Efficacy

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 (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 phase3,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 (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 phase3,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 end point 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 end points 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-11,2
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

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

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

PFS in NETTER-11
Progression-Free Survival	LUTATHERA With Long‑Acting Octreotide (30 mg) (n=116)	Long-Acting Octreotide (60 mg) (n=113)
Events, n (%)	27 (23%)	78 (69%)
Progressive disease, n (%)	15 (13%)	61 (54%)
Deaths, n (%)	12 (10%)	17 (15%)

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.

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-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

 

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 end point 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; 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]. Millburn, NJ: 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. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-certaindigestive-tract-cancers. Accessed February 24, 2021. 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.