World Neuroendocrine Cancer Awareness Day: Therapeutic Options for Well-differentiated NETs

Partners | <b>Cancer Treatment Centers of America</b>

Ajaz M. Khan, MD, MBA, CPE, a medical oncologist and chair of the CTCA Department of Medical Oncology, explores available treatments for patients with well-differentiated neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare neoplasms that account for about 0.5% of all newly diagnosed malignancies and comprise a heterogeneous tumor type with a prevalence of less than 200,000 in the United States.1 The most common primary sites are the gastrointestinal tract, in 62% to 67%, and lungs in 22% to 27%, and approximately 12% to 22% of patients are metastatic at presentation. The tumors are divided into 2 groups based on clinical behavior, histological profile, Ki-67, and proliferation rate: well-differentiated (low grade to intermediate grade with Ki-67 being <2% or 2%-20%) and poorly differentiated (high grade or Ki-67 of >20%)NETs.

Despite their rarity, these tumors have increased in incidence over the past few decades, due to early detection with increased availability of imaging and longer survival from improved therapies.2 The following treatments are choices available for patients with well-differentiated NETs.

Surgical and Hepatic-Directed Approaches

The backbone of curative treatment has been surgery, yet most NETs are diagnosed after metastases have developed, requiring chronic medical management to relieve symptoms and suppress tumor growth.1 To reduce tumor burden or help control hormone production, surgery such as complete metastasectomy may be indicated for palliative debulking.

For patients NETs who have hepatic disease, which is about 40% to 90% of patients with NETs upon presentation, treatment with yttrium-90 (Y-90) is also an option.3 These patients have the potential to respond to Y-90 therapy as selective internal radiotherapy, transarterial chemoembolization, transarterial embolization, or ablative therapy.1 A retrospective study in Canada showed a 53% partial response rate, and median overall survival of 27.2 months for 49 paitents.3

Targeted Radiopharmaceuticals

Most NETs express somatostatin receptors, visualizable with diagnostic gallium or indium somatostatin PET tracers, which have become a vital part of diagnostic imaging along with cross-sectional CT imaging and MRI.1 Somatostatin analogue (SSA) therapy, a foundation of antisecretory therapy in functioning NETs, provides both symptomatic management and antiproliferative effects.4

The PROMID trial (NCT00171873) of octreotide LAR in patients with metastatic midgut NETs and the CLARINET trial (NCT00353496) of lanreotide antiproliferative response in metastatic enteropancreatic NETs were both placebo-controlled, randomized phase 3 studies. These investigators demonstrated statistically significant prolongation of time to progression (TTP) and progression-free survival (PFS) with SSA treatment compared with placebo. In PROMID, the TTP was 14.3 months for octreotide LAR and 6.0 months with placebo (HR, 0.34; 95% CI, 0.20-0.59; P = .000072).5 Patients in the CLARINET study had not reached a median PFS in the lanreotide arm versus 18.0 months with placebo (HR, 0.47; 95% CI, 0.30-0.73; P < .001).6

The attraction for the same receptor binding with radioactive isotopes such as Y-90 or lutetium-177 (177Lu) for treatment purposes is referred to as peptide receptor radionuclide therapy (PRRT).4 The phase 3 NETTER-1 study (NCT01578239) of 177Lu-DOTATATE (Lutathera) plus octreotide LAR versus octreotide LAR alone was investigated in patients with inoperable, progressive, somatostatin receptor–positive midgut NET who did not respond to treatment with SSAs.7 The median OS was 48.0 months in the 177Lu-DOTATATE arm and 36.3 months in the control arm (HR, 0.84; 95% CI, 0.60-1.17; P = .30). Two out of the 111 patients receiving 177Lu-DOTATATE developed myelodysplastic syndrome, which suggests a cautious approach is needed when addressing patient selection. The trial resulted in a therapeutic landscape shift with the β-particle emitter 177Lu-DOTATATE now considered the standard of care for patients with NET progressing on SSAs.8

Although 177Lu-DOTATATE has a survival advantage, room remains for efficacy and safety improvements. One path is targeted α-emitter therapy with isotopes such as 212Pb (AlphaMedix). A recent phase 1 trial (NCT03466216) involving 20 patients with histologically confirmed NETs, prior positive SSA scans, and no prior history of PRRT, 177Lu, or Y-90 therapy received 4 cycles of 212Pb-DOTAMTATE administered at 8-week intervals.9 This trial demonstrated promising preliminary results with a radiologic objective response rate (ORR) of 80% without serious treatment-emergent adverse events. A phase 2 trial (NCT05153772) is planned to further assess the therapeutic benefit and safety of the therapy.

Small Molecule–Targeted Drugs

NET cells overexpress a wide range of proangiogenic molecules and receptors, which has heightened the interest in pursuing antiangiogenic strategies.10 The range of treatment strategies include mammalian target of rapamycin inhibitors such as everolimus (Afinitor) and multikinase inhibitors (MKIs). In the phase 3 RADIANT-3 trial (NCT00510068) in patients with advanced, pancreatic NETs, everolimus was compared with placebo and revealed a median PFS of 11.0 months versus 4.6 months, although ORRs were measured in the single digits.11

Another phase 3 trial (NCT00428597) of patients with advanced, pancreatic NETs receiving the multitargeted tyrosine kinase inhibitor sunitinib malate (Sutent) compared with placebo showed an ORR of 9.3% versus 0%, respectively, along with a median PFS of 11.4 months compared with 5.5 months.12

Further development and trials of targeted therapies led improved ORR and PFS. Cabozantinib (Cabometyx), an MKI that inhibits VEGFR2 and MET, was evaluated in a phase 2 trial (NCT01466036) in progressive, carcinoid or pancreatic NETs, which revealed an ORR of 15% and a median PFS of 21.8 months in pancreatic disease and 31.4 months in carcinoid disease.13 Comparably, in the phase 2 TALENT trial (NCT02678780), lenvatinib was evaluated in patients with advanced grade 1 and 2 pancreatic and gastrointestinal NETs; this trial demonstrated a median PFS of 15.7 months, and an overall response rate of 29.9% and 16.4% for pancreatic and gastrointestinal disease, respectively.14

The lack of prolonged response and PFS has been considered likely due to treatment-related resistance; it is common in patients treated with VEGF inhibitors with hyperactivation of FGF/FGFR signaling, considered a hallmark of NETs.10 The small-molecule inhibitor surufatinib, which targets VEGFR, FGFR1 and CSF1R, was investigated in a phase 1b/2 trial conducted in China of 42 patients had pancreatic NETs and 39 had extrapancreatic NETs.15 ORRs for pancreatic and extrapancreatic disease were 19% and 15%, respectively, with a median PFS of 21.2 months and 13.4 months. These results have driven increased interest in the development of possible dual kinase inhibitor therapy by targeting the mTOR and VEGF pathways.

Combination Therapies

The combination of chemotherapy as well as biologics has increased enthusiasm in leading to greater response and PFS. The dual chemotherapy combination with temozolomide (Temodar) and capecitabine (TC) was associated with a relatively long PFS of 22.7 months versus 14.4 months with temozolomide alone (HR, 0.58) in a phase 2 trial (NCT01824875).16 Similarly, temsirolimus (Torisel) and bevacizumab (Avastin) in a phase 2 trial (NCT01010126) showed a response rate of 41%, with a median PFS of 13.2 months and median OS of 34 months.17 Further investigation in combination therapies is warranted based upon improvement of survival and response.

Immunotherapies

The phase 2 KEYNOTE-158 trial (NCT02628067) investigated pembrolizumab (Keytruda) in 107 patients with advanced NETs, 40.2% of whom had received 3 or more prior therapies for advanced disease and 15.9% had PD-L1-positive tumors. The ORR was 3.7% (95% CI, 1.0-9.3), with no complete responses and 4 partial responses, and the median PFS was 4.1 months.18 Due to the lack clear efficacy with monotherapy, enthusiasm has tempered, but combination therapies may play a greater role in the future.

In the PLANET trial (NCT03043664), 22 patients with advanced gastroenteropancreatic NETs who received a median of 2 prior systemic therapies were treated with lanreotide and pembrolizumab until disease progression or intolerable toxicity.19 Approximately 40% of patients achieved stable disease. There median PFS was 5.4 months and median OS was not reached at a median of 15 months of follow-up.

Furthermore, in a phase 2 trial, bevacizumab and atezolizumab (Tecentriq) were prescribed for advanced, progressive pancreatic and extrapancreatic NETs until disease progression or unacceptable toxicity.20 Response was seen in 4 and 3 patients with pancreatic disease and extrapancreatic disease, respectively. The median PFS was 14.9 months and 14.2 months.

Conclusions

Fueled by significant developments in new therapies and ongoing research, the oncology community is striving for a brighter future for patients with NETs through novel targeted and combination therapies, as well as PRRTs—with hopes of improving response rates and PFS, while enabling the safest and most effective treatment delivery from bench to bedside. Newer pathways, such as DLL3, which is overexpressed in many NETs, are also being elucidated and may provide a clinically actionable target for small molecule drugs, as well as drug-antibody conjugates and chimeric antigen receptor T-cell therapy.21 As we look to the future, medical oncologists will be equipped with a significant armamentarium to deliver high-quality, personalized care, while also balancing safety and efficacy among the unique NET population.

References:

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. Tsang ES, Loree JM, Davies JM, et al. Efficacy and prognostic factors for Y-90 Radioembolization (Y-90) in metastatic neuroendocrine tumors with liver metastases. Can J Gastroenterol Hepatol. 2020;2020:5104082. doi:10.1155/2020/5104082

4. 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

5. Rinke A, Müller HH, Schade-Brittinger C, et al. 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: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656-4663. doi:10.1200/JCO.2009.22.8510

6. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224-233. doi:10.1056/NEJMoa1316158

7. Strosberg JR, Caplin ME, Kunz PL, et al. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752-1763. doi:10.1016/S1470-2045(21)00572-6

8. NCCN. Clinical Practice Guidelines in Oncology. Neuroendocrine and adrenal tumors; version 1.2022. Accessed November 3, 2022. https://bit.ly/3A7lFyn

9. Delpassand ES, Tworowska I, Esfandiari R, et al. Targeted α-emitter therapy with 212Pb-DOTAMTATE for the treatment of metastatic SSTR-expressing neuroendocrine tumors: first-in-humans dose-escalation clinical trial. J Nucl Med. 2022;63(9):1326-1333. doi:10.2967/jnumed.121.263230

10. Cives M, Pelle’ E, Quaresmini D, Rizzo FM, Tucci M, Silvestris F. The tumor microenvironment in neuroendocrine tumors: biology and therapeutic implications. Neuroendocrinology. 2019;109:83-99. doi:10.1159/000497355

11. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514-523. doi:10.1056/NEJMoa1009290

12. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501-513. doi:10.1056/NEJMoa1003825

13. Chan JA, Faris JE, Murphy, JE, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET). J Clin Oncol. 2017;35(suppl 4):228. doi:10.1200/JCO.2017.35.4_suppl.228

14. 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

15. Xu J, Li J, Bai C, et al. Surufatinib in advanced well-differentiated neuroendocrine tumors: a multicenter, single-arm, open-label, phase Ib/II trial. Clin Cancer Res. 2019;25(12):3486-3494. doi:10.1158/1078-0432.CCR-18-2994

16. Kunz PL, Graham NT, Catalano PJ, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol. 2022;101200JCO2201013. doi:10.1200/JCO.22.01013

17. Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33(14):1551-1556. doi:10.1200/JCO.2014.56.2082

18. 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

19. Morse M, Halperin DM, Uronis HE, et al. Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET). J Clin Oncol. 2021;39(suppl 3):369. doi:10.1200/JCO.2021.39.3_suppl.369

20. Halperin DM, Liu S, Dasari A, et al. Assessment of clinical response following atezolizumab and bevacizumab treatment in patients with neuroendocrine tumors: a nonrandomized clinical trial. JAMA Oncol. 2022;8(6):904-909. doi:10.1001/jamaoncol.2022.0212

21. Hermans BCM, Derks JL, Thunnissen E, et al. DLL3 expression in large cell neuroendocrine carcinoma (LCNEC) and association with molecular subtypes and neuroendocrine profile. Lung Cancer. 2019;138:102-108. doi:10.1016/j.lungcan.2019.10.010