Balancing Efficacy and Tumor Control in Pancreatic NET Therapy Sequencing

Pancreatic neuroendocrine tumors [pNETs] present unique therapeutic challenges, with a broader range of systemic treatment options compared with other NET subtypes. As patients progress through multiple lines of therapy, selecting the optimal sequence becomes increasingly complex.

During a Case-Based Roundtable event, Shagufta Shaheen, MD, discussed treatment strategies for pancreatic NETs, with a focus on later-line therapy selection and how clinical trial data guide decision-making.

This is part 2 of 2 from this event. Read part 1. 

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Targeted Oncology: How do treatment strategies differ in pancreatic NETs?

Shagufta Shaheen, MD: Pancreatic NETs offer more options, including targeted therapies and chemotherapy. After progression on somatostatin analogs and PRRT, treatment decisions become even more individualized.

What data support everolimus and sunitinib in pancreatic NETs?

The phase 3 RADIANT-3 trial [NCT00510068] demonstrated improved PFS with everolimus compared with placebo [11.0 vs 4.6 months; HR, 0.35; P < .001].⁴

Sunitinib has also demonstrated PFS benefit in this population, although both agents are associated with relatively low objective response rates.

When should chemotherapy be considered?

Chemotherapy, particularly capecitabine plus temozolomide [CAPTEM], plays an important role in pancreatic NETs, especially when tumor shrinkage is needed.

This regimen has demonstrated response rates of approximately 40% and improved PFS compared with temozolomide alone [23 vs 15 months].⁵ For patients with bulky or symptomatic disease, CAPTEM may be preferred due to its higher likelihood of inducing tumor regression.

What role does cabozantinib (Cabometyx) play in later-line pNETs?

Cabozantinib has shown promising activity in heavily pretreated pNETs, with response rates approaching 19% in clinical trials.³

This level of activity is notable in later-line settings, where many therapies primarily provide disease stabilization rather than tumor shrinkage.

How do you approach sequencing in later lines of therapy?

Sequencing is highly individualized and depends on several factors, including prior treatments, tumor growth rate, and symptom burden.

In general, PRRT is often used earlier due to its efficacy and tolerability, targeted therapies are used for disease stabilization, and chemotherapy is prioritized when tumor shrinkage is required. Cabozantinib is increasingly used in later lines due to its activity across multiple NET subtypes.

How do safety considerations influence treatment decisions?

Each therapy carries distinct toxicities that must be considered when selecting treatment. Everolimus is associated with metabolic and pulmonary toxicities, while cabozantinib is linked to cardiovascular and gastrointestinal toxicities. CAPTEM commonly causes hematologic toxicity and nausea. Balancing efficacy with tolerability is critical, particularly in patients receiving multiple lines of therapy.

What are the key takeaways for clinicians?

The treatment landscape for pNETs continues to expand, offering multiple effective options across lines of therapy. Targeted therapies provide disease control, while chemotherapy offers higher response rates when tumor reduction is necessary.

As more therapies become available, sequencing decisions will continue to evolve and should remain tailored to individual patient needs.

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

REFERENCES

1. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, nonfunctional neuroendocrine tumors of the lung or gastrointestinal tract (RADIANT-4): a randomized, 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. 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.

4. 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

5. 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