The results of the phase III NETTER-1 trial, recently published in The New England Journal of Medicine,1 have been met with great interest by clinicians who treat neuroendocrine tumors. In patients with advanced midgut lesions, treatment with the radiopharmaceutical lutetium-177-Dotatate (177-Lu-Dotatate; Lutathera) led to markedly longer progression-free survival and significantly higher response rates vs the control arm.
At the 2017 Gastrointestinal Cancers Symposium, principal investigator of NETTER-1, Jonathan Strosberg, MD, of Moffitt Cancer Center in Tampa, Florida, brought listeners up-to-date on this effective second-line therapy and looked ahead to future treatments of neuroendocrine tumors.2 He was joined by Arturo Loaiza-Bonilla, MD, of Cancer Treatment Centers of America at Eastern Regional Medical Center in Philadelphia, who also offered his perspectives on the use of 177-Lu-Dotatate.3
177-Lu-Dotatate, a peptide receptor radionuclide therapy, consists of the somatostatin analog octreotate connected with the beta- and gamma-emitting radiopharmaceutical lutetium-177. The two components are connected using the chelator DOTA. The treatment has received Orphan Drug status and Fast Track review designation from the U.S. Food and Drug Administration (FDA). According to Dr. Strosberg, the manufacturer (Advanced Accelerator Applications) is currently addressing FDA requests and will soon resubmit their application for review. In the meantime, an expanded-access program is available through the manufacturer, and a list of treatment sites is available on the patient association website.
“The phase III NETTER-1 trial was the first phase III randomized controlled study of a radiolabeled somatostatin analog,” Dr. Strosberg said. The study randomized 229 patients with well-differentiated metastatic or locally advanced inoperable midgut neuroendocrine tumors to receive 4 intravenous administrations (every 8 weeks) of the peptide receptor radionuclide therapy (plus best supportive care, including standard-dose octreotide long-acting repeatable [LAR]) or high-dose octreotide LAR alone.
Perhaps one of the most striking findings for this peptide receptor radionuclide therapy is the long median duration of progression-free survival.— Jonathan Strosberg, MD
Median progression-free survival was not reached and was estimated at 40 months, vs 8.4 months in the control arm—a 79% reduction in risk (P < .0001). Progression-free survival at 20 months was 65.2% vs 10.8%. Response rates were 18% and 3%, respectively (P = .0008).
Interim analysis suggested an overall survival benefit as well, with a hazard ratio for mortality of 0.398 (P = .0043). Although final survival analysis is awaited, noted Dr. Strosberg, “we’ve seen nearly twice as many deaths in the control arm at this interim timepoint for survival analysis.”
“Perhaps one of the most striking findings for this peptide receptor radionuclide therapy is the long median duration of progression-free survival,” he added. In the largest series of patients treated with 177-Lu-Dotatate (from Rotterdam, The Netherlands), median progression-free survival stretched to almost 3 years,4 revealed Dr. Strosberg, although some patients did not have progressive disease at entry.
The treatment is relatively well tolerated. Approximately 50% of patients may experience transient nausea and perhaps vomiting (< 10% grade 3/4), mostly during the infusion of amino acid (a renal protectant).
Position in the Armamentarium
Dr. Loaiza-Bonilla posed the question of whether 177-Lu-Dotatate is more effective than a similar peptide receptor radionuclide therapy containing the radioisotope yttrium-90. “To be completely honest, it’s hard to tell,” he -admitted, “but some data do suggest that 177-Lu-Dotatate outperforms 90-Y-Dotatate.”
Arturo Loaiza-Bonilla, MD
In a large multi-institutional German study, the newer agent almost doubled the progression-free survival time over 90-Y-Dotatate and improved overall survival at 4 years from about 40% to approximately 70%, with the greatest effect seen in small bowel neuroendocrine tumors.5 The results led to the NETTER-1 study, “showing 177-Lu-Dotatate to be a very promising radioisotope, and we hope it gains approval,” he commented.
As both speakers indicated, peptide receptor radionuclide therapy (90-Y-Dotatate or 177-Lu-Dotatate) is recommended for patients with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors that are progressing despite standard-dose long-acting somatostatin analog therapy and for pancreatic neuroendocrine tumors progressing after somatostatin analog therapy or everolimus (Afinitor). That said, Dr. Strosberg noted there are no phase III data for a radiolabeled somatostatin analog in pancreatic neuroendocrine tumors, so where it should be positioned in the treatment algorithm in that setting is controversial.
“Somatostatin analogs remain the first-line therapy based on their exceptionally good toxicity profile,” Dr. Strosberg said, “but for progressive disease, peptide receptor radionuclide therapy should be considered in the second line for patients with strong somatostatin receptor expression.”
He cited its advantages as a limited treatment course (four infusions), long progression-free survival, and relatively low toxicity, with the exception being the potential for bone marrow toxicity with long-term use. There are a number of second-line options, but their sequencing is unclear. “We hope that peptide receptor radionuclide therapy will become the standard in the future,” commented Dr. Strosberg.
The diagnosis of neuroendocrine tumors has also advanced with the FDA approval of 68-Ga-Dotatate positron-emission tomography/computed tomography (PET/CT) (Netspot), as discussed by Dr. Loaiza-Bonilla. In the “multifaceted staging of neuroendocrine tumors,” he noted, “the 68-Ga--Dotatate scan is a powerful tool for diagnosis, and it’s also helping us treat neuroendocrine tumors in a targeted way.”
In a meta-analysis of 16 studies, 68-Ga-Dotatate scan had a 93% sensitivity and a 91% specificity for detecting neuroendocrine tumors.6 “It offers utility in diagnosis, prognostication, assessment of response, and long-term follow-up and is poised to become the standard-of-care imaging modality for neuroendocrine tumors staging and peptide receptor radionuclide therapy patient selection,” he predicted.
Somatostatin analogs remain the first-line therapy,...,but for progressive disease, peptide receptor radionuclide therapy should be considered in the second-line options.— Jonathan Strosberg, MD
Appropriate patient selection, however, is still an evolving area. Helpful data have come from the Zentralklinik Bad Berka in Germany,7 where researchers developed the Bad Berka Score based on the following clinical aspects and molecular features: standardized uptake value for determining somatostatin receptor density, renal function, hematologic status, liver involvement, extrahepatic tumor burden, Ki67 index, tumor grade, 18-fluorodeoxyglucose (FDG) PET/CT status, tumor dynamics, performance status, weight loss, time since first diagnosis, functional activity of the tumor, and previous treatments.
Dr. Loaiza-Bonilla also advocated for the use of tumor growth rate to assess treatment response. Neuroendocrine tumor treatments usually stabilize, rather than shrink, tumors, he noted, but tumor growth rate can detect small changes, earlier. “RECIST [Response Evaluation Criteria in Solid Tumors] may identify neuroendocrine tumors as stable rather than progressing, despite their being steadily growing tumors that are amenable to treatment,” continued Dr. Loaiza-Bonilla. “That’s the rationale for using estimated tumor growth rate as a novel measure of response.”
A next step for 177-Lu-Dotatate will be to prove its value in other sites of neuroendocrine tumors. “Early-phase data suggest we may achieve even higher response rates in non-midgut neuroendocrine tumors, especially those originating in the pancreas,” Dr. Strosberg said. The issue of fixed dosing (as in NETTER-1) vs individual dosimetry is also being debated.
A promising strategy appears to be combining 177-Lu-Dotatate with chemotherapy to create “peptide receptor chemoradionuclide therapy, according to Dr. Loaiza-Bonilla. In a 2014 study in which patients received concomitant fluorouracil-radiosensitizing infusional chemotherapy, overall survival was not reached after 5 years of follow-up.8 The CONTROL NETs trial is currently testing this approach by comparing 177-Lu-Dotatate alone, capecitabine plus temozolomide, and the combination of these two treatments.
Other questions being investigated are the optimal timing of peptide receptor radionuclide therapy within the neuroendocrine tumors treatment paradigm, the relative benefit of one peptide receptor radionuclide therapy vs another, the use of tumor growth rate plus 68-Ga-Dotatate PET/CT to assess response to peptide receptor radionuclide therapy, the combination of peptide receptor radionuclide therapy and immunotherapy, the expansion of peptide receptor radionuclide therapy beyond gastroenteropancreatic neuroendocrine tumors into other sites, and the efficacy of other isotopes and targets.
“There are many receptors outside the somatostatin receptor that are overexpressed in neuroendocrine tumors. Agents can be chelated to analogs targeting these receptors,” Dr. Strosberg indicated. ■
Disclosures: Dr. Strosberg has financial relationships with Novartis, Ipsen, Lexicon, Genentech, and Pharmacyclics. Dr. Loaiza-Bonilla has served as a consultant or advisor to Bayer, Celgene, Genentech, Ipsen, Massive Bio, and Merrimack Pharmaceuticals.
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.
4. van der Zwan WA, Bodei L, Mueller-Brand J, et al: GEPNETs update: Radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol 172:R1-R8, 2015.
5. Hörsch D, Ezziddin S, Haug A, et al: Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up. Eur J Cancer 58:41-51, 2016.
6. Treglia G, Castaldi P, Rindi G, et al: Diagnostic performance of Gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours. Endocrine 42:80-87, 2012.
7. Baum RP, Kulkarni HR: THERANOSTICS: From molecular imaging using Ga-68 labeled tracers and PET/CT to personalized radionuclide therapy—The Bad Berka Experience. Theranostics 2:437-447, 2012.
8. Kong G, Thompson M, Collins M, et al: Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy. Eur J Nucl Med Mol Imaging 41:1831-1844, 2014.