World Neuroendocrine Cancer Awareness Day: Discussing Important Advances in Care

While patients with gastrointestinal neuroendocrine tumors (GI NETs) remain rare, treatment for this population has moved forward and begun to present a wider array of treatment options for physicians to choose from. In particular, there is hope for immunotherapies to make an impact in this space similar to other disease landscapes.

In an interview with Targeted Oncology, Casey J. Allen, MD, a surgical oncologist at the Allegheny Health Network in Pittsburgh, Pennsylvania, discussed the latest advancements in the field of treatment for patients with GI NETs. He highlighted the strides taken to better identify the disease and new testing techniques physicians should be aware of. Further, Allen speaks to the latest data in this space that is broadening the scope of treatment for these patients. However, challenges remain to meet the unmet needs of this patient population, especially for oncologists in the community setting.

Casey J Allen, MD

Targeted Oncology: How has the neuroendocrine setting changed in the past 5 years?

ALLEN: With regards to the treatment of patients with GI NETs, I think a lot has changed. There are various treatment modalities under investigation, but sequencing and targeted adjuncts are on the forefront.... How we detect and monitor the disease has also made some strides in recent years. The use of the traditional gallium dotatate is likely to be replaced by copper dotatate, which is a new tracer with longer half-life and potentially superior resolution compared with the traditional gallium dotatate imaging modality.¹ This will allow for more routine and readily compared images when compared with the gallium-based scan. In a study comparing the 2 scans, the copper-based dotatate allowed for the detection of more lesions in comparison to the gallium-based dotatate scan, and a phase 3 study confirmed the high accuracy of this modality.² So, that's a nice improvement in how we not only detect but monitor the disease progression in these patients.

With regards to monitoring and tracking, the way we monitor [patients] biochemically is improving as well. We traditionally use chromogranin A to monitor disease response and disease progression, but it can be very non-specific. There's a novel liquid biopsy biomarker called the NET test, which measures 51 different RNA transcripts relevant to NETs using quantitative real-time polymerase chain reactions. It's been recently reported to be much more favorable when compared with chromogranin A for monitoring response to treatment, following both surgery and radionuclide peptide receptor therapy [PRRT].³

What have been some of the most practice changing clinical trials in this space?

There are some landmark trials that anyone treating the disease should be very familiar with.... The PROMID [NCT00171873] and CLARINET [NCT00353496] studies are both phase 3 trials demonstrating the benefits of somatostatin-analogs over placebo in reducing tumor growth in patients with GI NETs....^4,5 This is why we use octreotide [Sandostatin] and lanreotide [Somatuline Depot] for many patients with GI NETs. The NETTER-1 [NCT01578239] phase 3 trial showed the superiority of lutetium-177 (177Lu)–dotatate over high dose somatostatin analogs alone.⁶ RADIANT-4 [NCT01524783] is a phase 3 trial showing the benefit of everolimus and an mTOR inhibitor in the management of patient's NETs.7

There are some additional [studies] comparing the use of everolimus before and after palliative therapy.⁸ The LUTIA trial [NCT03590119] is a trial evaluating intrahepatic arterial infusion of radiolabeled somatostatin analog therapy in patients with NETs. The CABINET trial [NCT03375320] is with cabozantinib [Cabometyx], a novel tyrosine kinase inhibitor, that is ongoing.^9,10 Finally, as immunotherapy is revolutionizing oncology, there are a couple new trials [looking at immunotherapy in this space including] KEYNOTE-158 [NCT02628067] and SWOG S1609 DART [NCT02834013] exploring the potential benefit of immunotherapies in NETs.^11,12

What is the role of targeted therapies and immunotherapies in GI NETs?

There are a lot of specific targeted options and trials ongoing, but I think something new in the setting is that of the potential of immunotherapy just like in any other disease. There are certain therapies being investigated that can potentially improve the [treatment] of patients with NETs. In the intensely developing field of immunotherapy, this includes methods such as tumor infiltrating lymphocytes, T-cell receptors, and chimeric antigen receptors T cells or genetically recombinant T cells designed to recognize specific tumor cells and induce apoptosis. There have been breakthroughs [with these] therapies in other diseases, but their utilization within this space is not known.

Oncolytic viruses produced by genetic engineering are also the future of immunotherapy, and this can potentially have a benefit within this population. This is in addition to other immunotherapy options such as checkpoint inhibition, and other modalities like PD-L1 inhibitors for augmenting the immune system to improve treatment to these types of tumors. I think that's the next forefront in terms of systemic treatment options.

What is your advice for community oncologists treating patients with this disease?

It's still rare disease, so even at a high-volume center it does take frequent reminding of the most recent and best evidence for the practice of [treating patients with] GI NETs. I would say for community oncologists managing patients with this disease, it's important to stay updated with the latest diagnostic and therapeutic advancements through review of the National Comprehensive Cancer Network guidelines.¹³ In question of complex cases, regularly referring to tertiary care, or better access to clinical trials and guidelines can ensure the best evidence-based care. Given the heterogeneity of NETs...a multidisciplinary approach involving the endocrinologist, surgeons, radiologists, and medical oncologists is often beneficial. We have these various therapies now, but we know surgery works in certain contexts…but it's the sequence and the timing [of these treatment methods] that is crucial to understand.

^References

^{1. Shell J, Keutgen XM, Millo C, et al. 68-Gallium DOTATATE scanning in symptomatic patients with negative anatomic imaging but suspected neuroendocrine tumor. Int J Endocr Oncol. 2018;5(1):IJE04. doi:10.2217/ije-2017-0005}

^{2. Johnbeck CB, Knigge U, Loft A, et al. Head-to-Head Comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: A Prospective Study of 59 Patients with Neuroendocrine Tumors. J Nucl Med. 2017;58(3):451-457. doi:10.2967/jnumed.116.180430}

^{3. Malczewska A, Oberg K, Kos-Kudla B. NETest is superior to chromogranin A in neuroendocrine neoplasia: a prospective ENETS CoE analysis. Endocr Connect. 2021;10(1):110-123. doi:10.1530/EC-20-0417}

^{4. Rinke A, Wittenberg M, Schade-Brittinger C, et al; PROMID Study Group. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology. 2017;104(1):26-32. doi:10.1159/000443612}

^{5. Caplin ME, Pavel M, Phan AT, et al; CLARINET Investigators. Lanreotide autogel/depot in advanced enteropancreatic neuroendocrine tumours: final results of the CLARINET open-label extension study. Endocrine. 2021;71(2):502-513. doi:10.1007/s12020-020-02475-2}

^{6. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376:125-135. doi:10.1056/NEJMoa1607427}

^{7. Yao JC, Fazio N, Singh S, et al; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977. doi:10.1016/S0140-6736(15)00817-X}

^{8. Pusceddu S, Verzoni E, Prinzi N, et al. Everolimus treatment for neuroendocrine tumors: latest results and clinical potential. Ther Adv Med Oncol. 2017 Mar;9(3):183-188. doi:10.1177/1758834016683905}

^{9. Ebbers S, Braat A, Moelker A, et al. Intra-arterial versus standard intravenous administration of lutetium-177-DOTA-octreotate in patients with NET liver metastases: study protocol for a multicenter, randomized controlled trial (LUTIA trial). Trials. 2020;141(21). doi:10.1186/s13063-019-3888-0}

^{10. Exelixis announces positive results from phase 3 CABINET pivotal trial evaluating cabozantinib in advanced pancreatic and extra-pancreatic neuroendocrine tumors. News release. Exelixis, Inc. August 24, 2023. Accessed November 10, 2023. https://tinyurl.com/577u7xcs}

^{11. Strosberg J, Mizuno N, Doi T, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Clin Cancer Res. 2020;26(9):2124-2130. doi:10.1158/1078-0432.CCR-19-3014}

^{12. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort. Cancer. 2021;127(17):3194-3201. doi:10.1002/cncr.33591}

^{13. NCCN. Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors, version 1.2023. Accessed November 10, 2023. https://tinyurl.com/38hd3eyv}