Major Breakthrough in Development of Systemic Targeted Therapy for Midgut Neuroendocrine Tumors


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Allan V. Espinosa, MD

Allan V. Espinosa, MD

Manisha H. Shah, MD

Manisha H. Shah, MD

This issue of The ASCO Post discusses a recent trial reported by Strosberg et al in The New England Journal of Medicine that is the first phase III randomized international multicenter clinical trial evaluating lutetium-177 (177Lu)-Dotatate as a peptide receptor radionuclide therapy in midgut neuroendocrine tumors. The Neuroendocrine Tumors Therapy (NETTER)-1 trial compared 177Lu-Dotatate plus best supportive care (including octreotide long-acting repeatable [LAR], or Sandostatin LAR) vs high-dose octreotide LAR, evaluating efficacy and safety in patients with advanced and progressive somatostatin receptor–positive midgut neuroendocrine tumors.1 

In this trial, 177Lu-Dotatate was found to be a safe therapy that dramatically improved progression-free survival and showed preliminary evidence of improvement in overall survival. The results of this trial are unprecedented for this patient population and represent a new and much better therapeutic option for patients who have had disease progression while on long-acting octreotide therapy. 

Study Background

Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of malignancies that have increased in incidence in recent decades.2 The midgut (jejunum, ileum, appendix, and proximal colon) is the most common primary site for neuroendocrine tumors. Low- or intermediate-grade midgut neuroendocrine tumors are also known as carcinoid tumors. 

About 40% of all gastroenteropancreatic neuroendocrine tumors are metastatic at the time of diagnosis, requiring systemic therapies.3 Particularly for metastatic midgut neuroendocrine tumors, the 5-year overall survival in the United States remains less than 50% with the standard of care, which consists of individualized strategies for local or regional disease control, somatostatin analogs, and everolimus (Afinitor).4 

“Data from this pivotal trial provide a solid foundation for setting a new standard of therapy that is safe and effective for patients with midgut neuroendocrine tumors.”
— Allan V. Espinosa, MD, and Manisha H. Shah, MD

For the past 3 decades, the therapeutic backbone for metastatic and symptomatic disease has been octreotide LAR. However, benefit has been limited to the palliative setting, with the inevitable development of tachyphylaxis and disease progression. By exploiting their selective binding affinity to somatostatin receptors 1 through 5 and their proven efficacy in the first-line setting, somatostatin analogs have been attached to different radionuclide isotopes with diagnostic and therapeutic intent. This treatment modality, known as peptide receptor radionuclide therapy, has been used in Europe since the early 1990s and has proven to be safe and efficacious.5

Peptide receptor radionuclide therapy uses compounds that are engineered by attaching a somatostatin analog (octreotide or octreotate [octreotide acid]) as a carrier for radionuclides with different radioactive emission capabilities, with the chelators DOTA (tetraazacyclododecane tetraacetic acid) and DPTA (diethylenetriamine pentaacetic acid) used as complex stabilizers.

Studies That Paved the Way 

The initial studies in humans in the 1990s were performed using indium-111 (111In)-DTPA octreotide—a radiolabeled somatostatin analog that releases Auger and gamma electron decay emissions.5,6 The results of these trials were encouraging and led to the development of other radiolabeled somatostatin analogs that deliver targeted radiation with deeper penetration into the tumors. 

The next generation of radiolabeled somatostatin analogs used radionuclides: yttrium-90 (90Y), which generates beta emissions, and 177Lu, which produces beta and gamma particles. Both compounds were used in several phase I and phase II studies with variable results, but they represented an improvement over their forerunner (111In-DTPA octreotide).7

90Y-Dotatoc is a radionuclide compound with high-energy emission, long tissue penetration capacity (11 mm), and a half-life of 2.7 days. Meta-analysis of phase I and II studies showed objective response rates ranging from 4% to 33%, median progression-free survival between 17 and 29 months, and median overall survival between 22 and 37 months.8 In the largest single-institution phase II trial of 90Y-Dotatoc in neuroendocrine tumors, involving 1,109 patients, 12.8 % of patients developed grade 3 and 4 hematologic toxicities and 9.2% experienced grade 4 or 5 permanent renal damage.9 The wide range in outcomes is likely secondary to differences in study designs that included dissimilar cycle doses, cumulative doses, and patient characteristics.

177Lu-Dotatate is another second-generation somatostatin analog radionuclide that has a medium-range energy emission capacity with acceptable tissue penetration (2 mm), a half-life of 6.7 days, and higher affinity than octreotide to, in particular, somatostatin receptor 2. Two phase II trials10,11 involving a combined 361 patients showed uniform results, with overall response rates between 30% and 33%, median progression-free survival between 33 and 36 months, median time to progression of 36 to 40 months, and improved symptoms in 40% to 70% of patients.12 These trials showed a 36% improvement in global health status among patients who started the trial with substandard Karnofsky performance scores, and performance status was preserved in patients with an initial Karnofsky performance score of 100%.12 

NETTER-1: Pivotal Clinical Trial

The NETTER-1 trial included a total of 229 patients with advanced, low- or intermediate-grade, well-differentiated neuroendocrine tumors of the midgut with radiologic progression within 3 years of randomization while on octreotide LAR for at least 3 months prior to the start of the trial. The experimental arm consisted of 177Lu-Dotatate administered intravenously at doses of 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses plus octreotide LAR at 30 mg every 4 weeks. The control arm received octreotide LAR at a dose of 60 mg given intramuscularly every 4 weeks. Notably, patients were evenly randomized according to tumor grade (Ki67 index < 3% or 3%–20%) and somatostatin receptor scintigraphy expression intensity (Krenning scale 0–4). 

“The results of this trial are unprecedented for this patient population and represent a new and much better therapeutic option for patients who have had disease progression while on long-acting octreotide therapy.”
— Allan V. Espinosa, MD, and Manisha H. Shah, MD

The primary endpoint of the study was achieved with improvement in progression-free survival at 20 months in the experimental group (65% vs 10.8% control); median progression-free survival was not reached vs 8.4 months (hazard ratio = 0.2, P < .001). Overall response rates were better in the experimental group (18% vs 3%, P < .001), and a preplanned interim analysis showed an improved overall survival, with a hazard ratio of 0.4 (P < .001). 

These results were achieved while maintaining a fairly benign safety profile, with grade 3 and 4 hematologic toxicities in single digits (1% neutropenia, 2% thrombocytopenia, 9% lymphopenia). Common adverse events were acute and of mild-to-moderate intensity, including nausea, vomiting, fatigue, anorexia, and headache.

In summary, data from this pivotal trial provide a solid foundation for setting a new standard of therapy that is safe and effective for patients with midgut neuroendocrine tumors. U.S. Food and Drug Administration approval of 177Lu-Dotatate is much anticipated. The extraordinary success witnessed in developing peptide receptor radionuclide therapy for midgut neuroendocrine tumors translates into much better cancer control and, very likely, longer lives for patients with low- or intermediate-grade midgut neuroendocrine tumors. 

DISCLOSURE: Drs. Espinosa and Shah reported no conflicts of interest.

REFERENCES

1. Strosberg J, El‑Haddad G, Wolin E, et al: Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125-135, 2017. 

2. Lawrence B, Gustafsson BI, Chan A, et al: The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 40:1-18, 2011.

3. Modlin IM, Oberg K, Chung DC, et al: Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9:61-72, 2008.

4. Yao JC, Hassan M, Phan A, et al: One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063-3072, 2008.

5. Krenning EP, Kooij PP, Bakker WH, et al: Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D-Phe1]-octreotide: A case history. Ann NY Acad Sci 733:496-506, 1994.

6. Anthony LB, Woltering EA, Espenan GD, et al: Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin Nucl Med 32:123-132, 2002.

7. Cives M, Strosberg J: Radionuclide therapy for neuroendocrine tumors. Curr Oncol Rep 19:9, 2017.

8. Kwekkeboom DJ, Krenning EP: Peptide receptor radionuclide therapy in the treatment of neuroendocrine tumors. Hematol Oncol Clin North Am 30:179-191, 2016.

9. Imhof A, Brunner P, Marincek N, et al: Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 29:2416-2423, 2011.

10. Kwekkeboom DJ, de Herder WW, Kam BL, et al: Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: Toxicity, efficacy, and survival. J Clin Oncol 26:2124-2130, 2008.

11. Bodei L, Cremonesi M, Grana CM, et al: Peptide receptor radionuclide therapy with (1)(7)(7)Lu-DOTATATE: The IEO phase I-II study. Eur J Nucl Med Mol Imaging 38:2125-2135, 2011.

12. Khan S, Krenning EP, van Essen M, et al: Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J Nucl Med 52:1361-1368, 2011.


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