Drugs

Drug Trials Snapshots: LUTATHERA

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the LUTHATERA Package Insert for complete information.

LUTATHERA (lutetium 177 dotate)
{Lou-Ta-ther-a}
Advanced Accelerator Applications, S.A.
Approval date: January 26, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

LUTATHERA is a drug for the treatment of adults who have a specific type of tumor called a gastroenteropancreatic neuroendocrine tumor (GEP-NET). NETs are rare tumors that develop in certain hormone-producing cells of the body.

LUTATHERA is intended for the treatment of throat, esophagus, stomach, and intestine neuroendocrine tumors that have somatostatin receptors.

How is this drug used?

LUTATHERA is given by a healthcare provider directly into the bloodstream. This is known as an intravenous or IV infusion. It takes about 30 minutes to receive a LUTATHERA infusion.

LUTATHERA is given once every 8 weeks for a total of 4 doses.

What are the benefits of this drug?

LUTATHERA increased the length of time tumors did not grow after treatment (progression free survival).

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results for the clinical trial NETTER-1 in patients with somatostatin-receptor positive midgut GEP-NETs. The primary endpoint was progression free survival, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1., from the date of randomization to tumor progression.

Table 2. Efficacy Results in NETTER-1

 LUTATHERA and Long-Acting Octreotide (30 mg)
N=116
Long-Acting Octreotide (60 mg)
N=113
PFS by IRC
Events (%)27 (23%)78 (69%)
Progressive Disease, n (%)15 (13%)61 (54%)
Death, n (%)12 (10%)17 (15%)
Median in months (95% CI)NRc (NE, NE)8.5 (5.8, 9.1)
Hazard ratioa (95% CI)0.21 (0.13, 0.32)
P-Valueb< 0.0001
OS (Updated)
Deaths (%)27 (23%)43 (38%)
Median in months (95% CI)NR (31.0, NE)27.4 (22.2, NE)
Hazard ratioa,d (95% CI)0.52 (0.32, 0.84)
ORR by IRC
ORR, % (95% CI)13% (7%,19%)4 (0.1%, 7%)
Complete response rate, n (%)1 (1%)0
Partial response rate, n (%)14 (12%)4 (4%)
P-Valuee0.0148
Duration of response, median in months (95% CI)NR (2.8, NE)1.9 (1.9, NE)

a: Hazard ratio based on the unstratified Cox model
b: Unstratified log rank test
c: Median follow-up 10.5 months at time of primary analysis of PFS (0 to 29 months)
d: Interim analysis of OS not statistically significant based on pre-specified significance criteria
e: Fisher’s Exact test

NR: Not reached; NE: Not evaluable
LUTATHERA Prescribing Information

Efficacy in the ERASMUS study was assessed, in a subset of 360 patients with GEP-NETs, whose tumors were assessed based on standardized imaging criteria called RECIST.The investigator-assessed overall response rate (ORR) was 16% (95% CI 13, 20). Three complete responses were observed (< 1%). Median duration of response (DoR) in the 58 responding patients was 35 months (95% CI: 17, 38).

LUTATHERA Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: LUTATHERA worked similarly in men and women.
  • Race: Most of the patients were White. Differences in how well the drug worked among races could not be determined because of the small number of patients in other races.
  • Age: LUTATHERA worked similarly in patients younger and older than 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table below presents efficacy results by subgroup in NETTER-1 trial.

Table 3. NETTER-1 Trial: Subgroup Analyses

 Sample Size (Censored/Events)Un-stratified HR
(95% CI)
LUTATHERA + Octreotide LAR (30 mg)
N=116
Octreotide LAR (60 mg)
N=113
Overall89/2735/780.21 (0.13, 0.32)
Sex
Men46/1716/370.24 (0.13, 0.43)
Women43/1019/410.16 (0.08, 0.33)
Age (years)
≤6547/1421/350.23 (0.12, 0.42)
>6542/1314/430.20 (0.11, 0.37)
Race
White67/2530/660.25 (0.16, 0.40)
Other22/25/120.08 (0.02, 0.34)
Region
Europe40/1013/310.17 (0.08, 0.35)
USA49/1722/470.24 (0.14, 0.42)

HR=hazard ratio

FDA Review

What are the possible side effects?

A part of LUTATHERA is radioactive. Treatment with LUTATHERA exposes patients to radiation, and may increase the risk of lifetime radiation exposure.

LUTATHERA may cause serious side effects including low levels of blood cells, abnormal blood cell production (secondary myelodysplastic syndrome), leukemia, kidney or liver injury, increased levels of hormones in the body, (neuroendocrine hormonal crisis), injury to a fetus, and infertility.

The most common side effects of LUTATHERA are nausea, vomiting, tiredness, abdominal pain, and diarrhea.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions in patients with somatostatin-receptor positive midgut GEP-NETs, who received at least one dose of LUTATHERA, in the NETTER-1 trial (safety popuation).

Table 4. Adverse Reactions Occurring in ≥ 5% (All Grades) of Patients Receiving LUTATHERA in NETTER-1

Adverse Reaction1LUTATHERA and Long-Acting Octreotide (30 mg)
 (N = 111)
Long-Acting Octreotide (60 mg)
(N = 112)
All Grades %Grades 3-4 %All Grades %Grades 3-4 %
Cardiac disorders
Atrial fibrillation5100
Gastrointestinal disorders
Nausea655122
Vomiting53790
Abdominal pain263193
Diarrhea263181
Constipation10050
General disorders
Fatigue381262
Peripheral edema16091
Pyrexia8030
Metabolism and nutrition disorders
Decreased appetite210113
Musculoskeletal and connective tissue disorders
Back pain132100
Pain in extremity11050
Myalgia5000
Neck Pain5000
Nervous system disorders
Headache17050
Dizziness17080
Dysgeusia8020
Psychiatric disorders
Anxiety12150
Renal and urinary disorders
Renal failure*12331
Radiation-related urinary tract toxicity**8030
Respiratory, thoracic and mediastinal disorders
Cough11160
Skin and subcutaneous tissue disorders
Alopecia12020
Vascular disorders
Flushing14190
Hypertension12272

1National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Only displays adverse reactions occurring at a higher incidence in LUTATHERA-treated patients [between arm difference of ≥5% (all grades) or ≥2% (grades 3-4)]

*Includes the terms: Glomerular filtration rate decreased, acute kidney injury, acute prerenal failure, azotemia, renal disorder, renal failure, renal impairment

**Includes the terms: Dysuria, micturition urgency, nocturia, pollakiuria, renal colic, renal pain, urinary tract pain and urinary incontinence

The following rates of serious adverse reactions were reported in 811 evaluable patients from the ERASMUS experience: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%).

LUTATHERA Prescribing Information

Were there any differences in side effects among sex, race and age?

  • Sex: The occurrence of side effects was similar in men and women.
  • Race: Most of the patients were White. Differences in the occurrence of side effects among races could not be determined, because of the small number of patients in other races.
  •  
  • Age: The occurrence of side effects was similar in patients younger and older than 65 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The table below summarizes the most common organ system based (gastrointestinal) adverse events by subgroup in safety population from NETTER-1 trial.

Table 5. Gastrointestinal Events by Subgroup in NETTER-1 Trial (Safety Population)

Demographic ParametersLUTATHERA + Long-Acting Octreotide
n/N (%)
Long-Acting Octreotide
n/N (%)
Sex
Men51/59 (86%)35/52 (67%)
Women51/53 (96%)41/59 (69%)
Age Group
<65 years of age55/58 (95%)39/54 (72%)
≥65 years of age47/54 (87%)37/57 (65%)
Race
White83/88 (94%)67/94 (71%)
African American or Black4/5 (80%)2/5 (40%)
Asian1/1 (100%)0/0 (0%)
Other6/6 (100%)3/4 (75%)

1Race and/or ethnicity was not collected for 21 patients, in France, due to local regulations

Clinical Trial Data

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved LUTATHERA based primarily on evidence from one clinical trial, NETTER-1 (NCT01578239) of 229 patients with somatostatin-receptor positive midgut GEP-NETs. The trial was conducted at 41 sites in Belgium, France, Germany, Italy, Portugal, Spain, United Kingdom, and the United States.

FDA also considered additional information from a large single-center experience (ERASMUS), in patients with somatostatin-receptor positive GEP-NETs other than those arising from the midgut. The patients were treated in the Netherlands. Demographics of these patients are presented in Table 7, under MORE INFO section.

Figure 1 summarizes how many men and women were enrolled in the clinical trial NETTTER-1 used to evaluate efficacy and safety.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trial, NETTER-1. In total, 116 men (51%) and 113 women (49%) participated in the clinical trial.

FDA Review

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trial NETTER-1.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race in the clinical trial. In total, 188 White (83%), 10 Black or African American (4%), 1 Asian (less than 1%%), 9 Other (4%), and 21 patients missing data for race (9%) participated in the clinical trials.

1 Race was not collected for 21 patients, in France, due to local regulations

FDA Review

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage
White18883%
Black or African American104%
Asian1less than 1%
Other94%
Missing1219%

1 Race was not collected for 21 patients, in France, due to local regulations

FDA Review

Figure 3 summarizes the percentage of patients by age in the clinical trial NETTER-1.

Figure 3. Baseline Demographics by Age

Pie charts summarizing how many individuals of certain age groups were in the clinical trials. In total, 117 patients were less than 65 years old (49%%) and 112 patients were 65 and older (51%).

FDA Review

Who participated in the trials?

The tables below summarize demographics of patients enrolled in the clinical trials.

Table 6. Demographic Characteristics of Patients Enrolled in NETTER-1 Trial

Demographic ParametersLUTATHERA + Long-Acting Octreotide (30 mg)
N=116
n (%)
Long-Acting Octreotide (60 mg)
N=113
n (%)
Total
N=229
n (%)
Sex
Men63 (54%)53 (47%)116 (51%)
Women53 (46%)60 (53%)113 (49%)
Age
Median (years)646564
Median (range)(28, 84)(34, 87)(28, 87)
Age Groups
< 65 years61 (53%)56 (50%)117 (51%)
≥ 65 years55 (47%)57 (50%)112 (49%)
Race
White92 (79%)96 (85%)188 (82%)
Black or African American5 (4%)5 (4%)10 (4%)
Asian1 (1%)0 (0%)1 (<1%)
Other6 (5%)3 (3%)9 (4%)
Missing112 (10%)9 (8%)21 (9%)
Ethnicity
Hispanic or Latino6 (5%)2 (2%)8 (3%)
Not Hispanic or Latino98 (84%)102 (90%)200 (87%)
Missing112 (10%)9 (8%)21 (9%)
Region
North America66 (57%)69 (61%)135 (59%)
Europe50 (43%)44 (39%)94 (41%)

1 Race and/or ethnicity was not collected for 21 patients, in France, due to local regulations

FDA Review

Table 7. Demographic Characteristics of Patients Treated on ERASMUS Protocol

Demographic ParametersN=1214
n (%)
Sex
Men658 (54%)
Women556 (46%)
Age
Median (years)58
Median (range)(16, 90)
Age group
< 65 years838 (69%)
≥ 65 years376 (31%)
Region
North America132 (11%)
Europe1021 (84%)
Latin America/Asia Pacific57 (5%)
Africa4 (<1%)

1Data on race and/or ethnicity were not reported in the ERASMUS database

Clinical Trial Report

How were the trials designed?

The benefit and side effects of LUTATHERA were primarily evaluated in one clinical trial, NETTER-1 (NCT01578239). Enrolled patients had tumors which could not be surgically removed and were worsening while receiving treatment with octreotide.

Patients were randomly assigned to receive either LUTATHERA with long-acting octreotide or long-acting octreotide, at a higher dose, alone. LUTATHERA was injected through the vein and long-acting octreotide was injected in the muscle. Both, patients and health care providers knew which treatment was given. The benefit of LUTATHERA was evaluated by measuring the length of time that tumors did not grow after treatment and compared it to the control group (progression free survival).

The FDA considered additional data from a single-center in the Netherlands, ERASMUS. All patients received LUTATHERA with octreotide. Patients and health care providers knew which treatment was given. The benefit of LUTATHERA was evaluated by measuring if and how much the tumor size changed during treatment (the overall response rate).

How were the trials designed?

NETTER-1 was an open-label, randomized, active controlled trial in adults with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive midgut carcinoid tumors. Patients were randomized to receive either LUTATHERA 7.4 GBq every 8 weeks via intravenous infusion for a maximum of 4 doses with octreotide intramuscularly 30 mg every 4 weeks, or octreotide 60 mg intramuscularly every 4 weeks. The primary efficacy outcome was progression free survival as determined by a blinded independent radiology committee (IRC) per RECIST v1. 1.

ERASMUS was a collection of data from a single center, open-label, single-arm treatment protocol of patients with midgut tumors and various somatostatin-receptor positive neuroendocrine tumors. All patients received LUTATHERA as 4 intravenous infusions of 7.4 GBq (200 mCi) at 6-13 week intervals. The primary efficacy outcome was overall response rate as evaluated by investigator using RECIST criteria.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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Page Last Updated: 02/20/2018
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