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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


January 26, 2018 with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf

On January 26, 2018, the Food and Drug Administration approved lutetium Lu 177 dotatate (LUTATHERA®, Advanced Accelerator Applications USA, Inc.) a radiolabeled somatostatin analog, for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

Approval was based on data from NETTER-1 (NCT01578239), a randomized, multicenter, open-label, active-controlled trial in 229 patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors. Patients were randomized (1:1) to receive either lutetium Lu 177 dotatate (7.4 GBq [200 mCi] every 8 weeks for up to 4 administrations; maximum cumulative dose of 29.6 GBq) with long-acting octreotide (30 mg by intramuscular injection every 4 weeks) or high-dose long-acting octreotide (60 mg by intramuscular injection every 4 weeks). Lutetium Lu 177 dotatate was co-administered with an amino acid solution as a renal protectant. In the US, patients enrolled in NETTER-1 received Aminosyn II 10%, a commercially available solution of amino acids.

The major efficacy outcome measure was progression free survival (PFS) determined by a blinded independent radiology committee using RECIST 1.1. The median PFS was not reached for lutetium Lu 177 dotatate and was 8.5 months in the high-dose long-acting octreotide arm (hazard ratio 0.21; 95% CI: 0.13, 0.32; p<0.0001).

The efficacy of lutetium Lu 177 dotatate was also assessed in a subset (n=360) of 1214 patients enrolled in the ERASMUS Medical Center (MC) study with GEP-NET tumors who were assessed according to RECIST criteria. At the ERASMUS MC, lutetium Lu 177 dotatate was initially provided as expanded access under a general peptide receptor radionuclide therapy protocol at a single site in the Netherlands. Lutetium Lu 177 dotatate (7.4 GBq [200 mCi]) was administered every 6 to 13 weeks for up to 4 doses. The ORR was 16% (n=58), including 3 complete responses in this subset of 360 patients with GEP-NETs who were assessed according to RECIST criteria.

In the NETTER-1 study, the most common grade 3-4 adverse reactions occurring with a greater frequency (at least 4%) among patients receiving lutetium Lu 177 dotatate with long-acting octreotide compared to patients receiving high-dose octreotide alone included lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea and elevated AST (5% each), and increased ALT, hyperglycemia, and hypokalemia (4% each). In NETTER-1, with a median follow-up of 24 months, myelodysplastic syndrome was reported in 2.7% of patients receiving lutetium Lu 177 dotatate with long-acting octreotide; no patients receiving high-dose octreotide LAR developed myelodysplastic syndrome.

The recommended dose of lutetium Lu 177 dotatate is 7.4 GBq (200 mCi) as an intravenous infusion over 30 minutes every 8 weeks for a total of 4 doses.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf

FDA granted priority review for this application and previously granted Orphan Drug designation to lutetium Lu 177 dotatate for treatment of GEP-NETs. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 


Pharmacist's Applications to Practice

Lutetium Lu 177 Dotatate for the Treatment of Somatostatin Receptor–Positive Gastroenteropancreatic Neuroendocrine Tumors

Author: Katie Sias, PharmD
Clinical Coordinator for Hematology/Oncology
MidMichigan Health
Midland, MI

What is the potential role for lutetium lu 177 dotatate in the treatment of gastroenteropancreatic neuroendocrine tumors?1-3

  • The U.S. Food and Drug Administration (FDA) granted lutetium lu 177 dotatate approval in January 2018 for the treatment of somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. Standard therapy for NETs typically includes the use of a somatostatin analog because these tumors commonly overexpress somatostatin receptors. Lutetium lu 177 dotatate contains a somatostatin analog component called octreotate, as well as a radioactive isotope. This is the first dual-component somatostatin analog-radioisotope approved for a therapeutic indication; however, others have been tested and used as imaging agents to assist in tumor location with positron emission tomography (PET) scans.
    • Lutetium lu 177 dotatate was studied in the NETTER-1 trial, a randomized multicenter open-label active-controlled trial of 229 patients with progressive, well-differentiated, locally advanced or inoperable or metastatic somatostatin receptor–positive midgut carcinoid tumors. Patients had disease progression over the course of a maximum period of 3 years during treatment with octreotide LAR. Patients were randomized 1:1 to receive either long-acting octreotide 60 mg every 4 weeks or lutetium lu 177 dotatate every 8 weeks (for up to 4 doses) plus long-acting octreotide 30 mg every 4 weeks. The major efficacy outcome measure was progression-free survival (PFS), which was not reached for lutetium lu 177 dotatate and was 8.5 months in the long-acting octreotide 60-mg arm (hazard ratio [HR] 0.21; 95% confidence interval [CI]: 0.13–0.32; p < .001). Objective tumor responses were observed in 18% of patients who received lutetium lu 177 dotatate versus 3% in the control group (p < .001).
    • Lutetium lu 177 dotatate was also assessed in the ERASMUS Medical Center study. This included 360 patients with foregut, midgut, and hindgut GEP-NETs. It was initially provided for expanded access under a general peptide receptor radionuclide protocol at a single site in the Netherlands; consequently, the data collection was performed retrospectively. Lutetium lu 177 dotatate was administered every 6–13 weeks, as compared with the every 8-week administration in the NETTER-1 trial, and 55% of patients received a concomitant somatostatin analog. The major efficacy outcome was investigator-assessed objective response rate (ORR), which was 16% (95% CI: 13–20).
  • First-line systemic therapy for GEP-NETs usually consists of a somatostatin analog for symptom control (e.g., hormonal secretion) and tumor growth. There are no standard second-line systemic treatment options aside from everolimus for the treatment of nonfunctional NETs. Although the responses to lutetium lu 177 dotatate compare favorably with those of other systemic therapy options, no completed clinical trials have compared these treatment strategies in the second-line setting.
    • The phase 3 NETTER-1 trial showed that the median PFS was significantly longer for patients receiving lutetium lu 177 dotatate versus long-acting octreotide 60 mg.
    • The NETTER-1 trial also included a planned interim analysis of overall survival. There were 14 deaths in the lutetium lu 177 dotatate group and 26 deaths in the control group. Final analysis will be needed before any conclusion on overall survival can be drawn—this is planned to be performed either after 158 deaths have occurred or 5 years after the last patient undergoes randomization, whichever occurs first.
    • The dose of lutetium lu 177 dotatate is 7.4 GBq (200 mCi) every 8 weeks for a total of four doses, to be infused intravenously over 30 minutes. During lutetium lu 177 treatment, long-acting octreotide 30 mg should be administered intramuscularly 4–24 hours after each lutetium lu 177 dotate dose and then monthly after completion of all four treatments.

What role can the pharmacist play in the management of patients on lutetium lu 177 dotatate? 1-3

  • Because lutetium lu 177 dotatate is a radiopharmaceutical, pharmacists at most institutions will likely not be handling the product directly; however, the pharmacist will have a role when premedications and concomitant medications are involved.
    • Somatostatin analogs
      • Before lutetium lu 177 dotatate is administered, pharmacists can assist by verifying that any long-acting somatostatin analogs were not used in the previous 4 weeks. Short-acting octreotide used for symptom control must be discontinued at least 24 hours before initiation of lutetium lu 177 dotatate.
      • Long-acting octreotide 30 mg should be administered intramuscularly 4–24 hours after each lutetium lu 177 dotatate dose. Short-acting octreotide may be given for symptom control during treatment as long as it is not given within 24 hours of administration of lutetium lu 177 dotatate.
      • Long-acting octreotide 30 mg should be continued every 4 weeks after completing lutetium lu 177 dotatate until disease progression or for up to 18 months following treatment initiation.
    • Amino acid solution
      • An intravenous amino acid solution containing L-lysine and L-arginine should be infused beginning 30 minutes prior to administration of lutetium lu 177 dotatate, continuing through the infusion of lutetium lu 177 dotatate and for at least 3 hours following. This is for renal protection because somatostatin analogs linked to radioactive isotopes have been found to cause serious kidney problems.
      • Of note, the NETTER-1 trial excluded patients with a serum creatinine greater than 1.7 mg/dl or a creatinine clearance of less than 50 ml/min, and no evidence of nephrotoxicity was observed in patients in the lutetium lu 177 dotatate group.
    • Antiemetic
      • An antiemetic should be administered 30 minutes before the amino acid solution. In the United States, patients enrolled in the NETTER-1 trial received Aminosyn II 10%, and nausea experienced by patients was attributed to the amino acid solution. Patients treated off-trial in Europe typically received infusions of only two amino acids, and significantly less nausea was observed.
  • Pharmacists can also monitor for lab abnormalities that could be signaling a developing toxicity—in some cases the dose of lutetium lu 177 dotatate may need to be reduced or withheld. In particular, it is important to monitor for hematologic adverse events such as thrombocytopenia, anemia, and neutropenia, as well as hepatotoxicity and renal toxicity (see package insert for specific hold parameters).

Clinical Pearls2-5

  • The most common adverse events seen among patients receiving lutetium lu 177 dotatate in the NETTER-1 trial were nausea (59%) and vomiting (47%). Many of these events were attributed to the amino acid infusion rather than to the lutetium lu 177 dotatate itself. Also, patients in the lutetium lu 177 dotatate group experienced statistically significantly higher rates of hematologic adverse events (any grade), including thrombocytopenia, anemia, lymphopenia, and leukopenia. These hematologic events were noted to be transient, and few were considered to be grade 3 or 4. Treatment may need to be withheld or a dose reduction may be warranted, depending on the degree of toxicity.
  • Pharmacists should ensure that patients are following the appropriate schedule for concomitant somatostatin analog administration and receive appropriate supportive care surrounding the lutetium lu 177 dotatate infusion with an antiemetic and amino acid infusion.
  • Prospective randomized studies of radiolabeled somatostatin analogs have not yet been completed in patients with advanced pancreatic NETs.

References

  1. U.S. Food and Drug Administration: Approved Drugs. FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS. January 26, 2018. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm594105.htm. Accessed February 14, 2018.
  2. Strosberg J, El-Haddad G, Wolin E, et al: Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376(2):125-135.
  3. Lutetium Lu 177 dotatate (Lutathera) [package insert]. Millburn, NJ: Advanced Accelerator Applications USA, Inc.; January 2018.
  4. National Comprehensive Cancer Network. Neuroendocrine Tumors. Version 3.2017. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed February 26, 2018.
  5. National Cancer Institute. New Therapy Benefits Patients with Neuroendocrine Tumors. February 2, 2018. https://www.cancer.gov/news-events/cancer-currents-blog/2017/new-treatment-neuroendocrine-tumors. Accessed February 14, 2018.
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