Lutetium Lu 177 Dotatate Enters the Pediatric Treatment Paradigm for SSTR+ GEP-NETs

Following its 2018 FDA approval for the treatment of adult patients with somatostatin receptor (SSTR)–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut NETs, lutetium Lu 177 dotatate (Lutathera) received an indication in April 2024 for pediatric patients 12 years or older, increasing access to the agent.¹

Lutetium Lu 177 dotatate’s approval in the pediatric population represents the first FDA approval of a radioactive drug, or radiopharmaceutical, for pediatric patients 12 years or older with SSTR-positive GEP-NETs. Pharmacokinetic, dosimetry, and safety findings from the phase 2 NETTER-P (NCT04711135) trial supported the approval along with efficacy data from the phase 3 NETTER-1 trial (NCT01578239), which originally supported lutetium Lu 177 dotatate’s indication in adult patients. In the pediatric indication, the recommended dose of lutetium Lu 177 dotatate is 7.4 GBq (200 mCi) every 8 weeks (±1 week) for a total of 4 doses. Notably, premedications and concomitant medications are recommended as needed.

“With the results of the phase 3 NETTER-2 trial [NCT03972488] and NETTER-P trial, we are seeing an expansion of the settings in which we’re able to use radioligand therapy, which does seem to consistently show significant benefit when used appropriately in the right patients. Expanding who has access to it [and who] we have the opportunity to give it to will be beneficial for our patients,” Daniel M. Halperin, MD, said.

Data from NETTER-2 presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium revealed that patients 15 years or older with advanced SSTR-positive well-differentiated grade 2 or 3 GEP-NETs treated with lutetium Lu 177 dotatate plus long-acting release (LAR) octreotide (n = 151) experienced significantly prolonged progression-free survival (PFS) compared with those who received high-dose octreotide (n = 75). The median PFS was 22.8 months (95% CI, 19.4-not estimable) vs 8.5 months (95% CI, 7.7-13.8), respectively (HR, 0.28; 95% CI, 0.18-0.42; P < .0001).²

In an interview with OncLive, Halperin, an associate professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, detailed findings in pediatric and adult patients treated with lutetium Lu 177 dotatate as well as safety data with the agent.

OncLive: What is the significance of this FDA approval?

Halperin: Pediatric NETs are extraordinarily rare—this is a one in a million diagnosis—and the evidence base around therapies for these patients is quite thin. Fortunately, on the adult side, we’ve made a lot of progress over the past 5 or 10 years, and we frequently get questions [from] our pediatric colleagues about what the options are. Given the success of peptide receptor radionuclide therapy for adults, expanding this to children is something that we hope will be helpful.

Lutetium Lu 177 dotatate is a [radiolabeled] somatostatin analogue, and [radioligand therapy] has been used in various forms in the NET field for decades dating back to the 1990s with some of the original pre–lutetium Lu 177 dotatate agents.

On the adult side, the regulatory story dates back to 2018 [with the approval of lutetium Lu 177 dotatate] after data from the phase 3 NETTER-1 trial demonstrated an approximate 80% reduction in progression or death for patients with midgut NETs [who received that agent compared with LAR octreotide]. The recent presentation of the phase 3 NETTER-2 trial data [demonstrated an approximate] 75% reduction in risk for progression or death for patients with more aggressive grade 2/3 GEP-NETs, [although] not all the data are out. But those studies [enrolled patients no younger than] 18 [and 15 years, respectively,] and although we get a lot of questions about whether pediatric patients can receive the therapy, we did not have any safety data to lean on for regulatory perspective until NETTER-P.

What data have been observed in pediatric patients in NETTER-P and adult patients in NETTER-1?

The data from NETTER-P aren’t publicly available, but we do know that the primary end points [were] target organ radiation dose and safety signals in terms of adverse effects [AEs] in the first 8-week cycle after [drug] administration. So far, there weren’t any untoward safety signals or differences in target tumor radiation or AE profile that would prompt us to be more concerned in the 4 patients with GEP-NETs [treated with lutetium Lu 177 dotatate] in NETTER-P.

In NETTER-1, patients with advanced midgut NETs who experienced disease progression over a relatively long period of time prior to enrollment were randomly assigned to receive lutetium Lu 177 dotatate or [LAR octreotide]. PFS was the primary end point, with a HR of 0.21 [observed in favor of lutetium Lu 177 dotatate, and there was] significant slowing in disease growth. The overall survival curves eventually came together with all the crossover in that trial; there certainly exists some debate about where exactly [this agent] fits into the treatment algorithm, but for patients with progressive disease, it’s in the treatment arsenal and very commonly used.

What should physicians know about the safety profile of lutetium Lu 177 dotatate?

Acutely, this [treatment] is very well tolerated. In the era of using compounded arginine and lysine amino acids and not the full 20 [amino acids], we still see some nausea and vomiting. We see a bit of fatigue, typically in the first week or two after therapy, but it’s self-limited.

Over the long term, and one of the reasons studies [with longer follow-up] such as NETTER-P [will be] so important, is we do see a bit of myelotoxicity and nephrotoxicity at low rates [of approximately] 5%, and they can take time to show up. Myelodysplasia and leukemia tend to [occur] 3, 4, or 5 years out at the median; [although there is an approximate] 5% risk, they are real and very relevant [AEs] when treating young patients particularly with indolent disease.

How can physicians ensure patients have access to this medication?

Access to radionuclides is a major theme in the field, and those of us who have lived through supply chain disruptions, particularly during the COVID-19 pandemic, are acutely attuned to how fragile our patients’ access is. But there are readily available resources to identify centers that may be near you. Being at a large-volume NET center, we always appreciate the opportunity to be involved in the care of these patients and form a multidisciplinary team around them. There are standard mechanisms for referrals, but for [physicians and patients] who don’t have access [to the medication], there are a lot of sites available that can be found easily [to aid in getting access].

In this field, there are a lot of options now, which is great, but it presents physicians with the difficult decision of figuring out which of them to use first and how to deploy agents in sequence. That’s one of the reasons that those of us who see patients with NETs all day, every day are always happy to be involved and help when we can. A lot of us think about what we understand of the disease burden and the patient in front of us, and we try to individualize the management [of the disease] as best we can. Trying to think about what symptoms patients are experiencing or may be experiencing and how to do as little harm as possible while getting them the treatment they need [is important].

References

1. FDA approves lutetium Lu 177 dotatate for pediatric patients 12 years and older with GEP-NETS. FDA. April 23, 2024. Accessed May 31, 2024. bit.ly/4e7bGLN
2. Singh S, Halperin DM, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: primary analysis of the phase 3 randomized NETTER-2 study. J Clin Oncol. 2024;42(suppl 3):LBA588. doi:10.1200/JCO.2024.42.3_suppl.LBA588