Landmark Trials Guiding Systemic Therapy in Advanced NETs

The therapeutic landscape for advanced neuroendocrine tumors (NETs) has evolved rapidly, driven by landmark trials evaluating everolimus (Afinitor) and peptide receptor radionuclide therapy (PRRT) across disease settings. During a live Case-Based Roundtable event in Vancouver, Washington, Hagen Kennecke, MD, medical oncologist at Oregon Health & Science University, reviewed the phase 3 RADIANT-4 (NCT01524783),¹ NETTER-1 (NCT01578239),² and NETTER-2 (NCT03972488)³ studies, underscoring how their findings established and refined the role of these systemic options in contemporary NET management.

Register today to join a Case-Based Roundtable near you.

Targeted Oncology: What were the study design and patient characteristics of the RADIANT-4 trial?

Hagen Kennecke, MD: This is a study published by James Yao in 2016 of the RADIANT series of trials when everolimus was the new kid on the block. This was the RADIANT-4 trial, which was quite inclusive of patients; everything but [pancreatic] NETs [PNETs] were included. Patients with progressive, previously treated disease were randomized to either everolimus at the standard dose or placebo. There was no crossover in this trial.

As you can see, the other [eligibility] criteri[on] was that the tumors were nonfunctional, and that was done because in the prior RADIANT trials, there was a signal that the nonfunctional NET seemed to benefit more from everolimus... RADIANT-2 [NCT00412061] was borderline positive, and so they dug down on this population. So, I think the key to remember is it’s quite an inclusive group of tumors, or everything but PNET.

What were the efficacy and safety findings of RADIANT-4?

Overall, there was an improvement in progression-free survival [PFS]. And I always like to think of treatment benefit in terms of hazard ratio [HR]… HR [was] 0.48, so a 50% reduction in the risk of progression. That translated into an approximately 7-month PFS benefit with everolimus single agent.

So what were the response rates? Super low. And…by far, the main benefit was stable disease. [For] subgroup analysis, there were no signals… I think what was interesting is both GI and lung NETs benefited, and lung [NETs] is an… orphan disease, they're super uncommon, and so it's nice to have some data in that disease site.

We're pretty used to all of the [adverse] effects [AEs] of everolimus by now. I think it's been around for about 20 years. Does everyone use standard dex[amethasone], liquid dex, swish-and-spit like reflex for everolimus? This trial might have been done before that was really embraced. I remember the bad old days when there w[ere] some patients that got the worst abscess ulcers, and I never want to see that again.

What were the study design and patient characteristics of the NETTER-1 trial?

[In] almost everywhere in Europe, PRRT has been done for many, many years, probably for 30 years. But this company, a Swiss company, came along and… patented PRRT, called it Lutathera [lutetium Lu 177 dotatate], and then did a trial in North America, and that's how the treatment was brought to North America.

It is the first randomized trial of the therapy. The results were published in 2017 and [included] patients with previously treated advanced NETs—these were midgut, so not excluding PNETs—were randomized to lutetium dotatate vs high-dose octreotide [long-acting repeatable]. In case you’re wondering…why not everolimus? It's simply because…most of these patients had already received it and they were heavily pretreated. There was really nothing else. The trial accrued quite quickly. And as you can see…all small bowel midgut NETs.

What were the efficacy and safety findings of NETTER-1?

The response rate…[HR] was 0.21 so 80% reduction in risk of progression, so really nice separation of the curve, which I think is pretty impressive particularly considering that most of these patients were heavily pretreated. Their absolute response rates were not super high, 17% in the treatment arm. The main benefit, again, was improved [PFS]. In terms of the disease subgroup, everyone benefited—functional [or] nonfunctional SSTR expression…and tumor grade 1 and 2, so really…a strong signal of benefit.

[Regarding AEs, these are] not significant, serious [AEs]. I think one thing I didn't see is that there is about a 2.5% [rate] of [acute myeloid leukemia; AML] and [myelodysplastic syndrome] with the PRRT, which is obviously a class effect. So, I think it is one of the reasons why we maybe sometimes don't think of it right away, but it is a significant event. I've treated probably 200 patients with PRRT, and I've I have 5 patients that had it so, and they don't usually survive. So it's real…it actually happens pretty early. It's almost like…the AML we get for breast cancer in the old days when we had the more intensive regimen. It's pretty early, so when I follow these patients after the PRRT I always do [complete blood count]… Otherwise, it is actually a remarkably well tolerated therapy; if we just go down the grade 3, 4 [AE] column, the thrombocytopenia, lymphopenia even isn't that significant overall with the treatment.

What were the study design and patient characteristics of the NETTER-2 trial?

The NETTER-2 trial was much more recently presented in 2025, last year. And what that trial asked is: if this this treatment works really well, and in heavily pretreated disease, maybe we should use it first. That's kind of what we do usually, right? As we develop new treatments, we say, “hey, let's bring them earlier.” So what [investigators] did…differently is they included all of the NETs, including the [PNETs]. Patients were randomized to either lutetium dotatate and octreotide or high-dose octreotide alone. These were the patient characteristics that were included: half the patients had PNETs, small bowel; 30% rectum, 5% stomach; and others 7[%].

One of the things that is notable about the study is that it only included patients with a higher Ki-67. The rationale to justify earlier PRRT was really in patients with more aggressive disease, so they were either grade 2, or they could even be grade 3. Grade 3 is a wee bit misleading in NETs because they are all well differentiated, but they can still be called grade 3 if they have a Ki-67 that is greater than 20%, so that's why you're seeing that dichotomy a little bit. But a lot of them had high-grade disease, which kind of explains why a lot of them were PNETs, because PNETs tend to be much more metabolically active.

What were the findings of NETTER-2?

Again, a very nice [HR]…[a] little more than 70% reduction [in the] risk of progression. If you compare [this with] something that doesn't really work that well, which is single unit statin analog, then you're going to look really good, but still, I mean, it's a pretty big difference: median PFS of 23 months vs 8 months. I tell all my PRRT patients, “Hey, if this treatment works, then usually you're good for 2 years.” Pretty high objective response rate, so much different than the NETTER-1 trial, probably because we're taking more metabolically active patients.

Register today to join a Case-Based Roundtable near you.

DISCLOSURES: Kennecke previously disclosed receipt of honoraria from Natera, Tersera, and Novartis; a consulting or advisory role with Tersera; serving on a speakers’ bureau at Natera; and receiving research funding from Taiho Pharmaceutical, Novartis, and Exelixis.

REFERENCES

1. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977. doi:10.1016/S0140-6736(15)00817-X

2. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of ¹⁷⁷Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376(2):125-135. doi:10.1056/NEJMoa1607427

3. Singh S, Halperin D, Myrehaug S, et al. [¹⁷⁷Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024;403(10446):2807-2817. doi:10.1016/S0140-6736(24)00701-3