胃腸胰腺神經內分泌瘤GEP-NETs/ 諾華 核醫藥物: Lutathera-177 (177Lu)-DOTATATE (Lutathera)

Long-lasting radionuclide therapy for advanced neuroendocrine tumors proves effective June 25, 2018, Society of Nuclear Medicine and Molecular Imaging

Scans were done at 2, 24, 72, 120 and 168 hours after the administration of 177Lu-DOTA-EB-TATE. The radiopharmaceutical cleared from the blood pool over time and persistently retained in the tumors (arrows). Credit: J Zhang et al., Peking …more

A first-in-human study presented at the 2018 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) demonstrates the benefits and safety of a new, long-lasting type of radionuclide therapy for patients with advanced, metastatic neuroendocrine tumors (NETs). Lutathera-177 (177Lu)-DOTATATE (trade name Lutathera), a peptide receptor radionuclide tharapy (PRRT) with radiolabeled somatostatin analogues (peptides), was recently approved by the U.S. Food and Drug Administration for the treatment of NETs. It is the therapeutic part of a nuclear medicine theranostic pairing. Gallium-68 (68Ga)-DOTATATE is the diagnostic agent used in positron emission tomography/computed tomography (PET/CT) scans that first locates and marks the lesions for follow-up with targeted PRRT delivery directly to the tumor cells which express high levels of somatostatin receptors (SSTRs). Because the PRRT binds to receptors expressed by the tumor cells, healthy cells are unharmed. However, the peptide quickly clears from the blood through the kidneys limiting the accumulation of radioactivity within tumors and making additional treatment cycles necessary to provide the therapeutic dose. This first-in-human, first-in-class, Phase I trial (ID: NCT03308682) investigated the safety and dosimetry of a novel long-lasting radiolabeled somatostatin analogue that adds an albumin-binding Evans blue (EB, an azo dye) derivative to 177Lu-DOTATATE. Albumin, the most abundant plasma protein in human blood, is a natural transport protein and has a long circulatory half-life.

"177Lu-DOTA-EB-TATE is a "three-in-one" therapeutic compound, with an octreotate peptide to find the tumor, an Evans blue motif, which uses endogenous albumin as a reversible carrier to effectively extend the half-life in the blood and substantially increase targeted accumulation and retention within the tumor, and a therapeutic radionuclide to kill the tumor cells, to finally provide effective treatment of NETs," explains Shawn(Xiaoyuan) Chen, Ph.D., senior investigator, of National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health , Bethesda, Maryland. For the study, conducted in collaboration with researchers at the U.S. National Institute of Biomedical Imaging and Bioengineering, 8 patients (6 men and 2 women ranging in age from 27 to 61 years old) with advanced metastatic neuroendocrine tumors were recruited from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences in Beijing, China. Each patient underwent whole-body 68Ga-DOTATATE PET/CT. Five of the patients then accepted intravenous injection with a single dose of 0.35-0.70 GBq of 177Lu-DOTA-EB-TATE within one week, and were monitored at 2, 24, 72, 120 and 168 hours after 177Lu-DOTA-EB-TATE administration with serial whole-body planar and single photon emission computed tomography (SPECT)/CT images acquired. The other 3 patients accepted a dose of 0.28-0.41 GBq of 177Lu-DOTATATE and were monitored at 1, 3, 4, 24 and 72 hours with the same imaging procedures. Complete physical examinations, including vital signs, blood count, biochemistry, and immunology analyses were performed immediately before and 1, 3, and 7 days, as well as 3 months, after treatment. Administration of 177Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms reported throughout the procedure and follow-up. The total effective dose equivalent and effective dose were 0.2048 ± 0.1605 and 0.0804 ± 0.0500 mSv/MBq for 177Lu-DOTA-EB-TATE and 0.1735 ± 0.0722 and 0.0693 ± 0.0317 mSv/MBq for 177Lu-DOTATATE. The liver, kidneys, bone marrow and total body received slightly higher doses (mGy/MBq) with 177Lu-DOTA-EB-TATE than with 177Lu-DOTATATE, while the spleen received lower doses with 177Lu-DOTA-EB-TATE. Blood clearance of 177Lu-DOTA-EB-TATE was also slower. Most importantly, 177Lu-DOTA-EB-TATE lasted in the tumors more than 4 times longer than 177Lu-DOTATATE. Jingjing Zhang and Zhaohui Zhu of Peking Union Medical College Hospital point out, "By introducing an albumin binding moiety, this long-lasting radiolabeled somatostatin analogue has remarkably enhanced uptake and retention in SSTR-positive tumors, which is important to increase the therapeutic efficacy in patients. With proper selection of patients with advanced metastatic neuroendocrine tumors, 177Lu-DOTA-EB-TATE has great potential to be a highly effective treatment, while providing a safe dose with less frequency of administration than is possible with 177Lu-DOTATATE."

治療罕見腫瘤，FDA批准首款多肽受體放射性核素療法 藥明康得/報導近日，美國FDA宣佈，批准諾華（Novartis）集團公司Advanced Accelerator Applications的Lutathera（lutetium Lu 177 dotatate）治療生長抑素受體陽性的胃腸胰腺神經內分泌腫瘤（GEP-NETs）。這也是美國FDA批准的首款多肽受體放射性核素療法（PRRT）。 神經內分泌腫瘤（NETs）是一類罕見的腫瘤，能病發於胃腸道、胰腺、肺等諸多器官中的神經內分泌細胞。罹患這類腫瘤的患者表現不一，有些患者會由於體內激素的過度產生而出現症狀，而有些患者則能多年無症狀。雖然這類腫瘤並不常見，但一旦患病，就會給患者的生命帶來很大的影響，據估計，一旦腫瘤出現分化，發生遠端轉移，這些患者的5年生存率就會只有35%。創新療法也就成了這些患者的救命稻草。本次獲批的Lutathera是一款放射性藥物，能結合腫瘤細胞表面的生長抑素受體，並進入細胞，通過放射性對腫瘤細胞造成損傷。之前，它曾獲得美國FDA的孤兒藥資格，也曾獲得優先審評資格。在兩項關鍵的3期臨床試驗裡，這款新藥的療效得到了驗證。在第一項試驗中，與最佳的標準護理手段（每四周30mg octreotide LA）相結合，Lutathera顯示出了良好的效果，能降低79%的疾病進展或死亡風險（HR 0.21，95% CI：0.13-0.32；p<0.001）；在第二項試驗裡，在1214名生長抑素受體陽性的腫瘤患者中，Lutathera在360名GEP-NETs患者組成的亞群裡，讓16%的患者出現部分腫瘤縮小。值得一提的是，第二項臨床試驗招募的患者是FDA"擴大使用"（expanded access）項目的一部分，該專案能讓罹患嚴重而危及生命疾病的患者獲得在研新藥，進行治療。基於這兩項試驗的資料，FDA也決定批准這款新藥上市，造福患者。"GEP-NETs是一類罕見的癌症，在初始治療失敗後，腫瘤會繼續生長，而患者的治療選擇很有限，"美國FDA腫瘤學卓越中心主任和血液病學與腫瘤學產品辦公室執行主任Richard Pazdur博士說道："這項批准為這些罕見癌症的患者帶來了新的治療方案。這也彰顯了FDA願意考慮'擴大使用'專案中的資料，來支援新療法的批准。""Lutathera的獲批標誌這一個重要的成就，也是對NET癌症群體的一個重要創新，" Advanced Accelerator Applications的主席兼總裁Susanne Schaffert博士說道："在30多年來，諾華一直開發NET和類癌綜合征的療法，支援NET群體。我們將一道推進創新核醫學療法，治療NET在內的多種腫瘤類型。我想不到有什麼更好的方法，來慶祝我們兩家公司的合作與未來。"我們祝賀諾華與Advanced Accelerator Applications斬獲這款新藥的獲批，也期待更多創新療法能層出不窮，造福患者。

參考資料：[1] Advanced Accelerator Applications Receives FDA Approval for Lutathera® for Treatment of Gastroenteropancreatic Neuroendocrine Tumors [2] FDA approves new treatment for certain digestive tract cancers

Clinically approved albumin-related formulations