Improving Upon Exciting Radionuclide Therapy in Neuroendocrine Tumors

Erik Mittra, MD, PhD

There is a great deal of excitement in the oncology field over the use of peptide receptor radionuclide therapy (PRRT) with lutetium-177 (¹⁷⁷Lu)-octreotate (¹⁷⁷Lu-Dotatate, Lutathera) for the treatment of patients with neuroendocrine tumors (NETs) following the positive results of the phase III NETTER-1 trial.¹As such, the treatment is being explored in potential combinations with other modalities, including with systemic treatment with PARP inhibitors, in this patient population.

During the 2017 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting that took place June 10 to 14 in Denver, Colorado, presenters explored the results of the NETTER-1 trial, as well as ways upon which this treatment could be further improved.

“There are many ways this is going to go in the future,” said Erik Mittra, MD, PhD, during a presentation at the meeting.

Radiolabeled somatostatin analogue therapy, or PRRT, is a targeted form of systemic radiotherapy that helps to deliver radionuclides directly to tumors that express somatostatin receptors. PRRT has demonstrated its efficacy among patients with inoperable or metastatic NETs. The radionuclide¹⁷⁷Lu-Dotatate binds to somatostatin receptor type 2s that are over expressed in NETs and delivers radiation within the cancer cell that induces the DNA strand to break, thereby causing apoptosis, according to Mittra, clinical associate professor of radiology/nuclear medicine, Stanford University Medical Center.

In the international, randomized, multicenter NETTER-1 trial, 177Lu-Dotatate was investigated in 229 patients with midgut NETs who had progressed on prior octreotide therapy. Patients were randomized to either 4 administrations of 7.4 GBq of 177Lu-Dotatate every 8 weeks plus 30 mg of octreotide or a higher dose of long-acting release (LAR) 60-mg octreotide every 4 weeks.

Mittra commented that¹⁷⁷Lu-Dotatate was not being compared with a placebo but with high-dose therapy. “In a way, the control is actually also experimental,” he said, because the higher dose of the octreotide could be effective as well.

Patients had to have inoperable, somatostatin receptor-positive and metastatic or locally advanced disease; they were either grade 1 or 2, with a Ki-67 index of ≤20%. All patients had a Karnofsky performance status score of ≥60.

As of data cutoff, the median progression-free survival had not yet been reached with¹⁷⁷Lu-Dotatate compared with 8.4 months (95% CI, 5.8-9.1) in the 60-mg octreotide LAR arm (HR, 0.21; 95% CI, 0.13-0.33; P <.001). As of the interim overall survival (OS) analysis, there was a signi ficant difference in the OS between the 2 arms favoring¹⁷⁷Lu-Dotatate (hazard ratio [HR], 0.40; P <.004). The objective response rate was 18% (95% CI, 10%-25%) with¹⁷⁷Lu-Dotatate versus 3% (95% CI, 0%-6%) with high-dose octreotide (P <.001).

Similar toxicities were noted between the 2 arms, although a higher degree of adverse events was noted in the¹⁷⁷Lu-Dotatate arm than in the control (95% vs 84%, respectively; P = .01). Rates of grade 3 or 4 lymphopenia (9%), thrombocytopenia (2%), and neutropenia (1%) were noted in the experimental arm that were not seen in the control arm.

&ldquo;At least based on the data we have now, [¹⁷⁷Lu-Dotatate] actually appears to be very safe, and the 2 main things that are of concern are hematologic toxicity and renal toxicity,&rdquo; said Mittra.

He concluded that this therapy would be beneficial for patients with well-differentiated NETs who have a lower Ki-67 index, but that it could also be used in anyone who expressed suf cient somatostatin receptors.

A new drug application for the radionuclide was accepted by the FDA in June of 2016 for the treatment of gastroenteropancreatic NETs. Advanced Accelerator Applications, the developer of 177Lu-Dotatate, received a complete response letter from the FDA in December asking for new subgroup and safety data to be resubmitted.

While 177Lu-Dotatate has not yet been FDA approved, Mittra noted that approval is expected sometime this year, and in the meantime, it is available in the United States under an expanded access program. The European Medicines Agency&rsquo;s Committee for Medicinal Products for Human Use has recommended the approval of the agent in the European Union. He suggested that the PRRT could be used in other indications and in combination with other treatment modalities in NETs, including with selective internal radiation therapy, chemotherapy,

kinase inhibitors, and antibodies.

In another presentation during the SNMMI meeting, Canadian investigators addressed the possibility of adding PARP inhibitors to PRRT with¹⁷⁷Lu-Dotatate, as PARP could make the tumor cells more sensitive to radiation therapy.²&ldquo;The use of PARP inhibitors is a promising approach to enhance targeted radionuclide therapy for neuroendocrine cancer,&rdquo; Samuel Adant, a member of the research team from the CHU de Québec—Université Laval Research Center in Quebec City, Canada, said in a statement. &ldquo;Furthermore, PARP inhibitors could enhance many other current and emerging radionuclide therapies.&rdquo;

In preclinical in vitro 3-D models of 2 human-derived NET cell lines, the combination of the 2 modalities was found to be more cytotoxic than either alone. The models were dosed for 5 days and monitored for 15 subsequent days. The cancer cells in the untreated models increased 16.7-fold from their original volume during the 15 days. Comparatively, the models treated with the combination regimen grew by only 1.9-fold compared with 5.1 and 11.0 times with PRRT or PARP inhibition alone, respectively.

The investigators believed that this was one potential promising combination approach to improve upon the benefit already seen with¹⁷⁷Lu-Dotatate in NETs.

References:

1. Strosberg J, El-Haddad G, Wolin E, et al; NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/NEJMoa1607427.
2. Adant S, Purohit NK, Shah RG, Shah G, Beauregard JM. Potentiation of 177Lu-octreotate PRRT by PARP inhibitors in a 3D spheroid model of human-derived neuroendocrine tumor cell lines. J Nucl Med. 2017;58(suppl 1, abstr 243).