Novel Somatostatin Analog Shows Early Activity in Metastatic NETs, Irrespective of Primary Tumor Site

The novel somatostatin analog for the Targeted Alpha-emitter Therapy 212Pb-DOTAMTATE (AlphaMedix) has demonstrated early efficacy and a tolerable safety profile in a small cohort of patients with metastatic somatostatin receptor–expressing neuroendocrine tumors (NETs), irrespective of location of the primary tumor, according to the first results of a phase 1 trial (NCT03466216) presented during the 2020 NANETS Virtual Symposium.¹

Results from the dose-escalation study identified a safe and highly effective dose of the therapy in this patient population, and the treatment is to be administered in 4 doses, once every 8 weeks. All in cohort 4 of the trial (n = 3/3) experienced an objective radiologic response with 212Pb-DOTAMTATE, with no significant hematologic, renal, or hepatic toxicities reported. Moreover, no disease progression was reported in these patients 15 months after the initiation of treatment.

“The main reason that alpha therapy is so effective is because it’s causing double-strand DNA damage as compared with a beta emitter, such as lutetium that causes mostly singular-strand DNA damage,” said Ebrahim Delpassand, MD, of the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center and Department of Nuclear Medicine at Baylor College of Medicine, in an oral presentation during the meeting. “Therefore, we attribute [impressive] effectiveness [that we’re seeing with] this drug to [the fact that it’s an] alpha emitter.”

212Pb-DOTAMTATE is a radiotherapeutic drug that was developed to address an unmet need in the field of peptide receptor radionuclide therapy (PRRT) for patients with NETs. The hypothesis was that by replacing the beta emitters, such as 177Lu or 90Y, that are currently being used with an alpha emitter 212Pb, investigators would be able to deliver significantly higher Linear Energy Transfer (LET) with a shorter path length.² Higher LET particles are theorized to result in more tumor cell death, and shorter path length could lead to less collateral damage of normal tissue, and thus, less adverse effects (AEs).

In the phase 1, non-randomized, open-label, dose-escalation, single-center phase 1 trial, investigators set out to examine the safety and biodistribution and preliminary efficacy of 212Pb-DOTAMTATE in adult patients with somatostatin receptor–expressing NETs. A total of 16 patients were enrolled; 7 were men and 9 were women. The median age was 68 years, and they all had unresectable or metastatic somatostatin receptor–positive NETs from different primary sites proven via biopsy.

The dose-escalation scheme was a conventional 3+3 phase 1 trial design. Three patients are enrolled in each cohort and if a dose-limiting toxicity (DLT) occurs, the cohort will expand to 6 subjects. If no additional patients experienced a DLT, dose-escalation will continue as planned. The trial began with a single-accelerating dose and then switched over to a multi-accelerating dose regimen upon either partial tumor response or DLT. The dosing range was defined based on dosimetry studies.

Patients were eligible for conclusion if they were 18 years of age or older, had an ECOG performance status ranging from 0 to 2, had a life expectancy of at least 12 weeks, and had a histologically confirmed diagnosis of somatostatin receptor–positive NETs, either unresectable or metastatic. Somatostatin receptor positivity had to have been based on the FDA-approved imaging within 4 weeks before the first cycle of study treatment. Patients also had to have measurable disease per RECIST v1.1 criteria on CT or MRI scans. Additionally, patients must have exhausted all FDA-approved options available to them, with the exception of PRRT.

If patients had previously received whole-body radiotherapy and PRRT using 177Lu/90Y/111In-DOTATATE/DOTATOC, they could not participate on the trial. Moreover, if they had a known hypersensitivity to 68Gallium, Octreotate, or any of the excipients of 68Ga-DOTATATE, AA infusion, or 212Pb-DOTAMTATE, they were excluded. If patients had received any somatostatin analogue, including octreotide acetate (Sandostatin LAR) within 28 days and octreotide (Sandostatin) within 1 day before study treatment, they also could not participate in the trial.

Any patients with unusual hematological parameters, including increased mean corpuscular volume of over 105, or who had prior chemotherapy, require further work-up from a hematologist to rule out myelodysplastic syndrome.

Results from the MAD4 cohort were presented during the 2020 NANETS Virtual Symposium and examined the agent in a total of 6 patients. MAD4-01 was a male Caucasian who received a cumulative dose of 21.99 mCi; MAD4-02 was a male Caucasian who received a dose of 21.54 mCi, MAD4-03 was a female African-American who received a dose of 19.2 mCi, MAD4-04 was a female African-American who received 21.82 mCi, MAD4-05 was a male Caucasian was received 23.57 mCi, and MAD4-06 was a female Caucasian who received a cumulative dose of 18.4 mCi. Specifically, MAD4-01, MAD4-02, and MAD4-03 completed 4 cycles of treatment.

Case 1

The first case, MAD4-01, was a 62-year-old male who had grade 2 metastatic small bowel NETs. The patient had been diagnosed in February 2017. The following month, March 2017, he had a small bowel resection and began treatment with octreotide. In April 2017, the patient had a left hepatic lobectomy and underwent a right lobe wedge resection. In April 2019, the patient was enrolled to the clinical trial. At this time, the patient’s disease was localized in the abdomen with liver and mesenteric metastases present.

“After 4 cycles, we saw a complete resolution of the abnormalities in the liver and uptake in the mesenteric lesion per RECIST criteria, with no AEs noted at this point,” said Delpassand.

Case 2

The second case, MAD4-02, was a 45-year-old male who had a history of metastatic lung carcinoid to the spine; he was diagnosed in December 2012 following the development of an upper respiratory tract infection. A bronchoscopy biopsy performed in January 2013 revealed a well differentiated NET. He then underwent a right upper lobectomy with a hilar lymphadenectomy the following month in February 2013.

In March 2014, a biopsy of the L3 vertebra revealed a high-grade NET. In April 2014, he began treatment on octreotide and denosumab (Xgeva). In 2018, serial scans showed disease progression in the liver and skeleton. The patient was receiving 3 kinds of narcotic drugs for painful bone metastases when he was enrolled on the trial.

“After 4 cycles, we saw complete resolution of the abnormalities on PET scan,” reported Delpassand. “At this point, the patient was asking for a nice place to play golf in Houston, Texas.”

Case 3

MAD4-03, was a 71-year-old woman who was diagnosed in 2014 with bronchial carcinoid. At the time, the tumor was invading the aorta and it was determined to be unresectable. The patient received prior chemotherapy, octreotide, and everolimus (Afinitor). Upon progressive disease, the patient was referred to the Excel Diagnostics Nuclear Oncology Center in Houston, Texas. She was enrolled on the trial in April 2019.

At that time, the patient had localized disease in the left lung, which was spreading through the pleural surface, as well as on the left side of the mediastinum. The patient was required constant oxygen because she was experiencing severe shortness of breath.

“After 4 cycles, we saw almost complete resolution by 68Ga-DOTATATE PET/CT scans in the left lung and no progression. The patient was oxygen independent at this point,” said Delpassand.

The MAD4 cohort has since been expanded and results are pending, concluded Delpassand.

References

1. Delpassand E. 212Pb-AlphaMedixTM Targeted Alpha Therapy (TAT): a potential breakthrough in treatment of metastatic SSTR expressing NET. Presented at: 2020 NANETS Symposium; October 2-3, 2020; Virtual. Abstract 193.
2. Phase 1 study of AlphaMedixTM in adult subjects with SSTR (+) NET. ClinicalTrials.gov. Updated July 10, 2020. Accessed October 3, 2020. https://clinicaltrials.gov/ct2/show/NCT03466216.