NETTER-1 study for patients with midgut NETs

Jun 15, 2021

Data showing an increase in progression free survival for patients with midgut neuroendocrine tumours (or NETs) using Lutathera has been released from NETTER-1 study.

  • At final analysis, the study showed clinically relevant improvement in median overall survival for patients with midgut NETs with a difference of 11.7 months between arms (Hazard ratio (HR): 0.84 with 95% CI: (0.60, 1.17) (p=0.30, two-sided))1 
  • No new safety signals emerged in long-term follow-up with median of 6.3 years; safety profile consistent with previously reported results1
  • Previously reported primary analysis demonstrated statistically significant improvement in progression free survival2

Novartis reported the final analysis from the NETTER-1 phase III study comparing treatment using Lutathera® (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) plus 30 mg octreotide LAR to 60 mg of octreotide LAR in patients with midgut NETs (neuroendocrine tumours). The previously reported primary analysis of the trial demonstrated a statistically significant improvement in progression free survival (PFS) (HR: 0.18, p < 0.0001)3. In the final analysis of overall survival, a secondary objective of the trial, treatment resulted in a clinically relevant prolongation in median overall survival of 11.7 months [48.0 months (95%CI: 37.4-55.2) compared to the control arm (36.3 months (95%CI: 25.9-51.7)]1. While this analysis did not reach statistical significance (Hazard ratio for OS (HR): 0.84 with 95% CI: (0.60, 1.17) (p=0.30, two-sided))1, the analyses of overall survival may have been impacted by multiple factors, including the crossover of patients from the control arm receiving subsequent radioligand therapy (36% of patients) as well as heterogenous subsequent anti-cancer treatments in both study arms1. No new safety signals emerged in the final analysis1. These results will be presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4.

Jonathan Strosberg, MD, Principal Investigator and Associate Professor, Section Head, Neuroendocrine Tumor Program at Moffitt Cancer Center, said, “Lutathera plus long-acting octreotide was associated with a nearly 12-month difference in median overall survival compared to high-dose long-acting octreotide in these difficult to treat patients with inoperable midgut NETs progressing under standard dose octreotide LAR treatment. While not statistically significant, I consider this difference to be clinically relevant for these patients. It is also important to emphasize that PFS was the primary endpoint of this study. Moreover, 36% of patients in the control arm crossed over to receive subsequent radioligand treatment, which may have impacted the comparison of survival between both study arms.”

John Tsai, Head of Global Drug Development and Chief Medical Officer for Novartis said, “We believe in the potential of targeted radioligand therapy and are investing in new discovery and expansion of this important platform, including exploration of new radioisotopes and combinations with complementary mechanisms of action, such as immunotherapy and inhibitors of DNA damage response.”

At this final analysis, no new safety signals emerged in the long-term safety follow-up with a median of 6.3 years. In terms of secondary hematological malignancies, no new cases of MDS or acute leukemia were reported in the long term follow up4.

Radioligand therapy combines a targeting compound that binds to receptors expressed by tumors and a radioactive isotope, causing DNA damage that inhibits tumor growth and replication and may lead to cell death5-7. In the case of Lutathera, it binds to somatostatin receptor type 2, which is over-expressed on certain types of cells, such as gastroenteropancreatic neuroendocrine tumor cells8,9.

About NETTER-1

NETTER-1 is a Phase III international, multicenter, controlled, randomised study that compared treatment using Lutathera® every eight weeks plus best standard of care (octreotide LAR 30 mg) to 60 mg of octreotide LAR (dosed every four weeks) in patients with inoperable midgut neuroendocrine tumours progressing under standard dose octreotide LAR treatment and overexpressing somatostatin receptors3.

The primary endpoint was to compare the progression-free survival (PFS) after treatment with Lutathera® plus octreotide LAR 30 mg versus octreotide LAR 60 mg using RECIST 1.1 criteria3. Secondary trial endpoints included comparing objective response rate, overall survival, time to tumor progression, duration of response and safety between the two study arms3.

About GEP-NETs

Neuroendocrine tumors (NETs) are a type of cancer that originate in neuroendocrine cells throughout the body. NETs are commonly considered slow-growing malignancies. However, some NETs are associated with rapid progression and poor prognosis10-11. In many cases, NET diagnosis is delayed until patients have advanced disease12. Symptoms such as fatigue, diarrhea, and abdominal pain can occur on a daily basis13. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are subdivided into two categories: tumors of the gastrointestinal (GI) tract and pancreas14. There is a need for additional treatment options for inoperable or advanced GEP-NET, including those who have progressed while taking first-line somatostatin analogs.

References

  1. Novartis Data on file
  2. Strosberg J, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. New England J Med 2017; 376:125-135 doi: 10.1056/NEJMoa1607427
  3. Summary of Product Characteristics: https://s3-adacap-product.s3.eu-west-1.amazonaws.com/wp-content/uploads/2021/01/26163646/ema-combined-h-4123-en_vs16.0_202101.pdf
  4. Strosberg J, et al. Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE inpatients with midgut neuroendocrine tumors 2021; 332-311
  5. Jurcic JG, Wong JYC, Knox SJ, et al. Targeted radionuclide therapy. In: Gunderson LL, Tepper JE, eds. Gunderson & Tepper’s Clinical Radiation Oncology. 4th ed. Philadelphia, PA: Elsevier, Inc.; 2016; 423-437.e19.
  6. Unak P. Targeted tumor radiotherapy. Braz Arch Biol Technol. 2002;45:97-110. doi:10.1590/S1516-89132002000500014
  7. Institute of Medicine and National Research Council. Advancing Nuclear Medicine Through Innovation. Washington, DC: The National Academies Press. 2007; doi:10.17226/11985
  8. Appetecchia M, Bardelli R. Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumours, current aspects and new perspectives. Clin Cancer Res. 2010; 29:19
  9. Fjällskog ML, Ludvigsen E, Stridsberg M, Öberg K, Eriksson B, Janson ET. Expression of Somatostatin Receptor Subtypes 1 to 5 in Tumor Tissue and Intratumoral Vessels in Malignant Endocrine Pancreatic Tumors. Med Oncology. 2003; 20:59–67.
  10. Man D, et al. Cancer Manag Res. 2018;10:5629–38 (SEER US registry data)
  11. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T, Yao JC. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol. 2017; doi:10.1001/jamaoncol.2017.0589
  12. Frilling A, Åkerström G, Falconi, M, et al. Neuroendocrine tumor disease: an evolving landscape. Endoc Related Cancer 2012; 19: R163-815.
  13. Singh S, et al. J Glob Oncol. 2016; 3(1):43–53. (Patient-reported information from a large, international survey)
  14. Modlin I, Oberg K, et al. Gastroenteropancreatic Neuroendocrine Tumours, The Lancet Oncology 2008; 9: 61-72,1470-2045, https://doi.org/10.1016/S1470-2045(07)70410-2

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