<p>The <strong>2026 ASCO Gastrointestinal (GI) Cancers Symposium</strong> spotlighted novel therapeutic approaches for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including the use of PRRT in combination with the radiosensitizer drug fulvestrant. Other promising therapeutic targets and treatment approaches include novel multitargeted TKI therapy and the use of alpha-emitting radioactive isotopes for PRRT.</p> <p><br></p> <p><em>Following these presentations, featured expert Diane L. Reidy-Lagunes, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Reidy-Lagunes on these findings are presented here.</em></p>

Patients with GEP-NETs represent a patient population with tremendous unmet needs. After platinum plus etoposide, we are very limited, and there is really no standard-of-care treatment option in the second line.

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A number of exciting GEP-NET–related studies were presented at the recent 2026 ASCO GI Cancers Symposium, many focusing on combination therapy. A study by Sarah Martin and colleagues presented during a Trials in Progress session (poster TPS649) combined the PRRT ¹⁷⁷Lu-dotatate with fulvestrant in patients with advanced, metastatic, pancreatic NETs (PanNETs). The combination of PRRT with another agent such as fulvestrant is thought to potentially help radiosensitive cancer, an idea that is based on work with ESR1 showing that, by blocking ESR1, you may improve the efficacy of PRRT by limiting the cancer cells’ ability to perform DNA repair.

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Another combination that is currently under investigation is ¹⁷⁷Lu-dotatate with the radiosensitizer triapine in patients with well-differentiated NETs. There is an ongoing phase 2 trial testing this combination.

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Previous studies have demonstrated the efficacy of PRRT in GEP-NETs. More recently, additional data from the phase 3 COMPETE study were presented at the North American Neuroendocrine Tumor Society (NANETS) 2025 Multidisciplinary NET Medical Symposium. This study looked at the PRRT ¹⁷⁷Lu-edotreotide vs everolimus in patients with GEP-NETs and showed that, across all subgroups, patients who received 4 cycles of PRRT experienced a benefit compared with those who received everolimus, irrespective of tumor grade (overall median progression-free survival, 23.9 months vs 14.1 months, respectively). I do not think that many of us are surprised by this, but I do think that these data demonstrated the potential utility of PRRT even earlier than we have traditionally used it.

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The use of PRRT with alpha-emitting radioactive isotopes, which recently moved into the NET space, also shows promise. We believe that using alpha- vs beta-emitting isotopes may result in a higher amount of radiation being delivered directly to the cancer, which hopefully will produce fewer off-target radiation-associated side effects. Early-stage studies have shown activity, but the jury is still out on whether they are more efficacious or if they are equally safe. There are still some side effects that we have to be mindful of (eg, renal toxicities and esophageal dysmotility).

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DLL3 therapies are another emerging targeted therapy for NETs that we are excited about. My group has looked at DLL3 expression in GEP-NETs, including poorly differentiated neuroendocrine carcinomas and well-differentiated NETs. We found that DLL3 was expressed in the vast majority of GEP neuroendocrine carcinomas (71%). DLL3 expression was also reported in high-grade well-differentiated PanNETs, although to a lesser degree (43%).

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Another study from a 2026 ASCO GI Cancers Symposium Trials in Progress session presented by Jennifer A. Chan, MD, MPH (ie, the phase 2/3 STELLAE-311 trial), is investigating the novel multitargeted TKI zanzalintinib vs everolimus in patients with previously treated advanced NETs (poster TPS647). Studies have shown that TKIs (eg, cabozantinib) do play a role in heavily treated patients with PanNETs. So, STELLAE-311 is asking: Can a TKI with multiple targets (ie, MET, VEGFR, AXL, and MER) be as effective while also being less toxic? Zanzalintinib has a shorter half-life than cabozantinib, so it could be a bit easier to tolerate.