, 86%, and 72%, respectively, in evaluable patients.
↵† Reported as median unless otherwise indicated.
↵‡ Reported as median months unless otherwise indicated. NR = not reached.
↵§ Median time to progression was 36 months.
↵|| Reported as mean.
CR = percentage of patients showing complete response; PR = percentage of patients showing partial response; SD = percentage of patients showing stable disease (including minor response, if reported); baseline PD = percentage of patients showing progressive disease before treatment; PD = percentage of patients showing progressive disease; NA = not available/assessable; DCR = disease control rate (percentage); FU = median follow-up (months) unless otherwise indicated; GEP = gastroenteropancreatic; WHO = World Health Organization; GEP/B = gastroenteropancreatic/bronchial; SWOG = Southwest Oncology Group; CCHMIAA = Central Clinical Hospital of Ministry of Internal Affairs and Administrations, Warsaw, Poland; IEO = Istituto Europeo di Oncologia, Milan, Italy; SSRT+ = (all) somatostatin receptor–positive tumors; IRST-IRCCS = Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori–Istituto Di Ricovero e Cura a Carattere Scientifico, Meldola, Italy; GI = gastrointestinal; EDNOC = Excel Diagnostics and Nuclear Oncology Center, Houston, Texas.

View popup

TABLE 4

Randomized Controlled Trials for Treatment of Advanced NETs (64)

Study	Trial name	Year	Tumor type	Intervention	Control	Median PFS (mo)	HR (95% CI)
Rinke et al. (58)	PROMID	2009	Midgut	Octreotide LAR (30 mg/4 wk)	Placebo	14 vs. 6	0.34 (0.20–0.59)
Caplin et al. (59)	CLARINET	2014	Pancreatic, midgut, hindgut	Lanreotide (120 mg/4 wk)	Placebo	NR at 24 vs. 18	0.47 (0.30–0.73)
Pavel et al. (60)	RADIANT-2	2011	NET + carcinoid syndrome	Everolimus (10 mg/d)^*	Placebo^*	16 vs. 11	0.77 (0.59–1.00)
Yao et al. (61)	RADIANT-3	2011	Pancreatic	Everolimus (10 mg/d)^*	Placebo^*	11 vs. 5	0.35 (0.27–0.45)
Yao et al. (62)	RADIANT-4	2016	Nonfunctioning lung/gastrointestinal tract	Everolimus (10 mg/d)^*	Placebo^*	11 vs. 4	0.48 (0.35–0.67)
Raymond et al. (63)		2011	Pancreatic	Sunitinib (37.5 mg/d)^*	Placebo^*	11 vs. 6	0.42 (0.26–0.66)
Strosberg et al. (45)	NETTER-1	2017	Midgut	[¹⁷⁷Lu-DOTA⁰-Tyr³]octreotate (7.4 GBq × 4 cycles)	Octreotide LAR, 60 mg/mo	NR vs. 8	0.21 (0.13–0.34)

↵* With continuation of somatostatin analog therapy.
PFS = progression-free survival (intervention vs. control); HR = hazard ratio for disease progression and (disease-related) death; LAR = long-acting and repeatable; NR = not reached.