From precision radiotherapeutics to small molecule inhibitors, Scott Paulson, MD, discusses a new array of pharmacological treatments for World Neuroendocrine Cancer Day.
Scott Paulson, MD, is the codirector of the Gastrointestinal Research Program for The US Oncology Network and medical director for the Neuroendocrine Research and Treatment Center at Texas Oncology-Baylor Charles A. Sammons Cancer Center.
Over the past 5 years, the treatment landscape for neuroendocrine cancer has undergone a significant transformation. In this field, as in many others, the COVID-19 pandemic has slowed the pace of change over the last 2 years, yet an evolution is still underway. From interventional radiology and nuclear medicine imaging to burgeoning drug therapies and new surgical techniques, numerous advances are transforming the neuroendocrine cancer treatment journey.
Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise mainly in the gastroenteropancreatic tract and lungs, and that are characterized by an overexpression of somatostatin receptors (SSTRs) on the cell membrane.1 Once considered rare, these tumors have increased in incidence and prevalence over the past few decades, partly due to early-stage tumor detection and longer survival from improved therapies.2
Advances in nuclear medicine imaging—in particular, the use of Gallium-68 (68Ga) and Copper-64 (64Cu) DOTATATE PET/CT—have changed the practice of neuroendocrine cancer treatment dramatically across the United States in recent years.3,4 Such imaging is playing an increasingly larger role in diagnosis, follow-up, and treatment planning for NETs, and has replaced SPECT-based tracers as a staging method in studies given improved accuracy and an ability to offer whole tumor biomarker profiling, which can be used for personalized therapeutic selections.5
The Rise in Targeted Radiopharmaceuticals
From a medical oncologist perspective, new pharmacological treatments for neuroendocrine cancers have seen expansive growth in the past 5 years. As little as a decade ago, pharmaceutical treatment relied on 1 class of medications, somatostatin analogs, used to manage the symptoms of excessive hormone secretion and control tumor growth.6 Somatostatin analogs remain a first-line treatment for gastroenteropancreatic NETs (GEP-NETs) that cannot be removed with surgery. However, we are now seeing a number of new approvals of targeted drug therapies for neuroendocrine cancers—most notably, radiopharmaceuticals known as peptide receptor radionuclide therapy (PRRT), a type of radiotherapy that targets peptide receptors to deliver localized treatment.7
Initially offered only in major neuroendocrine centers, PRRT is now increasingly available as a treatment option in community-based oncology practices, where it is becoming a reality for most patients closer to home. Among the most practice-changing PRRT therapies on the market today, Lutathera (lutetium Lu 177 dotatate) received FDA approval in January 2018 for the treatment of patients with somatostatin receptor-positive GEP-NET who do not respond to treatment with somatostatin analog hormone therapy; approval was based on data from the randomized, phase 3 NETTER-1 trial.8 Using Lutathera is a biomarker-driven strategy pursued in patients that clearly express somatostatin receptors, as evidenced with nuclear medicine PET imaging.
Looking to the future, other targeted radiotherapies are under investigation, including alpha emitters such as 212Pb-DOTAMTATE, which have shown promising results in early clinical studies.9
Small Molecule Inhibitors Under Development
NET diagnosis generally falls into 2 categories: low-grade and high-grade NETs. Low-grade NETs tend to be a more genetically homogeneous group, so our understanding of molecular, personalized targets beyond the somatostatin receptor are fairly limited. Therapies that have found activity in this space include VEGF-directed therapies, such as sunitinib (Sutent) for PNET, and mTOR inhibitors, such as everolimus.
Surufatinib is a new VEGF inhibitor therapy, or antiangiogenic agent, under investigation in patients with GEP-NETs. An oral, small-molecule tyrosine kinase inhibitor, surufatinib was approved by China’s National Medical Products Administration for the treatment of patients with pancreatic and extra-pancreatic neuroendocrine tumors based on data from the phase 3 SANET-p and SANET-ep clinical trials.10,11 Surufatinib has shown results that are promising in the Chinese population and has re-demonstrated efficacy in an American population. The implications could be practice changing for all types of neuroendocrine cancers, including cancers of the lung, pancreas, and gastrointestinal tract.
Ongoing studies are investigating combinations of drugs such as surufatinib and additional small molecule inhibitors, such as lenvatinib (Lenvima), axitinib (Inlyta), cabozantinib (Cabometyx), and pazopanib (Votrient), which have shown efficacy in phase 2 clinical trials.9 The data for lenvatinib in pancreatic NETs is compelling, showing a response rate that is markedly higher than what we tend to see in pancreatic NETs.12 While the data on these therapies looks promising, further studies will be needed to merit FDA approval.
A Cautious Approach With an Eye to the Future
Among the targeted, personalized therapies for GEP-NETs, the radiopharmaceuticals or PRRT therapies arguably represent the most momentous change in the field of neuroendocrine cancer treatment. However, these promising therapies do carry significant potential adverse events; while rare, the risks of secondary myelodysplasias and leukemias mean that providers will want to reserve these treatments only for patients who have truly progressive disease or a high symptom burden. Notably, many patients with NETs do extremely well with minimal treatments for years or even decades. Further study is needed to investigate the timing, combination, and sequencing of PRRT therapies to treat patients in the safest and most effective manner possible.
Additional drugs, including small molecule inhibitors, are in development alongside radiopharmaceuticals, and all of these therapies can be integrated into the treatment of neuroendocrine cancers. As we await future studies to provide more data and further insight on treatment protocols, medical oncologists can look forward to having more pharmacological tools available and a widening array of options to treat patients with NETs.
1. Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia. 2017;19(12):991-1002. doi:10.1016/j.neo.2017.09.002
2. Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342. doi:10.1001/jamaoncol.2017.0589
3. Sanli Y, Garg I, Kandathil A, et al. Neuroendocrine tumor diagnosis and management: 68Ga-DOTATATE PET/CT. Am J Roentgenol. 2018;211(2):267-277. doi:10.2214/AJR.18.19881
4. Delpassand ES, Ranganathan D, Wagh N, et al. 64Cu-DOTATATE PET/CT for Imaging Patients with Known or Suspected Somatostatin Receptor-Positive Neuroendocrine Tumors: Results of the First U.S. Prospective, Reader-Masked Clinical Trial. J Nucl Med. 2020;61(6):890-896. doi:10.2967/jnumed.119.236091
5. Delpassand ES, Ranganathan D, Wagh N, et al. 64Cu-DOTATATE PET/CT for imaging patients with known or suspected somatostatin receptor-positive neuroendocrine tumors: results of the first U.S. prospective, reader-masked clinical trial. J Nucl Med. 2020;61(6):890-896. doi:10.2967/jnumed.119.236091
6. Stueven AK, Kayser A, Wetz C, et al. Somatostatin analogues in the treatment of neuroendocrine tumors: past, present and future. Int J Mol Sci. 2019;20(12):3049. doi:10.3390/ijms20123049
7. Starr JS, Sonbol MB, Hobday TJ, Sharma A, Kendi AT, Halfdanarson TR. Peptide receptor radionuclide therapy for the treatment of pancreatic neuroendocrine tumors: recent insights. Onco Targets Ther. 2020;13:3545-3555. doi:10.2147/OTT.S202867
8. Das S, Al-Toubah T, El-Haddad G, Strosberg J. 177Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2019;13(11):1023-1031. doi:10.1080/17474124.2019.1685381
9. Cives M, Pelle' E, Strosberg J. Emerging treatment options for gastroenteropancreatic neuroendocrine tumors. J Clin Med. 2020;9(11):3655. doi:10.3390/jcm9113655
10. Xu J, Shen L, Bai C, et al. 1156O Surufatinib (s) for patients (pts) with advanced pancreatic neuroendocrine tumours (SANET-p): a randomized, double-blind, placebo (p)-controlled phase III trial (NCT02589821). Ann Oncol. 2021;31(suppl 4):S770. doi:10.1016/j.annonc.2020.08.1369
11. Xu J, Shen L, Zhou Z, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(111):1500-1512. doi:10.1016/S1470-2045(20)30496-4
12. Capdevila J, Fazio N, Lopez C, et al. Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the phase II TALENT trial (GETNE1509). J Clin Oncol. 2021;39(20):2304-2312. doi:10.1200/JCO.20.03368