Dr Reidy-Lagunes on the Evolving NET Treatment Paradigm

“[The year 2024] has been exciting in that we had 2 important studies that were reported that help us add to the therapies we have to offer to our patients with advanced NETs.”

Diane Reidy-Lagunes, MD, vice chair, Oncology Operations, Regional Care Network, Memorial Sloan Kettering Cancer Center, discusses key trials that have expanded the treatment paradigm for patients with neuroendocrine tumors (NETs).

The 2024 release of data from 2 pivotal phase 3 clinical trials, CABINET (NCT03375320) and NETTER-2 (NCT03972488), marked significant advancements in the management of advanced NETs, Reidy-Lagunes begins. These studies provided evidence supporting valuable additions to the treatment paradigm for this heterogeneous patient population, which includes patients with both indolent and aggressive forms of disease, she says.

The CABINET trial evaluated cabozantinib (Cabometyx), an oral TKI, in heavily pretreated patients with pancreatic and extrapancreatic NETs. Patients were randomly assigned in a 2:1 fashion to receive cabozantinib or placebo. Improved progression-free survival (PFS) outcomes were observed with cabozantinib in both the pancreatic and extrapancreatic patient cohorts, highlighting the efficacy of this agent following prior treatment with somatostatin analogs, everolimus, and other prior therapies, Reidy-Lagunes notes. In the extrapancreatic NET cohort, the median PFS was 8.4 months (95% CI, 7.6-12.7) with cabozantinib (n = 134) vs 3.9 months (95% CI, 3.0-5.7) with placebo (n = 69; HR, 0.38; 95% CI, 0.25-0.59; 

 < .001). In the pancreatic NET cohort, the median PFS was 13.8 months (95% CI, 9.2-18.5) with cabozantinib (n = 64) vs 4.4 months (95% CI, 3.0-5.9) with placebo (n = 31; HR, 0.23; 95% CI, 0.12-0.42; 

 < .001). This trial established cabozantinib as a promising therapy for patients with limited treatment options, she emphasizes.

The NETTER-2 trial investigated lutetium Lu 177 dotatate (Lutathera) in combination with octreotide in patients with intermediate- to high-grade gastroenteropancreatic NETs with a Ki-67 proliferation of up to 55%. The study compared this combination with high-dose octreotide monotherapy. Results revealed a median PFS of 22.8 months (95% CI, 19.4-not estimated) in the lutetium Lu 177 dotatate arm (n = 226), along with an overall response rate of 43.0% (95% CI, 35.0%-51.3%).

Both CABINET and NETTER-2 provide the basis for the growing treatment arsenal for advanced NETs, Reidy-Lagunes concludes.

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Diane Reidy-Lagunes, MD, discusses key trials that have expanded the treatment paradigm for patients with neuroendocrine tumors.

Diane Reidy Lagunes, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the necessity of tailored approaches in the treatment of patients with neuroendocrine tumors (NETs).

The disease itself is extremely heterogeneous, and physicians are trying to define a more personalized approach for each patient. Currently, physicians don’t have the data to sequence treatments to know which should go first, second, third, or fourth.

However, physicians are hoping to use new technology for genetic sequencing, biomarkers, and other important correlatives. If physicians are able to define patients genetically, they can better understand each patient’s disease and prognosis and ultimately tailor therapies for each patient.

One such example would be defining which patients would do better with peptide receptor radionuclide therapy earlier versus later. Although there are indications that patients with smaller burden of disease would do better, there is a lot of selection bias in that, Reidy Lagunes says.

Dr. Lagunes on the Importance of Developing More Personalized Treatments in NETs

Diane Reidy Lagunes, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses ongoing clinical trials and recent approvals that will shape the standard of care in the treatment of patients with neuroendocrine tumors (NETs).

An ongoing clinical trial is looking at the use of chemotherapy, specifically the combination of temozolomide (Temodar) plus capecitabine (Xeloda). The trial had a very high response rate of 70%, and though not randomized, questioned whether temozolomide is effective as a single agent, or whether it has to be combined with capecitabine.

The recent FDA approval of peptide receptor radionuclide therapy (PRRT) based on the phase III NETTER-1 trial which compared Lutathera (lutetium Lu 177 dotate) with high-dose octreotide LAR for patients with grade 1 or 2 metastatic midgut NETs will jumpstart an enormous number of treatments. The approval comes in the wake of ongoing studies looking at the combinations of cytotoxic drugs with PRRT which may segue into combinations of PRRT with immunotherapy.

Dr. Lagunes on Potential Combinations in the Treatment of Patients With NETs

Diane Reidy-Lagunes, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the FDA approval of telotristat ethyl (Xermelo) as a treatment for carcinoid syndrome in patients with metastatic neuroendocrine tumors (NETs).

Dr. Reidy-Lagunes on FDA Approval of Telotristat Ethyl for Carcinoid Syndrome

Diane Reidy-Lagunes, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses sequencing various treatments for patients with neuroendocrine tumors (NETs).

There are currently no trials aimed at determining optimal sequence of therapies, Reidy-Lagunes explains. To stay parallel with NCCN guidelines, she often chooses somatostatin analogs as a first-line treatment for patients. This is because this type of therapy is said to be well-tolerated with a significant disease-control rate.

An additional option includes everolimus (Afinitor) for patients with pancreatic, lung, and gastrointestinal NETs as a second-line therapy. For pancreatic NETs specifically, sunitinib (Sutent) and cytotoxic therapies are also available. Peptide receptor radionuclide therapy is a potential treatment for patients with midgut NETs, though researchers are unsure where that would fit in the treatment course, Reidy-Lagunes says.

Dr. Reidy-Lagunes on Sequencing Therapies for Patients With NETs

Diane Reidy Lagunes, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the potential of immunotherapy agents in the treatment of patients with neuroendocrine carcinoma.

High mutational burdens exist in high-grade neuroendocrine carcinoma, non—small cell lung cancer (NSCLC), and melanoma, Reidy Lagunes explains. Therefore, since there are high response rates with immunotherapy in patients with NSCLC and melanoma, researchers hypothesize that such agents could demonstrate activity in the former tumor type, as well.

Interferon is one of the earliest and most common immunotherapy agents available, Lagunes says. However, though the agent shows promise, interferon is associated with flu-like symptoms, suggesting that other immunotherapies should be studied in this space.

Dr. Reidy Lagunes on the Potential of Immunotherapy in NETs

Diane Reidy-Lagunes, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses an analysis looking at a practical method of determining the site of unknown primary in metastatic neuroendocrine tumors (NETs). This was presented by Jessica E. Maxwell, MD, MBA, from the University of Iowa, at a clinical science symposium at the 2014 NANETS Symposium.

Approximately 20% of patients with NETs have an unknown primary. In this analysis, an algorithm involving gene and protein expression was created from over 100 metastases from known small bowl and pancreatic primaries. With over 90% accuracy, researchers were able to evaluate immunohistochemistry, define small bowel or pancreatic NETs by pathology, and confirm it with genetic testing.

This method has not yet been validated with unknown primaries.

Diane Reidy-Lagunes, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses an analysis looking at a practical method of determining the site of unknown primary in metastatic neuroendocrine tumors (NETs).

Diane Reidy Lagunes, MD

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