Advanced Extrapancreatic NETs: Sequencing Treatment Strategies

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies with an expanding number of systemic treatment options, particularly in the advanced and metastatic setting. As more therapies become available, determining optimal sequencing strategies has become increasingly complex.

During a live Case-Based Roundtable event, Shagufta Shaheen, MD, a gastrointestinal medical oncologist at Stanford University, discussed the rationale behind selecting and sequencing therapies for patients with advanced NETs. The discussion focused on real-world decision-making following progression on somatostatin analogs and how clinical trial data inform treatment selection.

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Targeted Oncology: What is your clinical impression of everolimus in the second-line setting for small bowel NETs?

Shagufta Shaheen, MD: What we saw here, as we see for our target agents, in small bowel NETs, the response [rates] are very, very low…only 2%, but the median progression-free survival [PFS] was significant as compared to placebo.¹ The majority of the disease was stable, and the response is very low, but it was the PFS benefit. We all are aware of the everolimus toxicities. I think we know the stomatitis and, although pneumonitis is rare, that's something we always keep in mind, and then diarrhea and risk of infection.

How Did the NETTER-1 trial (NCT01578239) establish 177Lu-dotatate (Lutathera) as a standard-of-care option?

NETTER-1 enrolled 229 patients with progressive, inoperable, locally advanced or metastatic midgut NETs who were randomized to 177Lu-dotatate plus best supportive care [n = 116] or high-dose octreotide LAR [n = 113].² Most patients had ileal primaries. The ORR was 18% for 177Lu-dotatate vs 3% for octreotide LAR. Median PFS was not reached vs 8.4 months (HR, 0.21; 95% CI, 0.13-0.33; P < .001]. Final median OS was 48.0 vs 36.3 months. Treatment-related adverse events [TRAEs] included nausea [59%], fatigue/asthenia [40%], and thrombocytopenia 25%. A 1%-3% myelodysplastic syndrome risk has been noted.]

How do you view the NETTER-1 efficacy results in the context of treating GI NETs today?

This study showed a response rate of 18%, which was at that time very impressive. I don't think we have any target agent that has a response rate of 18% in midgut tumors. With pancreatic tumors, you always will have better response rates, but for midgut, that's pretty phenomenal. If you look at the final [median] PFS, it was about 26 months, which is pretty impressive. The [median] overall survival was about a year more than the control arm. It wasn't statistically significant, but this study had about 33% crossover. So, keeping that in mind, there was clinical benefit, but not statistically significant overall survival benefit.

What does NETTER-2 (NCT03972488) show  about peptide receptor radionuclide therapy (PRRT) vs everolimus?

NETTER-2 enrolled 226 patients with locally advanced or metastatic, well-differentiated gastroenteropancreatic NETs and Ki-67 >=10%, randomized 2:1 to 177Lu-dotatate plus octreotide LAR or high-dose octreotide LAR alone.³ Approximately 16% had received prior somatostatin analog [SSA] therapy. The ORR was 43% vs 9.3%, and median PFS was 22.8 vs 8.5 months [HR, 0.276; P < .0001]. Benefit was consistent across grade 2 [HR, 0.31] and grade 3 (HR, 0.27) subgroups.

What are the key sequencing takeaways from NETTER-2, especially relative to everolimus?

What we know now is PFS is better, lutetium is better than everolimus. We saw better PFS in the lutetium arm as compared to everolimus, in both first and second line. A lot of this benefit is driven by grade 2 as compared to grade 1. Perhaps patients with grade 1 disease may not need PRRT right away, but that's kind of a debate. But overall, they still had better PFS as compared to everolimus.

In the everolimus arm, around 15% actually discontinued because of TRAEs, and about 50% had dose reduction—as compared to lutetium, which seemed much better tolerated. One other thing I wanted to highlight: in NETTER-1, we dosed patients every 8 weeks. In NETTER-2, it was every 3 months, so maybe we don't need to dose them every 2 months. That was one good observation here.

What did CABINET (NCT03375320) show for cabozantinib (Cabometyx) in extrapancreatic NETs?

In the CABINET trial's extrapancreatic NET cohort, 203 patients were randomly assigned 2:1 to cabozantinib 60 mg daily [n = 134] or placebo [n = 69].⁴ Patients were heavily pretreated, with a median of 2 prior systemic therapies excluding SSAs. The ORR was 5% versus 0%, and median PFS was 8.4 vs 3.9 months [HR, 0.38; 95% CI, 0.25-0.59; P < .001] Benefit was observed across gastrointestinal [HR, 0.47] and lung/thymus [HR, 0.17] subgroups, and across all tumor grades. Grade 3 to 5 TRAEs included hypertension [21%], fatigue [13%], and diarrhea [11%].

Where does cabozantinib fit in the treatment sequence after CABINET, and how does it compare with everolimus?

The patients were pretty refractory…in the extrapancreatic cohort, patients had, on average, received two prior lines excluding somatostatin analogs. So they were pretty heavily treated, either [having] received everolimus or received PRRT or perhaps chemotherapy. Perhaps the PFS benefit was driven a lot by lung and thymus, but we did see a lot of stable disease overall. They also broke it down by grade, and all grades had benefit…If you need response, I think either [everolimus or cabozantinib] will be the same, but there will be better PFS with cabozantinib. And the other thing with cabozantinib is it showed benefit in both functional and nonfunctional small bowel NETs as compared to everolimus. So if you have a patient with carcinoid syndrome, I wouldn't use everolimus, I would use cabozantinib.

What factors influence your choice between PRRT and targeted therapy after SSA progression?

I would still favor lutetium for many reasons. I think PRRT is much better tolerated and is better for patient quality of life: you dose them every 2 months, and now we have data for every 3 months, vs cabozantinib, where they have to take a pill every day. But I still feel like if you need response, and people have low-volume disease, you may give them a little bit of mileage with cabozantinib…[for a] very selective patient. But for the majority of the patients, I think PRRT is sequenced earlier than the TKIs.

What safety considerations most influence your choice between agents?

Sometimes the patient's performance status and their underlying comorbidities will drive your decision. If someone has poorly controlled diabetes, probably everolimus is not a better choice for them. If they have poorly controlled hypertension, would we use cabozantinib? Starting a little bit lower dose or doing dose reduction early on is probably a little more gentle for the patients.

_{DISCLOSURES: Shaheen previously reported advisory and/or consulting roles with Novartis, Ipsen, and Exelixis, and has received research funding from industry sponsors.}

REFERENCES

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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

4. Chan JA, Kulke MH, Fuchs CS, et al. Cabozantinib in advanced neuroendocrine tumors (CABINET): a randomized, placebo-controlled, phase 3 trial. N EnglJ Med . 2025;392(7):653-665.

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6. Kunz PL, Catalano PJ, Nimeiri H, et al. A randomized study of temozolomide versus temozolomide plus capecitabine in patients with advanced pancreatic neuroendocrine tumors (E2211). J Clin Oncol. 2018;36(15_suppl):4004. doi:10.1200/JCO.2018.36.15_suppl.4004