Novel Approaches Optimize Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Rising interest in SSTR2-targeted radiopharmaceuticals has led to the evaluation of numerous ways to optimize peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors (NETs), according to Amir Iravani, MD.

“Despite the efficacy and acceptable safety profile of PRRT, we know that not all patients respond favorably. Consequently, optimizing PRRT is of key importance to improve efficacy while reducing, or maintaining, acceptable toxicity in [patients with] neuroendocrine tumors…and optimize or personalize treatment for patients,” Iravani, an assistant professor of radiology in the Division of Nuclear Medicine at Washington University School of Medicine in St Louis, Missouri, said in a presentation during the Society of Nuclear Medicine and Molecular Imaging 2021 Virtual Annual Meeting.¹

Novel approaches currently being explored to build upon the efficacy of PRRT include the use of dosimetry to optimize PRRT, combination regimens, and novel radiopharmaceuticals.

“There is limited knowledge on the radiobiology of radionuclide therapy, and dosimetry may play a pivotal role to enhance our understanding of the radiobiology of radiopharmaceuticals, not only macroscopic dosimetry but also microscopic dosimetry at the level of the tumor cells—and that would help us derive the rational combination of treatments and be able to optimize and individualize treatment based on patient characteristics and tumor biology,” Iravani said.

He pointed to the P-PRRT trial (NCT02754297) as an example of how dosimetry could be used to modify treatment.² The ongoing phase 2 study is looking at the use of personalized treatment with lutetium Lu ¹⁷⁷ (177Lu) octreotate in patients with NETs to maximize the absorbed radiation dose direct to the tumor. Treatment was personalized based on glomerular filtration rate and body surface area in the first cycle and based on prior renal absorbed dose in the following cycles.

Preliminary results from the trial showed that 65% of patients completed 4 cycles of treatment and that among 39 evaluable patients, 23% had a partial response to treatment and 36% had a minor response. Further, the rate of grade 3/4 hematologic toxicities was minimal, below 10%, and no severe renal impairment was observed after a follow-up of 9 months.

Combination therapies under consideration include the addition of Hedgehog pathway inhibition, immune checkpoint inhibition, DNA damage repair inhibition, cellular growth inhibition, and more.

One such promising approach includes the use of radiosensitizing chemotherapy with capecitabine, in part due to its antiangiogenic effects. One study explored the use of peptide receptor chemoradionuclide therapy in patients with fludeoxyglucose F 18 (FDG)–avid NETs.³ Three months after completion of treatment, 2% had a complete response and 28% had a partial response. The median progression-free survival (PFS) was 48 months, and the median overall survival was not reached. Additionally, few grade 3/4 toxicities were observed.

“This intensified approach changed the poor prognostic factor of the patients [who were FDG avid] and brought them into a better prognostic group [non–FDG avid]. So it’s very important [to do] patient stratification based on biological characteristics and molecular imaging,” Iravani said.

The ongoing phase 2 CONTROL NETS study (NCT02358356) also explored the combination of 177Lu octreotate PRRT and capecitabine with added temozolomide (Temodar) in patients with pancreas and midgut NETs.⁴ Among patients with mid-gut NETs, the 15-month PFS rate was 90%, the response rate was 31%, and the clinical benefit rate was 97%. In the pancreatic NETs population, the 12-month PFS rate was 76%, the response rate was 68%, and the clinical benefit rate was 100%. Grade 3/4 treatment-related adverse events were significantly higher in the midgut group.

“It’s important, in patient selection, [to make sure], if you want to use intensified treatments, [that it is] justified for the patients to have higher toxicity and be the best use for the patients who have poorer prognosis,” Iravani said.

The addition of PARP inhibition is another approach of interest for combinations with PRRT because it can synergize with the ¹⁷⁷Lu dotatate (Lutathera) and increases DNA damage. However, a preclinical study suggested that although ¹⁷⁷Lu dotatate and PARP inhibition would lead to an increased number and persistence of double-stranded breaks, the in patients with well-differentiated phase 1 (NCT04375267) and phase 1/2 (NCT04086485) studies are already underway adding olaparib (Lynparza) to ¹⁷⁷Lu dotatate in patients with NETs.⁷ However, there was a high degree of unexpected grade 4 hematologic toxicity in 57% of patients.

Albumin hitchhiking with Evans blue is another modification approach under consideration. Iravani explained that albumin is the most abundant protein in the blood plasma; Evans blue reversibly attaches to albumin and improves the pharmacokinetics of the treatment. An analysis showed an increased tumor and critical organ uptake due to longer absorption time.

A Chinese study of this conjugation combination would be associated with more bone marrow and gastrointestinal toxicities.⁵

Phase 1 (NCT04375267) and phase 1/2 (NCT04086485) studies are already underway adding olaparib (Lynparza) to ¹⁷⁷Lu dotatate in patients with NETs.

Iravani explained that investigators are also looking to modulate somatostatin receptor expression to increase the therapeutic index of the treatment with the addition of synergistic agents, such as HDAC inhibitors, DNMT inhibitors, and other classes of agents, to create novel radiopharmaceuticals.

For example, SSTR antagonists bind to the receptor but are poorly internalized; in preclinical models, this led to significantly higher and stronger receptor binding.6 Additionally, long tumor retention was observed as well as a higher tumor-to-background ratio. Currently there are 3 SSTR antagonist candidates, Iravani said, with 2 different chelators and several radiometal options, all in early clinical trials.

A phase 1 dosimetry study (NCT02609737) of one of the candidates, ¹⁷7Lu satoreotide tetraxetan, showed a promising objective response rate of 45% and high tumor retention (¹⁷⁷Lu-DOTA-EB-TATE) in patients with NETs showed promising disease control in patients receiving higher dose levels, but the rate of toxicities also increased with higher doses.⁸

Other radioisotopes are also being introduced into the treatment of patients with NETs, including copper radioisotope Cu 64 (64Cu) because it has a longer half-life and 67Cu, which compares favorably with ¹⁷⁷Lu in terms of beta and gamma emission. In a preclinical study, 67Cu-CuSarTATE was well tolerated and effective against NET tumors in vivo.⁹

Alpha-radionuclide therapy, on the other hand, leads to higher linear energy transfer, which increases DNA double-strand breaks, but can have a complex decay scheme. Also, it is unreliable for posttreatment dosimetry and has had limited clinical experience.¹⁰

Preliminary results from an ongoing phase 1 study (NCT03466216) of ²¹²Pb-DOTAMTATE (AlphaMedix) showed an objective radiological response rate of 83% in patients with SSTR-expressing NETs and no significant toxicities related to treatment.¹¹ “We are enthusiastically looking forward to seeing how this trial will unfold in a larger cohort of patients,” Iravani commented.

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_{4. Pavlakis N, Ransom DT, Wyld D, et al. Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: phase II study evaluating the activity of ¹⁷⁷Lu-octreotate peptide receptor radionuclide therapy (LuTate PRRT) and capecitabine, temozolomide CAPTEM)— f irst results for pancreas and updated midgut neuroendocrine tumors (pNETS, mNETS). J Clin Oncol. 2020;38(suppl 15):4608. doi:10.1200/ JCO.2020.38.15_suppl.4608}

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_{6. Cescato R, Waser B, Fani M, Reubi JC. Evaluation of ¹⁷⁷Lu-DOTAsst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro. J Nucl Med. 2011;52(12):1886-1890. doi:10.2967/ jnumed.111.095778}

_{7. Reidy-Lagunes D, Pandit-Taskar N, O’Donoghue JA, et al. Phase I trial of well-differentiated neuroendocrine tumors (NETs) with radiolabeled somatostatin antagonist ¹⁷⁷ Lu-satoreotide tetraxetan. Clin Cancer Res. 2019;25(23):6939-6947. doi:10.1158/1078-0432.CCR19-1026}

_{8. Tian R, Jacobson O, Niu G, et al. Evans blue attachment enhances somatostatin receptor subtype-2 imaging and radiotherapy. Theranostics. 2018;8(3):735-745. doi:10.7150/thno.23491}

_{9. Cullinane C, Jeffery CM, Roselt PD, et al. Peptide receptor radionuclide therapy with 67 Cu-CuSarTATE is highly efficacious against a somatostatin-positive neuroendocrine tumor model. ˆ 2020;61(12):1800-1805. doi:10.2967/jnumed.120.243543}

_{10. Kratochwil C, Giesel FL, Bruchertseifer F, et al. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014;41(11):2106-2119. doi:10.1007/s00259-014-2857-9}

_{11. Delpassand E, Tworowska I, Torgue J, et al. ²¹²Pb-AlphaMedix targeted alpha therapy (TAT): a potential breakthrough in treatment of metastatic SSTR expressing NET. Presented at: 2020 NANETS Multidisciplinary Net Medical Virtual Symposium; October 2-3, 2020. Accessed July 27, 2021. https://bit.ly/3i3A4Tu}