The rising incidence and prevalence of gastroenteropancreatic endocrine tumors make them the second-most prevalent gastrointestinal cancer.1 Although most of these tumors are relatively slow growing, their histologic grade and differentiation are closely correlated with their clinical behavior.2,3 Most guidelines advocate first-line treatment with somatostatin analogs for patients with advanced-stage gastroenteropancreatic endocrine tumors.4,5 After disease progression on somatostatin analogs, subsequent lines of therapy can include everolimus, peptide receptor radionuclide therapy with the addition of lutetium Lu-177 dotatate for all gastroenteropancreatic endocrine tumors, and chemotherapy or sunitinib for pancreatic neuroendocrine tumors, though optimal sequencing of agents is still up for debate.6
The phase III NETTER-1 trial of peptide receptor radionuclide therapy using Lu-177 dotatate was associated with a greater median progression-free survival with Lu-177 dotatate compared with high-dose octreotide (hazard ratio [HR] = 0.21, P < .001) and a higher objective response rate. Lu-177 dotatate also provided a significant quality-of-life benefit and improved symptom burden.7 There was no evidence of renal toxicity, and a small percentage of patients given Lu-177 dotatate developed myelodysplastic syndrome after long-term follow-up (1.8%). This therapy was approved by the U.S. Food and Drug Administration for patients with somatostatin receptor–positive gastroenteropancreatic endocrine tumors in 2018.8
Namrata Vijayvergia, MD, FACP
Pamela L. Kunz, MD
Overall Survival Benefit
In the final overall survival analysis of NETTER-1, reported by Strosberg and colleagues and summarized in this issue of The ASCO Post, an updated post hoc analysis (5-year follow-up) showed that the progression-free survival benefit was maintained with Lu-177 dotatate, and an exploratory analysis demonstrated that the benefit was maintained through subsequent systemic anticancer therapy. The final overall survival showed a benefit with Lu-177 dotatate that was numerically (but not statistically) better than the control. Notably, this was a secondary analysis, confounded by a 36% crossover rate, and a high 5-year overall survival in both groups.9
The nonsignificant overall survival benefit from peptide receptor radionuclide therapy is consistent with results from prior neuroendocrine neoplasm trials; however, in contrast is the clinically meaningful 1-year absolute difference in overall survival between the arms in NETTER-1. The long survival after disease progression, also seen in other neuroendocrine neoplasm trials, and the high number of postprogression treatments preclude the use of overall survival as a practical clinical trial endpoint for neuroendocrine tumors. Recognizing this, the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting (NET-CTPM) summary in 2011 recommended progression-free survival as the preferred primary endpoint for phase III neuroendocrine tumor studies, as well as for phase II studies in which a delay in disease progression is expected in the absence of significant radiologically defined tumor responses.10
The overall benefit of peptide receptor radionuclide therapy has been supported by other nonrandomized studies.11-13 Additionally, an improvement in survival, symptom burden, and quality of life with Lu-177 dotatate leads to its cost-effectiveness. For instance, in a recent UK analysis with a willingness to pay threshold of GBP 30,000 per quality-adjusted life year gained, Lu-177 dotatate was found to be cost-effective compared with everolimus, sunitinib, and best supportive care.14
The long survival after disease progression...and the high number of postprogression treatments preclude the use of overall survival as a practical endpoint for neuroendocrine tumors.— Namrata Vijayvergia, MD, FACP, and Pamela L. Kunz, MD
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Next Steps
There is interest in predictive biomarkers for peptide receptor radionuclide therapy to help individualize therapy and provide early evidence of response. Blood-based tests such as the peptide receptor radionuclide therapy prediction quotient and clinical scores hold promise as early markers of response.15,16 The recent 2021 NET-CTPM’s executive summary focused on treatment of neuroendocrine tumors in the era of peptide receptor radionuclide therapy, making combination and retreatment strategies the highest priority.17 Also, novel radiopeptide approaches including somatostatin antagonists18 or alpha emitter radionuclides19 are being actively developed, with promising early-phase data.
Conclusion
We believe that peptide receptor radionuclide therapy has taken center stage in the management of neuroendocrine neoplasms, and long-term survival data will further strengthen our practice patterns—such as the statistically significant improvement in progression-free survival and clinically meaningful improvement in overall survival observed in NETTER-1.
We believe that peptide receptor radionuclide therapy has taken center stage in the management of neuroendocrine neoplasms....— Namrata Vijayvergia, MD, FACP, and Pamela L. Kunz, MD
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DISCLOSURE: Dr. Vijayvergia has received research funding from Merck and Bayer. Dr. Kunz holds stock or other ownership interests in Guardant Health; has served as a consultant or advisor to Acrotech Biopharma, Amgen, Crinetics Pharmaceuticals, Genentech/Roche, HUTCHMED, Ipsen, Lexicon, Natera, Novartis (Advanced Accelerator Applications), RayzeBio, and SunPharma; and has received institutional research funding from Brahms (Thermo Fisher Scientific), Ipsen, Lexicon, Novartis (Advanced Accelerator Applications), and Xencor.
REFERENCES
1. 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.
2. Klimstra DS, Modlin IR, Coppola D, et al: The pathologic classification of neuroendocrine tumors: A review of nomenclature, grading, and staging systems. Pancreas 39:707-712, 2010.
3. Kim JY, Hong SM, Ro JY: Recent updates on grading and classification of neuroendocrine tumors. Ann Diagn Pathol 29:11-16, 2017.
4. 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 27:4656-4663, 2009.
5. Caplin ME, Pavel M, Ćwikła JB, et al: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224-233, 2014.
6. Shah, MH, Goldner WS, Benson AB, et al: Neuroendocrine and adrenal tumors. version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 19:839-868, 2021.
7. Strosberg J, Wolin E, Chasen B, et al: Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with 177Lu-dotatate in the phase III NETTER-1 trial. J Clin Oncol 36:2578-2584, 2018.
8. Lutathera (lutetium Lu 177 dotatate) prescribing information. Advanced Accelerator Applications, revised January 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf. Accessed March 7, 2022.
9. 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 22:1752-1763, 2021.
10. Kulke MH, Siu LL, Tepper JE, et al: Future directions in the treatment of neuroendocrine tumors: Consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol 29:934-943, 2011.
11. Brabander T, van der Zwan WA, Teunissen JJM, et al: Long-term efficacy, survival, and safety of [177Lu-DOTA0, Tyr3] octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res 23:4617-4624, 2017.
12. Baum RP, Kulkarni HR, Singh A, et al: Results and adverse events of personalized peptide receptor radionuclide therapy with (90) yttrium and (177) lutetium in 1,048 patients with neuroendocrine neoplasms. Oncotarget 9:16932-16950, 2018.
13. Khan MS, Stamp E, Sammon C, et al: Matching-adjusted indirect treatment comparison of [177Lu] Lu-DOTA-TATE, everolimus and sunitinib in advanced, unresectable gastroenteropancreatic neuroendocrine tumours: Relative effectiveness of [177Lu] Lu-DOTA-TATE in gastroenteropancreatic neuroendocrine tumours. EJC Suppl 16:5-13, 2021.
14. Glover M, Caplin M, Leeuwenkamp OR, et al: Use of [177Lu] Lu-DOTA-TATE in the treatment of gastroenteropancreatic neuroendocrine tumours: Results of a UK cost-effectiveness modelling study. EJC Suppl 16:14-23, 2021.
15. Bodei L, Kidd M, Modlin IM, et al: Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 43:839-851, 2016.
16. Das S, Du L, Schad A, et al: A clinical score for neuroendocrine tumor patients under consideration for Lu-177-DOTATATE therapy. Endocr Relat Cancer 28:203-212, 2021.
17. National Cancer Institute Gastrointestinal Steering Committee Neuroendocrine Tumor Clinical Trials Planning Meeting: Treatment in the Era of Peptide Receptor Radionuclide Therapy. Available at https://www.cancer.gov/about-nci/organization/ccct/steering-committees/nctn/gastrointestinal/gisc-net-prrt-ctpm-execsum.pdf. Accessed March 7, 2022.
18. Baum RP, Zhang J, Schuchardt C, et al: First-in-humans study of the SSTR antagonist 177Lu-DOTA-LM3 for peptide receptor radionuclide therapy in patients with metastatic neuroendocrine neoplasms: Dosimetry, safety, and efficacy. J Nucl Med 62:1571-1581, 2021.
19. Delpassand E, Tworowska I, Esfandiari R, et al: Phase I dose-escalation study of AlphaMedix for targeted-alpha-emitter therapy of PRRT-naive neuroendocrine patients. 2021 ASCO Annual Meeting. Abstract 4117.
