Abstract 1102P
Background
In the prespecified final analysis of overall survival (OS) in the NETTER-1 study, with median follow-up of more than 6.3 years, 177Lu-DOTATATE prolonged median OS by 11.7 months versus high-dose octreotide in patients with advanced, progressive, well-differentiated midgut neuroendocrine tumours, although OS difference did not reach statistical significance (HR, 0.84 [95% CI: 0.60, 1.17]; p = 0.30). This analysis used the proportional-hazards assumption.
Methods
In this international open-label trial, 231 patients were randomized 1:1 to receive four cycles of 177Lu-DOTATATE 200 mCi every 8 weeks plus long-acting octreotide 30 mg (177Lu-DOTATATE arm), or long-acting octreotide 60 mg every 4 weeks (control arm). OS was evaluated in subgroups of age, Karnofsky performance status and baseline tumour burden (OctreoScan). The proportional-hazards assumption for the Cox regression analysis of OS was examined using Schoenfeld residuals. Analysis of restricted mean survival time (RMST; area under the survival curve up to a specific time point) at 2, 3, 4 and 5 years was specified before final data cut-off to estimate treatment effect in the presence of non-proportional hazards.
Results
OS was consistent across most prespecified subgroups. During long-term follow-up, more than 60% of patients in each arm received further anti-cancer therapies, including ‘cross-over’ to peptide receptor radionuclide therapy (PRRT) in 36% of patients in the control arm. The proportional-hazards assumption for the Cox analysis of OS was not met (p = 0.034). RMST was numerically longer in the 177Lu-DOTATATE arm versus control at all timepoints (table). Table: 1102P
Restricted mean survival time analysis at 2, 3, 4 and 5 years
| Time since randomization, years | 177Lu-DOTATATEN = 117 | ControlN = 114 | |
| 2 | Deaths, n (%) | 26 (22.2) | 39 (34.2) |
| RMST, months (95% CI) | 21.2 (20.2, 22.3) | 19.3 (18.0, 20.7) | |
| Difference, months (95% CI) | 1.9 (0.1, 3.6) | ||
| 3 | Deaths, n (%) | 41 (35.0) | 51 (44.7) |
| RMST, months (95% CI) | 29.7 (27.7, 31.6) | 26.0 (23.7, 28.3) | |
| Difference, months (95% CI) | 3.7 (0.7, 6.7) | ||
| 4 | Deaths, n (%) | 53 (45.3) | 58 (50.9) |
| RMST, months (95% CI) | 36.2 (33.4, 39.0) | 31.5 (28.3, 34.8) | |
| Difference, months (95% CI) | 4.6 (0.3, 8.9) | ||
| 5 | Deaths, n (%) | 65 (55.6) | 63 (55.3) |
| RMST, months (95% CI) | 41.2 (37.6, 44.9) | 36.1 (31.9, 40.4) | |
| Difference, months (95% CI) | 5.1 (–0.5, 10.7) |
Conclusions
Prespecified final analysis of OS was likely confounded by multiple factors, including cross-over to PRRT and a high 5-year survival rate, confirmed by non-proportional extensions of RMST over time. Nevertheless, 177Lu-DOTATATE prolonged median OS by 11.7 months.
Clinical trial identification
Protocol number: AAA-III-01. Release date: 5 June 2014. EudraCT 2011-005049-11.
Editorial acknowledgement
Under the guidance of the authors, Dr Charlie Foster from Oxford PharmaGenesis provided medical writing support for this abstract, with funding from Advanced Accelerator Applications, a Novartis Company.
Legal entity responsible for the study
Advanced Accelerator Applications, a Novartis company.
Funding
Advanced Accelerator Applications, a Novartis company.
Disclosure
P.B. Ruszniewski: Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Advisory Role: ITM; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Funding: Ipsen; Financial Interests, Personal, Funding: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Funding: ITM; Financial Interests, Personal, Other, Travel/Accommodation/expenses: Ipsen. M.E. Caplin: Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Sirtex; Financial Interests, Personal, Speaker’s Bureau: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Speaker’s Bureau: Ipsen; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Sirtex; Financial Interests, Institutional, Funding: Advanced Accelerator Applications, a Novartis company; Financial Interests, Institutional, Funding: Ipsen. P.L. Kunz: Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Lexicon; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Ownership Interest: Guardant Health; Financial Interests, Institutional, Funding: Advanced Accelerator Applications, a Novartis company; Financial Interests, Institutional, Funding: Lexicon; Financial Interests, Institutional, Funding: Ipsen; Financial Interests, Institutional, Funding: Xencor; Financial Interests, Institutional, Funding: Brahms. L. Bodei: Non-Financial Interests, Personal, Speaker’s Bureau: Advanced Accelerator Applications, a Novartis company; Non-Financial Interests, Personal, Speaker’s Bureau: ITM; Non-Financial Interests, Personal, Speaker’s Bureau: IBA; Financial Interests, Personal and Institutional, Funding: Advanced Accelerator Applications, a Novartis company; Non-Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Non-Financial Interests, Personal, Advisory Role: ITM; Non-Financial Interests, Personal, Advisory Role: Clovis Oncology; Non-Financial Interests, Personal, Advisory Role: Curium; Non-Financial Interests, Personal, Advisory Role: IBA. A.E. Hendifar: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Perthera; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Abbvie; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Halozyme; Financial Interests, Personal, Funding: Ipsen. E. Mittra: Financial Interests, Personal, Other, Honoraria: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Other, Honoraria: Curium; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Institutional, Funding: Advanced Accelerator Applications, a Novartis company; Financial Interests, Institutional, Funding: Nordic Nanovector. E.M. Wolin: Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Advisory Role: Lexicon; Financial Interests, Personal, Advisory Role: Progenics. J.C. Yao: Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Chiasma; Financial Interests, Personal, Advisory Role: Hutchison Medi Pharma; Financial Interests, Personal, Funding: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Funding: Novartis; Financial Interests, Personal, Advisory Role: Crinetics. M.E. Pavel: Financial Interests, Personal, Other, Honoraria: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Ipsen; Financial Interests, Personal, Other, Honoraria: Riemser; Financial Interests, Personal, Other, Honoraria: Bohringer lngelheim; Financial Interests, Personal, Other, Honoraria: Hutchinson; Financial Interests, Personal, Advisory Role: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Riemser; Financial Interests, Institutional, Funding: Advanced Accelerator Applications, a Novartis company; Financial Interests, Institutional, Funding: Ipsen; Financial Interests, Institutional, Funding: Novartis. E. Grande: Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb; Financial Interests, Personal, Other, Honoraria: IPSEN; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: Eisai; Financial Interests, Personal, Other, Honoraria: Eusa Pharma; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: Genzyme; Financial Interests, Personal, Other, Honoraria: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Pierre Fabre; Financial Interests, Personal, Other, Honoraria: Lexicon; Financial Interests, Personal, Other, Honoraria: Celgene; Financial Interests, Personal, Other, Honoraria: Janssen-Cilag; Financial Interests, Personal, Other, Honoraria: Astellas Pharma; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Lilly; Financial Interests, Personal, Funding: Roche; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Ipsen; Financial Interests, Institutional, Funding: Molecular Templates; Financial Interests, Institutional, Funding: Lexicon; Financial Interests, Institutional, Funding: Astellas Pharma; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche/Genentech; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Pfizer; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Janssen-Cilag; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Ipsen; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pfzier; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb. E. Van Cutsem: Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: SERVIER; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Merck KGaA; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Halozyme; Financial Interests, Personal, Advisory Role: Array BioPharma; Financial Interests, Personal, Advisory Role: Biocartis; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Sirtex Medical; Financial Interests, Personal, Advisory Role: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Celgene; Financial Interests, Institutional, Invited Speaker: Ipsen; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Merck KGaA; Financial Interests, Institutional, Invited Speaker: SERVIER; Financial Interests, Institutional, Invited Speaker: Bristol-Myers Squibb. A. Demange: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. S. Mutevelic: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. E.P. Krenning: Financial Interests, Personal, Full or part-time Employment: Cyclotron Rotterdam BV; Financial Interests, Personal, Ownership Interest: GlaxoSmithKline; Financial Interests, Personal, Ownership Interest: AstraZeneca; Financial Interests, Personal, Ownership Interest: Roche; Financial Interests, Personal, Ownership Interest: Merck; Financial Interests, Personal, Other, Travel/accommodation/expenses: Advanced Accelerator Applications, a Novartis company; Financial Interests, Personal, Other, Was a co-owner or co-inventor on some patents licensed or acquired by AAA: Advanced Accelerator Applications, a Novartis company. J.R. Strosberg: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Speaker’s Bureau: Ipsen; Financial Interests, Personal, Speaker’s Bureau: Lexicon; Financial Interests, Personal, Funding: Novartis. All other authors have declared no conflicts of interest.