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

Abstract

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate.

Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.

Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.

Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

Keywords: 177Lu-Dotatate; Liver tumour burden; NETTER-1; Neuroendocrine tumour; Octreotide.

Conflict of interest statement

J. Strosberg reports fees for consulting or advisory roles with Novartis; participation in speakers’ bureaus with Ipsen and Lexicon; and research funding from Merck and Novartis.

P. L. Kunz reports fees for consulting or advisory roles with Advanced Accelerator Applications, Ipsen, Lexicon, and Novartis; research funding from Advanced Accelerator Applications, Ipsen, Lexicon, Xencor, and Brahams; and is a stockholder with Guardant Health.

A. Hendifar reports fees for consulting or advisory roles with Novartis and Ipsen; and research funding from Halo, Ipsen, Novartis, Merck, Xencor, AbbVie.

J. Yao reports fees for consulting or advisory roles with Novartis, Ipsen, Hutchison Medi Pharma, and Tarveda.

D. Bushnell reports honoraria from Novartis, Advanced Accelerator Applications; consulting or advisory roles with Novartis, Advanced Accelerator Applications; and research funding from Novartis, Advanced Accelerator Applications.

M. H. Kulke reports fees for consulting or advisory roles with Novartis, Lexicon, Ipsen, Tarveda; and research funding from Lexicon and Ipsen; and providing expert testimony on behalf of Novartis.

R. P. Baum reports fees for consulting or advisory roles with ITG; and is a stockholder with Advanced Accelerator Applications and Endocyte.

M. Caplin reports honoraria from Advanced Accelerator Applications, Novartis, Ipsen, and Pfizer; consulting or advisory roles with Advanced Accelerator Applications, Novartis, Ipsen, and Pfizer; participation in speakers’ bureaus with Advanced Accelerator Applications, Novartis, Ipsen, and Pfizer; research funding from Advanced Accelerator Applications and Ipsen; and travel, accommodations, or expenses from Advanced Accelerator Applications and Ipsen.

P. Ruszniewski reports honoraria from Ipsen, Novartis, Advanced Accelerator Applications, ITN, and Keocyt; fees for consulting or advisory roles with Ipsen, Novartis, and Advanced Accelerator Applications; travel, accommodations, or expenses from Ipsen; and research funding from Novartis; and fees for providing expert testimony on behalf of Advanced Accelerator Applications.

E. Delpassand reports honoraria from Advanced Accelerator Applications and Endocyte; fees for consulting or advisory roles with Endocyte; participation in speakers’ bureaus with Advanced Accelerator Applications; patents, royalties or other intellectual property with Radiomedix, Inc.; travel, accommodations, or expenses from Endocyte, Advanced Accelerator Applications ITG/ITM GmbH; and is a stockholder with Radiomedix, Inc., Excel Diagnostics, Westchase Imaging, Endocyte, and GE.

C. Verslype reports fees for consulting or advisory roles with Ipsen, Novartis, Bayer, Sirtex; participation in speakers’ bureaus with Bayer; and research funding from Ipsen and Bayer;

A. Benson reports fees for consulting or advisory roles with Bristol-Myers Squibb, Guardant Health, Eli Lilly & Company, Exelixis, Purdue Pharma, inVentive Health Inc., Axio, Genentech, Bayer, Merck, Rafael Pharmaceuticals, Astellas, Terumo, Taiho, Thera Bionic, LSK, Axio, and Incyte Corporation; and research funding from Acerta, Celegene, Advanced Accelerator Applications, Novartis, Infinity Pharmaceuticals, Merck Sharp and Dohme, Taiho, Bristol-Myers Squibb, MedImmune/AstraZeneca, Xencor, PreECOG, Astellas, Amgen, and ECOG-ACRIN.

R. Srirajaskanthan reports honoraria from Novartis, Ipsen, and Mylan; fees for participation in speakers’ bureaus with Mylan; and travel, accommodations, or expenses from Ipsen.

M. Pavel reports honoraria from Novartis, Ipsen, Pfizer, and Lexicon; fees for consulting or advisory roles with Novartis, Ipsen, Pfizer, and Lexicon; and research funding from Novartis, Ipsen, Pfizer, and Lexicon.

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M. Morse reports honoraria from Genetech, Bayer, Exelixis, Eisai, Lexicon, Novartis, Advanced Accelerator Applications, and Taiho; fees for participation in speakers’ bureaus with Genetech, Bayer, Exelixis, Eisai, Lexicon, Novartis, Advanced Accelerator Applications, and Taiho; and research funding from BMS, Medimmune/AstraZeneca, and Eisai; and has held a patent with Duke University for targeting HER3.

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C. M. Deroose reports fees for consulting or advisory roles with Ipsen, Novartis, Terumo, and Advanced Accelerator Applications; participation in speakers’ bureaus with Terumo and Advanced Accelerator Applications; and travel, accommodations, or expenses with General Electric and Terumo.

C. M. Grana reports fees for consulting or advisory roles with Norgine and Ipsen; and travel, accommodations, or expenses with Iason, Ipsen - IBA.

L. Bodei reports honoraria from Advanced Accelerator Applications and Ipsen; fees for consulting or advisory roles with Advanced Accelerator Applications and Ipsen; participation in speakers’ bureaus with Advanced Accelerator Applications and Ipsen; and travel, accommodations, or expenses from Advanced Accelerator Applications.

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B. Degirmenci Polack is an employee of, has had leadership roles with, and is a stockholder with Advanced Accelerator Applications.

B. He is an employee of Advanced Accelerator Applications, a Novartis company, and is a stockholder with Novartis.

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G. Gericke reports travel, accommodations, or expenses from Novartis AG, CH; is a stockholder with Novartis AG, CH; has held patents, royalties, or other intellectual property from Novartis AG, CH.

P. Santoro is an employee of and a stockholder with Advanced Accelerator Applications.

J. L. Erion reports travel, accommodations, or expenses from Advanced Accelerator Applications; and is an employee of, has held leadership roles at, has held patents, royalties, or other intellectual property from, and is a stockholder with Advanced Accelerator Applications, Inc.

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T. Hobday, E. Seregni, A. Al-Nahhas, F. Giammarile, J. Mora, G. Paganelli, D. Taïeb, and T. M. O’Dorisio have no disclosures to report.

Figures

Fig. 1

Kaplan-Meier analysis of progression-free survival by treatment arm (patients randomised to four cycles of peptide receptor radionuclide therapy with 177Lu-Dotatate + octreotide LAR 30 mg or octreotide LAR 60 mg) and baseline extent of liver tumour burden (low [< 25%], moderate [25–50%], or high [> 50%]). Liver tumour burden is calculated according to liver tumour volume divided by total liver volume by computed tomography or magnetic resonance imaging. Data cutoff: 24 July 2015. HRs with corresponding 95% CIs and P-values were estimated using a Cox regression model with randomised treatment, liver tumour burden at baseline, and liver tumour burden × randomised treatment interaction term as covariates. Log-rank test used for within-treatment arm comparisons of PFS. CI: confidence interval, HR: hazard ratio, LAR: long-acting release, NR: not reached, PFS: progression-free survival

Fig. 2

Kaplan-Meier analysis of progression-free survival by treatment arm (patients randomised to four cycles of peptide receptor radionuclide therapy with 177Lu-Dotatate + octreotide LAR 30 mg or octreotide LAR 60 mg) and baseline normal (≤ ULN) or elevated (> ULN) alkaline phosphatase levels (based on institutional ULN). Data cutoff: 24 July 2015. One-hundred twelve patients in either treatment arm had evaluable baseline ALP levels and were included in this analysis. HRs with corresponding 95% CIs and P-values were estimated using a Cox regression model with randomised treatment, alkaline phosphatase level, and alkaline phosphatase level × randomised treatment interaction term as covariates. Log-rank test was used for within-treatment arm comparisons of PFS. ALP: alkaline phosphatase, CI: confidence interval, HR: hazard ratio, LAR: long-acting release, NR: not reached, PFS: progression-free survival, ULN: upper limit of normal

Fig. 3

Kaplan-Meier analysis of progression-free survival by treatment arm (patients randomised to four cycles of peptide receptor radionuclide therapy with 177Lu-Dotatate + octreotide LAR 30 mg or octreotide LAR 60 mg) and presence or absence of at least one large (> 30 mm diameter) target lesion at any site of the body at baseline imaging with computed tomography or magnetic resonance imaging. Data cutoff: 24 July 2015. HRs with corresponding 95% CIs and P-values were estimated using a Cox regression model with randomised treatment, presence/absence of large target lesion, and presence/absence of large target lesion × randomised treatment interaction term as covariates. Log-rank test was used for within–treatment arm comparisons of PFS. CI: confidence interval, HR: hazard ratio, LAR: long-acting release, NR: not reached, PFS: progression-free survival

Fig.  4

Least squares mean percentage change from baseline in the size of liver lesions at each study visit in the 177Lu-Dotatate arm, stratified by baseline liver lesion size. Data cutoff: 30 June 2016. A lesion-based mixed model repeated measures analysis included study visit, baseline target liver lesion size (≤ 30 mm or > 30 mm), and baseline target liver lesion size × study visit interaction as fixed effects