Reviewing Progress in Systemic Therapy for Pancreatic NETs

Treatment options for pancreatic neuroendocrine tumors (PNETs) have expanded considerably based on data from pivotal trials such as RADIANT-3 (NCT00510068),¹ Study A6181111 (NCT00428597),² ECOG-ACRIN E2211 (NCT01824875),³ and CABINET (NCT03375320).⁴ During a live Case-Based Roundtable event in Vancouver, Washington, Hagen Kennecke, MD, medical oncologist at Oregon Health & Science University (OHSU), discussed evidence from these 4 trials, highlighting their clinical implications for treatment selection and sequencing in PNETs.

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Targeted Oncology: What were the background and key efficacy/safety findings of the RADIANT-3 trial? We talked about RADIANT-4 [previously]. RADIANT-3 was just PNETs, similar pre-[peptide receptor radionuclide therapy; PRRT] era. James Yao, MD, did this trial as well [in] 2011. [The trial] was patient-randomized, everolimus [Afinitor] vs placebo. [Patients] all had PNETs. And almost all PNETs have liver metastases.

The disease benefit [for median progression-free survival (PFS) was] 11 months vs approximately 5 [months].¹ The hazard ratio [was] 0.35, so a 65% reduction in risk of progression, and similar to the small bowel population, not a huge response rate, but predominant benefit is in stable disease. By disease subgroups, regardless of prior therapy and tumor grade, they all seem to respond, so really nothing that exciting here; there’s consistent benefit. In terms of the adverse events [AEs], again, [everolimus is a] fairly common agent that we’re familiar with.

What were the background and key efficacy/safety findings of Study A6181111?

I feel like many of us…remember when sunitinib [Sutent] was the new kid on the block and we tried it in every single cancer we could think of, including PNETs. This was the big study published in 2017 but presented much, much earlier. [The trial evaluated] sunitinib vs placebo in patients with PNETs [who were] heavily pretreated.

We had a significant improvement in [PFS]….² This is the one where we generally see that the investigators are more pessimistic than the central reviewers, and it speaks to how poor our measurement is of NETs and disease, but…overall, the benefits were similar, regardless of whether it’s central- or investigator[-reviewed]. In terms of the response rates, not super high, but 7%, [in] striking distance of what we saw for everolimus. Again, we had pretty consistent benefit. PNETs are even less likely than non-PNETs to be secretory. Those are the insulinomas and glucagonomas and VIPomas. And when you have them, it’s terrible because you can’t manage all those sites. It’s just terrible. You just have to debulk them, debulk the liver metastases, because medical therapy usually doesn’t work….

We’re quite familiar with the AE profile [of sunitinib]. It’s…maybe a little bit easier tolerated. This was the dose of 37.5 mg, the one we’re familiar with. That was [the trial of] sunitinib, which is why it’s on the NCCN [guidelines].

What was the background and design of ECOG-ACRIN E2211?

This is Pamela Kunz, MD’s ECOG trial. There’s a good story to [capecitabine and temozolomide; cap-tem]. Temozolomide is an alkylator, and it’s kind of the oral version of streptozotocin, but much easier to give. From single-arm experiences, there were a lot of…strong signals that it’s a good drug for PNETs. And then the question was, should we add capecitabine? Because there was some evidence that 2 [drugs] are better than 1. The trial [involved] patients with PNETs… If they don’t have a PNET, you probably shouldn’t be giving chemotherapy. [Patients] are treated with temozolomide vs cap-tem, and [the patient characteristics show] a fairly typical profile of patients [with PNETs]. [Investigators] did some interesting work on MGMT methylation, which didn’t quite pan out.

What were the key efficacy/safety findings of ECOG-ACRIN E2211?

Overall, I think we did see a difference which was not quite reached in significance.³ There was an improvement in having the doublet, but it just barely missed the statistical significance. But there [are] a few things that are worth noting. First of all, the median PFS is quite long, like 15 months [for temozolomide] and cap-tem 23 [months], and then the response rates are pretty high, 20% vs 26%. So, one of the things that we took from this is, [PNETs] tend to respond to chemotherapy better, and cap-tem seems to work for quite some time.

[For] response by grade…regardless of grade, you had a good response, and it was a little bit better if you used 2 drugs or 1. I think it’s an interesting study, because sometimes when I have a patient and I can’t give them capecitabine, and it’s a PNET, I’ll still give them single-agent temozolomide. And I think this study justifies it, so that’s an idea, too.

We’re pretty familiar with the [AEs] overall. It’s a bit clunky because it’s…a 14-day capecitabine regimen, but it’s a reduced dose; I think it’s 750 mg/m². And then the last 5 days, so [days] 10 to 14, is temozolomide at the 250-mg dose. So there’s a lot of patient education [involved]. I think we have, at OHSU…a…regimen for it; it has lanreotide [Somatuline Depot] attached to it, but you can just nix that one out. And so...the patient [has] to know what they’re doing. But if you have a bulky PNET, it’s a relevant treatment to consider, in my opinion.

What were the background and key efficacy and safety findings of the CABINET trial?

This is the CABINET trial [of] cabozantinib [Cabometyx], and this is the PNET portion of it… There was a smaller cohort, and…a minority were functional; it’s only 15%. [In terms of the] benefit curve, there was a significant improvement in PFS, which was the primary end point—13 months [with cabozantinib] vs 4 [months with placebo]. The response rates were [19% vs 0%, respectively]. It’s a decent response rate that you get with cabozantinib in PNETs, even in this very advanced, previously treated population, and that was published [in 2025].⁴

In terms of subgroups of PNETs, pretty much all of them benefited, regardless of grade, which is important to know.⁵ Again, [they were a] heavily pretreated cohort; many of them had [prior] everolimus and PRRT. In terms of the [AEs], we have the usual transaminases, fatigue, [and] hematologic toxicity.

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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, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523. doi:10.1056/NEJMoa1009290

2. Faivre S, Niccoli P, Castellano D, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017;28(2):339-343. doi:10.1093/annonc/mdw561

3. Kunz PL, Graham NT, Catalano PJ, et al. Randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol. 2023;41(7):1359-1369. doi:10.1200/JCO.22.01013

4. Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med. 2025;392(7):653-665. doi:10.1056/NEJMoa2403991

5. Strosberg, J. Efficacy and safety of cabozantinib (CABO) for advanced Grade 3 (G3) neuroendocrine tumours (NETs) after progression on prior therapy: Subgroup analysis of the phase III CABINET trial (Alliance A021602). Presented at: 2025 European Neuroendocrine Tumor Society Conference; March 5–7, 2025; Kraków, Poland. Abstract 4518.