Long-Term Toxicity Data Confirm the Tolerability of Lutathera in NETs

Edward M. Wolin, MD

Longer-term data demonstrated that treatment with the radiopharmaceutical Lutathera (lutetium-177 dotatate) continued to show low rates of toxicity among patients with somatostatin receptor–positive neuroendocrine tumors (NETs), said Edward M. Wolin, MD, who added that the positive findings open the potential for novel combinations with the agent. 

In January 2018, the FDA approved Lutathera for the treatment of patients with somatostatin receptor–positive gastroenteropancreatic NETs based on findings from the phase 3 NETTER-1 trial. In the study, Lutathera induced a 79% reduction in the risk of progression or death compared with octreotide (Sandostatin).¹

However, in December 2016, a complete response letter was issued by the FDA requesting new subgroup data, a safety update, and that revisions be made to the previously submitted data.

To that end, the US Expanded Access Program trial assessed the long-term toxicity of Lutathera in patients with advanced, somatostatin receptor–positive NETs. Patients were treated with the product ahead of its marketing approval.

Findings from the program, which were presented virtually during the 2020 NANETS Multidisciplinary NET Medical Symposium, showed mild to moderate rates of treatment-related adverse effects (TRAEs) that were mainly gastrointestinal in nature, such as nausea and vomiting.² Additional TRAEs included fatigue and thrombocytopenia.

One instance each of grade 3 carcinoid crisis, grade 3 vomiting, and grade 3 dehydration were observed. No grade 4 or 5 TRAEs were observed with Lutathera.

“I think these findings will encourage people to use this treatment earlier rather than later,” said Wolin. “Instead of waiting until every other treatment [is given] and patients are very debilitated, [we can] use [Lutathera] earlier to give patients a longer quality of life. That would be a major practice-changing [event].”

In an interview with OncLive, Wolin, director of the Center for Carcinoid and NETs and a professor of medicine, hematology, and medical oncology at the Ruttenberg Treatment Center of Mount Sinai Hospital, discussed the current state of treatment for patients with NETs, the clinical impact of the long-term toxicity results with Lutathera, and other developments in the pipeline.

OncLive: What is the prevalence of NETs?

The prevalence of these tumors in the general population is approximately 5 in every 100,000 people; that is with all types of NETs combined in the United States population. Also, this represents a significant increase in incidence in the last 30 years.

What options are currently available to treat NETs?

Currently, we have somatostatin analogs, which interact with NETs. We also have certain types of biologics like everolimus (Afinitor), which is a targeted [systemic] chemotherapy. Additionally, we have Lutathera.

We also have treatments that are directed specifically against tumors, including surgical resection, interventional radiology, and tumor ablation, particularly of the liver. Radioembolization of the hepatic artery can also kill tumors. So, we have several kinds of treatment for metastatic disease.

At this time, the only treatments that are approved are somatostatin analogs like lanreotide (Somatuline Depot). Everolimus is also approved as a targeted biologic. Then we have Lutathera, which is also known as peptide receptor radionuclide therapy treatment. We have a diagnostic test that predicts who is likely to respond to Lutathera, which is the Gallium 68-dotatate (68Ga-dotatate) PET scan. We can also use a Copper 64- dotatate PET scan. If we do those types of PET scans and they are positive, it means the tumor has some metastatic receptors. Then, we use a nearly identical molecule for treatment. Instead of Ga 68-dotatate, we use Lutathera. By making that substitution, we go from a diagnostic isotope to a [therapeutic] killer isotope to nuke the tumors. It is basically a targeted, internal type of radiation, and is a very exciting type of treatment for patients with NETs.

What was your involvement with the development of Lutathera?

I was very much involved in the development of this type of therapy as part of the NETTER-1 trial, which [demonstrated] the effectiveness of Lutathera. After that study, we had not yet gotten an approval from the FDA [for Lutathera]. There was a big trial known as Expanded Access, which was a follow-up to the first NETTER-1 trial. The study evaluated the long-term toxicity [of Lutathera] in 299 patients who were treated before this drug became available for general use. These patients were followed very closely. 

What patients were included in the study?

Eligible patients had NETs. Initially, [the study enrolled] patients with midgut NETs that started in the intestine. Later though, [the protocol was amended] to include all types of NETs, as long as they were well differentiated, so the cells were not proliferating excessively fast.

Ki-67 [expression], which is a marker of proliferation, was typically less than 20% in the patients on this trial. Patients had to have already [received] standard treatment [for NETs] and [could not have] significant kidney function problems or overwhelming medical conditions that would [prevent] them from tolerating therapy. All patients [had not undergone] surgery, radiotherapy, or chemotherapy for a 12-week period prior to [initiation of Lutathera]. Importantly, at the time of treatment, patients were not on other non-radioactively labeled somatostatin analogs as that would compete with the radioactively labeled ones for binding to the cell surface. Patients who were previously on octreotide or lanreotide had to be off those medications at the time of treatment [with Lutathera].

What long-term safety signals were observed with Lutathera?

The average follow-up was 130 days at the time of the data analysis. The toxicities [observed] were mostly mild. Severe grade 3/4 toxicities were extremely uncommon, and patients were not experiencing life-threatening toxicities.

The most common mild or grade 1/2 toxicities were nausea, which happened in [31]% of patients, and vomiting, which happened in about [14]% of patients. In almost all cases, [nausea and vomiting] were not caused by Lutathera, but rather by amino acids that were given to protect the kidneys. Partway through the trial, many patients were switched from the initial amino acid mix that was causing a lot of nausea, to a new amino acid mix containing arginine and lysine. [Although] it did not have the other amino acids, it protected the kidneys equally well and did not cause nausea. So, the subsequent experience [causes] much less nausea than we initially saw, but even in this study, nausea was mild, [and managed] with standard nausea preventives.

Other toxicities that were seen included fatigue in [9.4%] of patients and thrombocytopenia in about [6]% of patients.

Severe toxicities [that occurred] in less than 1% of patients, included carcinoid crisis and vomiting that led to dehydration. We are talking about [incidence] in the neighborhood of 0.3%, so very rare.

How would you describe the efficacy of the agent?

The efficacy is quite excellent with [Lutathera], which is why the FDA approved the agent. [Many of] the patients who are being treated with the medication have cancer control for years, [with tumor reductions or stable disease].

In the original trial, there was a randomization between the double dose of a non-radioactive somatostatin analog versus this radioactive form. The difference [in progression-free survival (PFS)] was [significant]. With the placebo group, the average PFS was in the neighborhood of 8 months and was not reached with [Lutathera] at the time of the publication. To this day, the PFS is estimated to be approaching 4 years, with 3 to 4 years of cancer control on average. So, it is really an effective antitumor drug for a disease that is highly resistant to most chemotherapies and where only a limited number of treatments are available.

How can these data be applied to clinical practice?

The most important clinical implication of these findings is that Lutathera is safe. Serious toxicities were not observed [in the majority of patients]. Theoretically, we know Lutathera can injure the kidneys and bone marrow, even to the point of myelodysplasia or leukemia. It is extremely rare and probably very late [that we would see those] because we didn’t see those [in the trial].

Are there any next steps planned to further evaluate Lutathera in other settings?

The success of Lutathera as an anticancer drug has opened up a lot of ongoing clinical trials all around the country and world. These trials are using, for example, different radioactive molecules. Instead of Lutathera, which is a beta emitter, there are trials using other isotopes that are alpha emitters. Instead of targeting the somatostatin receptor with a somatostatin analog, which is what Lutathera is, using somatostatin receptor antagonists combined with Lutathera.

Additionally, there are trials of these kinds of drugs in combination with immunotherapy, targeted therapy, and chemotherapy, to [induce] higher response rates and longer duration of [response]. Whenever we develop something good in oncology, we always ask, Where are we going to go from here? There is always a next step. Perhaps [Lutathera] can be given directly into the hepatic artery for treating tumors in the liver; maybe that would be better than giving it intravenously. These are all investigational questions that were stimulated by this initial positive [trial].

References:

1. Strosberg J, Wolin EM, Chasen B, et al. NETTER-1 phase III in patients with midgut neuroendocrine tumors treated with 177Lu-Dotatate: efficacy and safety results. J Nuclear Med. 2016;57(suppl 2):629.
2. Allen-Auerbach MS, Wolin EM, Nassiri V, et al. Safety of 177Lu-DOTATATE in patients with advanced neuroendocrine tumors: data from a US Expanded Access Program. Presented at: NANETs 2020 Multidisciplinary NET Medical Virtual Symposium; October 2-3, 2020; Virtual. Poster 118.