¹⁷⁷Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors

ABSTRACT

Introduction: ¹⁷⁷Lutetium-[DOTA°,Tyr³]octreotate (¹⁷⁷Lu-DOTATATE) is a type of peptide receptor radionuclide therapy that garnered FDA approval in January 2018 for the treatment of somatostatin receptor-positive gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients. The therapy approval was based on findings from the randomized international phase III NETTER-1 trial as well as outcome data from a large European registry. The mechanism of the drug stems directly from its structure: a somatostatin analog (octreotate) selectively binding to somatostatin receptor expressing cells and being internalized, along with a chelated beta-emitting isotope ¹⁷⁷Lu.

Areas Covered: Herein we describe the pharmacology, clinical efficacy and adverse event data from prospective and retrospective studies with ¹⁷⁷Lu-DOTATATE. We discuss the role of ¹⁷⁷Lu-DOTATATE within the current treatment landscape for GEP NET patients.

Expert Opinion: ¹⁷⁷Lu-DOTATATE represents a unique addition to the treatment armamentarium for GEP NETs because of its potential to elicit tumor cytoreduction, which is rare among other existing treatment options, and prolonged disease control. Where ¹⁷⁷Lu-DOTATATE fits into the treatment sequence for GEP NET patients remains an area of active investigation.

KEYWORDS:

• Peptide receptor radionuclide therapy
• ¹⁷⁷Lu-DOTATATE
• gastroenteropancreatic neuroendocrine tumor patients
• somatostatin receptor agonist
• somatostatin receptor antagonist

Article highlights

• ¹⁷⁷Lu-DOTATATE is a radiolabeled somatostatin agonist (SSA), which is approved for the treatment of somatostatin receptor positive well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients in Europe, the United States, and Canada.

• ¹⁷⁷Lu-DOTATATE belongs to a class of therapeutic agents called peptide receptor radionuclide therapy (PRRT). In the context of NETs, each agent includes a peptide, which is an SSA or somatostatin receptor antagonist, a chelator which serves as a linking molecule, and a specific radioisotope.

• Radiolabeled SSAs have been trialed in Europe since 1994. The initial radiolabeled SSAs tested in phase I studies were ¹¹¹In-DOTATOC (very weakly cytotoxic) and ⁹⁰Y-DOTATOC. ¹⁷⁷Lu-based PRRT was shown to have a more favorable therapeutic index than ⁹⁰Y, particularly with respect to renal toxicity. Octreotate combined with the chelator DOTA (DOTATATE) showed increased somatostatin receptor 2 avidity and longer intra-tumoral radioactivity residence based on preclinical and dosimetry studies, respectively.

• The NETTER-1 trial randomized midgut NET patients to four treatments of ¹⁷⁷Lu-DOTATATE followed by standard-dose octreotide LAR or high-dose octreotide LAR. It is the only reported randomized phase III study involving any radiolabeled SSA. In the ¹⁷⁷Lu-DOTATATE arm, progression-free (PFS) was markedly prolonged compared to the high-dose octreotide arm: hazard ratio [HR] 0.21; p < 0.001.

• Quality of life (QOL) was analyzed on the NETTER-1 study using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires. Time to deterioration was significantly prolonged in the ¹⁷⁷Lu-DOTATATE arm compared to patients in the high-dose octreotide arm with regards to global health status, physical functioning, diarrhea and fatigue.

• Other radiolabeled SSAs and somatostatin antagonists which carry theoretical advantages over ¹⁷⁷Lu-DOTATATE are now being tested in early safety-focused clinical trials. Two notable agents include the SSA ¹⁷⁷Lu-DOTA-EB-TATE and the somatostatin receptor antagonist ¹⁷⁷Lu-OPS201. ¹⁷⁷Lu-DOTA-EB-TATE has demonstrated increased intra-tumoral radioactivity uptake preclinically and a longer plasma half-life due to its albumin binding moiety, compared to ¹⁷⁷Lu-DOTATATE. ¹⁷⁷Lu-OPS201 has demonstrated an increased capacity to elicit DNA damage preclinically and increased intra-tumor radioactivity uptake in a small pilot study clinically, compared to ¹⁷⁷Lu-DOTATATE.

• Ongoing studies are exploring whether PRRT is more effective in earlier treatment lines in GEP NET patients, whether additional cytoreductive treatments should be added to PRRT to improve its anti-tumor efficacy and what other patients (such as those with paragangliomas, pheochromocytomas, meningiomas, lung NETs) may benefit clinically from PRRT.

Declaration of interest

S. Das has received honoraria from Targeted Oncology, Lexicon, Medsphere and Clarivate Analytics. J. Strosberg has received honoraria from Novartis, Lexicon and Ipsen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

Vanderbilt clinical oncology research career development award: 5K12CA090625-19.