Oncology

Gastroenteropancreatic Neuroendocrine Tumors

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Gastroenteropancreatic Neuroendocrine Neoplasms: New Frontiers and Novel Treatment Strategies

conference reporter by Jennifer R. Eads, MD
Overview

New approaches are required to increase the number of safe and effective treatment options for patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Researchers at the North American Neuroendocrine Tumor Society (NANETS) 2024 Multidisciplinary NET Medical Symposium provided information on new treatment strategies and targets for GEP-NENs, ongoing efforts to improve the understanding of their biologies, and the development of better preclinical models to test potential therapies.

 

 

 

Following these presentations, featured expert Jennifer R. Eads, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Eads are presented here.

 

“Historically, research in immunotherapy has not been very active for NENs, especially for well-differentiated NETs. One of the struggles with treating cold tumors is determining how we can make them hot or if there is some element of the immune system that might be capitalized on to make immunotherapy more effective.”
— Jennifer R. Eads, MD

At the NANETS 2024 Multidisciplinary NET Medical Symposium, Mauro Cives, MD, discussed new treatment strategies and targets with a focus on neuroendocrine tumors (NETs), and he also spoke about the emphasis on research in DLL3-targeted agents for high-grade neuroendocrine carcinomas (NECs). The recent US Food and Drug Administration (FDA) accelerated approval of the DLL3-targeted agent tarlatamab for extensive-stage small cell lung cancer is getting people excited about the possibility of these agents being useful for other types of high-grade NECs too, whether that means using an ADC, a bispecific antibody, or another type of agent. Some clinical trials of other DLL3-targeted agents are ongoing. Although fewer data are available with these agents, they seem like they will be a major area of interest in high-grade NECs.

 

Historically, research in immunotherapy has not been very active for NENs, especially for well-differentiated NETs. One of the struggles with treating cold tumors is determining how we can make them hot or if there is some element of the immune system that might be capitalized on to make immunotherapy more effective. Xianxin Hua, MD, PhD, discussed CAR T-cell strategies for NETs during his talk at NANETs 2024. A phase 1/2 trial investigating CAR T-cell therapy in bowel NETs has recently launched, and I am principal investigator of that trial. The CAR T-cell therapy that is being investigated is CHM-2101, which targets CDH17, a cell surface marker that is overexpressed in the intestinal epithelium of bowel NETs. The clinical trial is evaluating CHM-2101 not only in NETs but also in colorectal and gastric cancers. Right now, the trial is in the dose-escalation phase.

 

Jennifer Chan, MD, MPH, gave the “NET Year in Review” presentation at the NANETS 2024 Multidisciplinary NET Medical Symposium, and it included a section on the basic sciences. Historically, we have had a difficult time developing effective models to do laboratory research prior to moving on to people. This is one reason why NETs are so difficult to study. More recently, there has been some success with developing patient-derived organoid models. Hopefully, the development of these organoids means that there will be better models available in the laboratory to test agents before they are tested in humans.

 

There has also been work done to try to better understand NETs at a molecular level, as well as their underlying genetics. We have already gained a better understanding with high-grade NENs in the sense that we now have a distinction between grade 3 well-differentiated NETs and poorly differentiated NECs. However, I think that there is still a lot of gray area there because the classification is based only on Ki-67 proliferation index levels and histology. I think that there is some idea of underlying mutations that are present, particularly for primary pancreatic tumors, but it is still being actively investigated.

 

At NANETS 2024, there was a debate about whether 177Lu-dotatate should be integrated into first-line therapy based on the results of the NETTER-2 trial. I think that a concern with NETTER-2 is whether it is really necessary to give someone radioligand therapy (RLT) right away when you might be able to sustain them on SSA therapy alone for a reasonable amount of time before having to introduce another therapy. We know a lot about the toxicity of RLT, but we do not know about all of it. I am concerned about moving it into earlier and earlier lines of therapy because that allows more time for patients to develop long-term toxicities. NETTER-2 was a positive study and definitely showed improvement with the combination of RLT and SSAs over SSAs alone in terms of progression-free survival. It also had a decent response rate, which is something that we do not always see in neuroendocrine trials. However, RLT does not work fast, and it may take several months for there to be a response. For some patients, we need something that works faster.

 

A main reason to give a therapy beyond SSAs in the frontline setting is when you are treating a patient with symptoms or with a high degree of tumor burden. Generally, the goal in those situations is to try to debulk the tumor, shrinking it to help alleviate the patient’s symptoms. And chemotherapy is likely the fastest way of doing that. For patients with pancreatic NETs, that is probably what will continue to be done. However, chemotherapy does not really work for bowel NETs. Most of the FDA-approved agents for bowel NETs, apart from RLT, have low response rates, which means that they are more tumor stabilizing than tumor shrinking, and they often do not help symptom burden and disease control much. For people who have bowel NETs and need a response, introducing PRRT in addition to SSA therapy is probably where I would see NETTER-2 being most useful. Still, though, the problem with RLT is that it is not fast, and it is a long therapy. However, for bowel NETs, of all the therapies that are available, the addition of PRRT is most likely to give a response and may be better than anything else.

References

Chan J. NET year in review. Session presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

Cives M. Next big thing: top preclinical (or early clinical) projects most likely to change the face of NET therapy in the next decade [session: Future directions: ongoing/upcoming trials]. Session presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

ClinicalTrials.gov. A phase 1/2 study to evaluate CHM-2101, an autologous cadherin 17 chimeric antigen receptor (CAR) T cell therapy. Updated September 19, 2024. Accessed December 12, 2024. https://www.clinicaltrials.gov/study/NCT06055439

 

Feng Z, He X, Zhang X, et al. Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. Nat Cancer. 2022;3(5):581-594. Published correction appears in Nat Cancer. 2024;5(4):691.

 

Hua X. CAR-T [NET session 7: New and upcoming therapeutics/resources]. Session presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

Pegna C. Con for 1st line PRRT [session: The great debate: NETTER-2 – 177Lu-DOTATATE: 1st line or 2nd+ for ki-67 >10%]. Session presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

Reidy-Lagunes D. Pro for 1st line PRRT [session: The great debate: NETTER-2 – 177Lu-DOTATATE: 1st line or 2nd+ for ki-67 >10%]. Session presented at: North American Neuroendocrine Tumor Society 2024 Multidisciplinary NET Medical Symposium; November 21-23, 2024; Chicago, IL.

 

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

 

Strosberg J, Cives M. Is NETTER-2 a practice-changing trial? Nat Rev Clin Oncol. 2024;21(10):705-706. doi:10.1038/s41571-024-00925-8

 

 

 

This information is brought to you by Engage Health Media and is not sponsored, endorsed, or accredited by the North American Neuroendocrine Tumor Society.

Jennifer R. Eads, MD

Professor of Medicine
Physician Lead, GI Clinical Research
Director, National Clinical Trials Network
Director, Penn Neuroendocrine Tumor Program
Division of Hematology and Oncology
University of Pennsylvania, Abramson Cancer Center
Perelman Center for Advanced Medicine
Philadelphia, PA

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