IMPORTANT SAFETY INFORMATION AND INDICATION

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Radiation Exposure: Treatment with LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure and is associated with an increased risk for cancer. Radiation can be detected in the urine for up to 30 days following LUTATHERA administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with LUTATHERA consistent with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient release guidance, and instructions to the patient for follow-up radiation protection at home.

INDICATION

LUTATHERA^® (lutetium Lu 177 dotatate) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

Efficacy

NETTER-1 Study Design

More Than 200 Patients With SSTR-Positive Midgut NETs Were Evaluated in a Phase 3 Clinical Trial of LUTATHERA^1,2

NETTER-1: a pivotal, phase 3, randomized, multicenter, open-label, active-control trial of LUTATHERA

1:1 Randomization	LUTATHERA Arm (n=116)	7.4 GBq (200 mCi) LUTATHERA every 8 weeks (±1 week for a total of 4 IV doses, maximum cumulative dose of 29.6 GBq) plus long-acting octreotide 30 mg IM 4 to 24 hours after each dose of LUTATHERA and every 4 weeks after completion of treatment with LUTATHERA until disease progression or until Week 76 of the study	5-year follow-up of patients who entered long-term follow-up phase^3,a
	Active- Control Arm (n=113)	High-dose, long-acting octreotide (60 mg IM every 4 weeks)

1:1 Randomization	LUTATHERA Arm (n=116)	7.4 GBq (200 mCi) LUTATHERA every 8 weeks (±1 week for a total of 4 IV doses, maximum cumulative dose of 29.6 GBq) plus long-acting octreotide 30 mg IM 4 to 24 hours after each dose of LUTATHERA and every 4 weeks after completion of treatment with LUTATHERA until disease progression or until Week 76 of the study	5-year follow-up of patients who entered long-term follow-up phase^3,a
	Active- Control Arm (n=113)	High-dose, long-acting octreotide (60 mg IM every 4 weeks)

^aThe final analysis of overall survival was planned to be performed when 158 deaths had occurred or 5 years from the date of randomization of the last patient, whichever occurred first.³

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to documented disease progression (as evaluated per RECIST v1.1 by independent central review by radiologists who were unaware of the treatment) or death from any cause^1,2
Secondary endpoints were overall response rate (ORR), duration of response (DOR), overall survival (OS), and safety¹
Patients in both arms could receive short-acting octreotide for symptom management; however, short-acting octreotide was withheld for at least 24 hours before each dose of LUTATHERA¹

Final analysis

After centrally confirmed disease progression, discontinuation of study treatment without confirmed progression, or completion of the 18-month treatment period, patients entered long-term follow-up³

– In total, 200 (87%) of 231 patients entered long-term follow-up, including 101 (86%) of 117 patients in the LUTATHERA arm and 99 (87%) of 114 patients in the control arm^b

Median duration of follow-up was 76.3 months (range, 0.4–95.0 months) in the LUTATHERA arm and 76.5 months (range, 0.1–92.3 months) in the control arm³

36% (41 of 114) of patients in the long-acting octreotide-alone arm received subsequent PRRT during the long-term follow-up³

^bIncluded 2 patients randomized after the primary PFS analysis data cutoff (July 24, 2015).³

Inclusion and Exclusion Criteria in NETTER-1^1,2
Key Inclusion Criteria	Key Exclusion Criteria
Patients with midgut NETs that had metastasized or were locally advanced, that were inoperable, and that had progressed during treatment with long-acting octreotide Karnofsky performance score ≥60 Tumor with well-differentiated histologic features (Ki-67 index ≤20%) Confirmed presence of SSTRs on all lesions (OctreoScan uptake ≥ normal liver) Patients must have progressive disease based on RECIST v1.1, while receiving an uninterrupted fixed dose of long-acting octreotide (20-30 mg/3-4 weeks) CrCL ≥50 mL/min No prior treatment with PRRT No prior external radiation therapy to >25% of the bone marrow	Serum creatinine level >150 μmol/L or CrCL <50 mL/min Hemoglobin level <8.0 g/dL White blood cell count <2000/mm³ Platelet count <75,000/mm³ Total bilirubin level >3 times ULN Serum albumin >3.0 g/dL unless prothrombin time is within the normal range Treatment with >30 mg long-acting octreotide within 12 weeks before randomization PRRT at any time before randomization Any surgery, liver-directed transarterial therapy, or chemotherapy within 12 weeks before randomization

LUTATHERA is the first FDA-approved RLT for the treatment of adult patients with SSTR-positive GEP-NETs.⁴

Progression-Free Survival

A 79% reduction in the risk of disease progression or death in the LUTATHERA arm vs active-control arm¹

Progression free survival chart for LUTATHERA® (lutetium Lu 177 dotatate)

^cAt time of analysis detailed in Prescribing Information for LUTATHERA.¹

PFS in NETTER-1¹
Progression-Free Survival	LUTATHERA With Long‑Acting Octreotide (n=116)	Long-Acting Octreotide (n=113)
Events, n (%)	27 (23%)	78 (69%)
Progressive disease, n (%)	15 (13%)	61 (54%)
Deaths, n (%)	12 (10%)	17 (15%)

Based on the PFS results, consider LUTATHERA for after initial progression on long-acting octreotide.^1,5

Overall Response Rate

A 3 times greater ORR in LUTATHERA arm vs active-control arm¹

There was a 13% ORR for LUTATHERA with long-acting octreotide 30 mg compared with a 4% ORR for high-dose, long-acting octreotide 60 mg (P=.0148): a 3-fold increase.¹

Complete response (CR) was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have a reduction in the short axis to <10 mm.⁶ Partial response (PR) was defined as a ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.⁶

RECIST criteria have several drawbacks for identifying progression in clinical practice.

Median duration of response was not reached for LUTATHERA (95% CI, 2.8 months-NE) compared with 1.9 months for high-dose, long-acting octreotide alone (95% CI, 1.9 months-NE).¹

Overall Survival

Final Analysis of NETTER-1

In the final OS analysis, there was no statistically significant difference in OS between the 2 treatment arms
Certain data from the final analysis are not included in the full Prescribing Information for LUTATHERA¹
At the time of the final OS analysis, which occurred 66 months after the primary PFS analysis, 117 patients were randomized to the LUTATHERA arm and 114 patients were randomized to the octreotide arm¹
The required assumptions for the Cox model for OS were not fulfilled, therefore making the HR uninterpretable³

^dThe prespecified final analysis of OS was completed 5 years after the last patient was randomized because this occurred before the alternative cutoff of 158 deaths (data cutoff date, January 18, 2021).³

^eIncluded 2 patients randomized after the primary PFS analysis data cutoff (July 24, 2015). Median duration of follow-up was 76.3 months in the LUTATHERA arm and 76.5 months in the control arm.³

Patient-Reported Symptom Diaries

Patient-reported symptom-free days from NETTER-1

Data from the patient symptom diaries should be interpreted with caution
Patient symptom diaries are a nonvalidated instrument collected per protocol in NETTER-1; analysis methods for symptom scores were not prespecified; patients were unable to be blinded to treatment due to the open-label nature of the trial; and n values decreased over time^2,7
Patient symptom diaries data are not included in the Prescribing Information for LUTATHERA

^fAnalysis of patient-reported daily symptom diaries from NETTER-1.

All patients enrolled in the NETTER-1 trial were asked to record the presence or absence (in the preceding 24 hours) of 18 predefined symptoms in a paper-based, daily diary⁷
A “symptom score” was defined as the number of days with each symptom within the 4-week period between clinic visits during treatment⁷
The change from baseline in the mean number of days with symptoms was assessed using a mixed model for repeated measures, adjusting for baseline symptom status, time from randomization, treatment, and the interaction between time from randomization and treatment⁷
Shown above are the 3 symptoms considered most clinically relevant to patients with midgut NETs, namely abdominal pain, diarrhea, and flushing⁷

Post Hoc Progression-Free Survival

PFS Within Subgroups of the NETTER-1 Trial⁸

In a post hoc subgroup analysis of patients in the NETTER-1 trial, the impact of liver tumor burden, alkaline phosphatase (ALP)⁸ elevation, and target lesion size on PFS was assessed in the ¹⁷⁷Lu-Dotatate plus high-dose octreotide arm vs control.

Results are based on a post hoc analysis of the key primary endpoint and are observational in nature; as such, they were not powered to show statistical significance.

PFS by extent of liver tumor burden

In patients with high vs low tumor burden, correlation was assessed between liver function tests and baseline tumor burden*:

High Tumor Burden (>50%): Median PFS was NR (n=19) vs 5.4 months in the control arm (n=30)

Low Tumor Burden (<25%): Median PFS was NR (n=71) vs 9.1 months in the control arm (n=70)

*Findings in patients with tumor burden >50% do not translate to results in patients with extreme tumor burden (eg, >90%). A limitation of this study was that central readers did not specify patients with extreme tumor burden (>90%), and therefore no specific safety analysis in that subgroup was possible.⁸

PFS by normal or elevated ALP

In patients with elevated vs normal baseline ALP, correlation was assessed between PFS and serum ALP elevation^†^‡:

Normal ALP Baseline Group: Median PFS was NR (n=71) vs 8.5 months in the control arm (n=75)

Elevated Baseline ALP Group: Median PFS was NR (n=41) vs 5.8 months in the control arm (n=37)

^†Normal or > ULN. ALP was based on institutional ULN, and the log-rank test was used for within–treatment arm PFS comparisons.⁸
^‡No significant difference in PFS was observed among patients with normal versus elevated ALP in the high-dose octreotide control arm (log-rank P=.0911).⁸

PFS by presence or absence of a large lesion

Patients were stratified into 2 subgroups based on the presence or absence of at least 1 target lesion >30 mm in diameter at any body site on CT or MRI at baseline^§^∥:

Presence of ≥1 Large Tumors (>30 mm diameter): Median PFS was NR (n=79) vs 8.5 months in the control arm (n=74)

Absence of Large Tumors (<30 mm diameter): Median PFS was NR (n=37) vs 8.3 months in the control arm (n=39)

^§Patients were stratified into 2 subgroups based on the presence or absence of at least 1 target lesion >30 mm in diameter at any body site on CT or MRI at baseline. The approximate size threshold has been described in previous literature as distinguishing "large" tumors from smaller ones in animal studies of PRRT.⁸
^‖Among target lesions in patients within the ¹⁷⁷Lu-Dotatate arm, 128 large tumors (>30 mm diameter) were identified, of which 89 (70%) were liver tumors; in the high-dose octreotide arm, 134 large tumors were identified; 93 (69%) were liver tumors.⁸

Next: Safety

5-HIAA, 5-hydroxyindoleacetic acid; CgA, chromogranin A; CrCL, creatinine clearance; CT, computed tomography; FDA, US Food and Drug Administration; GEP-NET, gastroenteropancreatic neuroendocrine tumor; HR, hazard ratio; IM, intramuscular; ITT, intent to treat; IV, intravenous; MRI, magnetic resonance imaging; NE, not evaluable; NETs, neuroendocrine tumors; NR, not reached; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors; RLT, radioligand therapy; SSTR, somatostatin receptor; ULN, upper limit of normal.

References: 1. Lutathera. Prescribing information. Advanced Accelerator Applications. 2. Strosberg J, El-Haddad G, Wolin E, et al; for the NETTER-1 trial investigators. Phase 3 trial of ¹⁷⁷Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. 3. Strosberg JR, Caplin ME, Kunz PL, et al; NETTER-1 investigators. 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. 2021;22(12):1752-1763. 4. US Food and Drug Administration. FDA approves new treatment for certain digestive tract cancers [press release]. January 26, 2018. Accessed February 24, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-certain-digestive-tract-cancers 5. Hope TA, Bodei L, Chan JA, et al. NANETS/SNMMI consensus statement on patient selection and appropriate use of ¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy. J Nucl Med. 2020;61(2):222-227. 6. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 7. Strosberg J, Srirajaskanthan R, El-Haddad G, et al; NETTER-1 study group. Symptom diaries of patients with midgut neuroendocrine tumors treated with ¹⁷⁷Lu-DOTATATE. J Nucl Med. 2021;62:1712-1718. 8. Strosberg J, Kunz PL, Hendifar A, et al; NETTER-1 study group. Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with ¹⁷⁷Lu-dotatate: an analysis of the NETTER-1 study. Eur J Nucl Med Mol Imaging. 2020;47(10):2372-2382.

INDICATION

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Radiation Exposure: Treatment with LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure and is associated with an increased risk for cancer. Radiation can be detected in the urine for up to 30 days following LUTATHERA administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with LUTATHERA consistent with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient release guidance, and instructions to the patient for follow-up radiation protection at home.
Myelosuppression: In the NETTER-1 clinical trial, myelosuppression occurred more frequently in patients receiving LUTATHERA with long-acting octreotide compared with patients receiving high-dose long-acting octreotide (all grades/grade 3/4): anemia (81%/0 vs 54%/1%), thrombocytopenia (53%/1% vs 17%/0), and neutropenia (26%/3% vs 11%/0). In NETTER-1, platelet nadir occurred at a median of 5.1 months following the first dose. Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels. The median time to platelet recovery was 2 months. Fifteen of the 19 patients in whom platelet recovery was not documented had post-nadir platelet counts. Among these 15 patients, 5 improved to grade 1, 9 to grade 2, and 1 to grade 3. Monitor blood cell counts. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of myelosuppression.
Secondary Myelodysplastic Syndrome and Leukemia: In NETTER-1, with a median follow-up time of 76 months in the main study, myelodysplastic syndrome (MDS) was reported in 2.3% of patients receiving LUTATHERA with long-acting octreotide compared with no patients receiving high-dose long-acting octreotide. In ERASMUS, a phase 2 clinical study, 16 patients (2.0%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to onset was 29 months (range, 9-45 months) for MDS and 55 months (range, 32-125 months) for acute leukemia.
Renal Toxicity: In ERASMUS, 8 patients (<1%) developed renal failure 3 to 36 months following LUTATHERA. Two of these patients had underlying renal impairment or risk factors for renal failure (eg, diabetes or hypertension) and required dialysis. Administer the recommended amino acid solution before, during, and after LUTATHERA to decrease the reabsorption of lutetium Lu 177 dotatate through the proximal tubules and decrease the radiation dose to the kidneys. Advise patients to hydrate and to urinate frequently before, on the day of, and on the day after administration of LUTATHERA. Monitor serum creatinine and calculated creatinine clearance. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of renal toxicity. Patients with baseline renal impairment may be at increased risk of toxicity due to increased radiation exposure; perform more frequent assessments of renal function in patients with baseline mild or moderate impairment. LUTATHERA has not been studied in patients with baseline severe renal impairment (creatinine clearance <30 mL/min) or those with end-stage renal disease.
Hepatotoxicity: In ERASMUS, 2 patients (<1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with 1 patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure. Monitor transaminases, bilirubin, serum albumin, and the international normalized ratio during treatment. Withhold dose, reduce dose, or permanently discontinue LUTATHERA based on the severity of hepatotoxicity.
Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema, occurred in patients treated with LUTATHERA. Monitor patients closely for signs and symptoms of hypersensitivity reactions, including anaphylaxis, during and following LUTATHERA administration for a minimum of 2 hours in a setting in which cardiopulmonary resuscitation medication and equipment are available. Discontinue the infusion upon the first observation of any signs or symptoms consistent with a severe hypersensitivity reaction and initiate appropriate therapy. Premedicate patients with a history of grade 1/2 hypersensitivity reactions to LUTATHERA before subsequent doses. Permanently discontinue LUTATHERA in patients who experience grade 3/4 hypersensitivity reactions.
Neuroendocrine Hormonal Crisis: Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm, and hypotension, occurred in <1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial LUTATHERA dose. Two (<1%) patients were reported to have hypercalcemia. Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction, or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated.
Embryo-Fetal Toxicity: LUTATHERA can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating LUTATHERA. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LUTATHERA and for 7 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LUTATHERA and for 4 months after the last dose.
Risk of Infertility: LUTATHERA may cause infertility in males and females. Radiation absorbed by testes and ovaries from the recommended cumulative LUTATHERA dose falls within the range in which temporary or permanent infertility can be expected following external beam radiotherapy.

ADVERSE REACTIONS

The most common grade 3/4 adverse reactions (≥4% with a higher incidence in the LUTATHERA arm) observed in NETTER-1 were lymphopenia (44%), increased gamma-glutamyl transferase (20%), vomiting (7%), nausea (5%), increased aspartate aminotransferase (5%), increased alanine aminotransferase (4%), hyperglycemia (4%), and hypokalemia (4%).

In ERASMUS, the following serious adverse reactions have been observed with a median follow-up time of >4 years after treatment with LUTATHERA: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Patients should be counseled and monitored in accordance with the LUTATHERA Prescribing Information.

DRUG INTERACTIONS

Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of LUTATHERA. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. Administer short- and long-acting octreotide during LUTATHERA treatment as recommended.

Glucocorticoids can induce downregulation of subtype 2 somatostatin receptors. Avoid repeated administration of high doses of glucocorticoids during treatment with LUTATHERA.

SPECIFIC POPULATIONS

Lactation: Because of the potential risk for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LUTATHERA and for 2.5 months after the last dose.

Please see full Prescribing Information.