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

Jonathan Strosberg ,David Taïeb,David Bushnell,Nicholas Reed,Christophe M Deroose,Thomas M O’Dorisio,Kjell Öberg,Chris Verslype,Rajaventhan Srirajaskanthan,Martyn Caplin,Maurizio Mariani ,Michael A Morse ,Marianne Pavel,Edward M Wolin ,Chiara Maria Grana ,Enrique Grande,Paola Santoro,Erik Mittra,Richard Baüm ,Berna Polack ,Lisa Bodei,Giovanni Paganelli,Adil Al‐Nahhas ,Francesco Giammarile,Rachida Lebtahi,Laura Ravasi,Philippe Ruszniewski,James C Yao ,Al B Benson ,Jordan Berlin,F Courbon ,Andrew Eugene Hendifar ,Ettore Seregni,Pamela L Kunz,Timothy J Hobday ,C Ansquer ,Éric Baudin ,Jack L Erion,David C Metz,Jaume Mora,Stefano Severi,Beilei He,Matthew H Kulke,Ebrahim S Delpassand ,Germo Gericke,Eric P Krenning

doi:10.1007/s00259-020-04709-x

Abstract

PurposeTo assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate.MethodsIn 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.ResultsSignificantly 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.Conclusions177Lu-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

Highlights

The liver is the dominant site of metastatic disease amongst patients with stage IV well-differentiated neuroendocrine tumours (NET) [1]
Prior Presentation This study has been presented in part at the 31st Annual Congress of the European Association of Nuclear Medicine (EANM); October 13–17, 2018; Dusseldorf, Germany; and at the European Society for Medical Oncology (ESMO) 2018 Annual Congress; October 19–23, 2018; Munich, Germany
We evaluated the predictive and prognostic power of elevated alkaline phosphatase (ALP), whether presence of ≥ 1 target lesion >3 cm in diameter impacted progression-free survival (PFS) benefit with

Summary

Introduction

The liver is the dominant site of metastatic disease amongst patients with stage IV well-differentiated neuroendocrine tumours (NET) [1]. In the phase 3 PROMID study (which randomised patients with midgut NET to octreotide long-acting release [LAR] versus placebo), liver tumour burden > 10% was associated with a hazard ratio (HR) for progression of 2.63 on multivariate analysis [2]. Another prognostic factor is serum alkaline phosphatase (ALP) [9,10,11,12,13], which may be elevated with extensive liver involvement and bone metastases [10, 14]. Correlation between tumour size and 177Lu effectiveness has not been evaluated in a randomised controlled trial

Methods

Results

Conclusion