Overall survival and long-term safety data from the NETTER-1 trial: 177-Lu-Dotatate vs. high-dose octreotide in patients with progressive midgut NETs

Background In the primary analysis of the phase 3 NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide, with a HR of 0.18 (95% CI: 0.11, 0.29; p < 0.0001), in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut neuroendocrine tumors (NETs). Here we report final overall survival (OS) and long-term safety data for NETTER-1. Methods Eligible patients were randomized to receive either four cycles of 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 weeks plus long-acting octreotide 30 mg or high-dose long-acting octreotide 60 mg every 4 weeks (control arm). After disease progression or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further anti-cancer treatment as recommended by their physicians. The primary endpoint was PFS per RECIST 1.1 and OS was a key secondary endpoint. Primary intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first. Results 231 patients were randomized. Of these, 101/117 (86.3%) in the 177Lu-DOTATATE arm and 99/114 (86.8%) in the control arm entered long-term follow-up. Final analysis occurred 5 years after the last patient was randomized, following 142 deaths, with a median follow-up of more than 76 months. During long-term follow-up, 41/114 (36%) of patients in the control arm received subsequent radioligand therapy (“cross-over”). Median OS was 48.0 months (95% CI: 37.4, 55.2) in the 177Lu-DOTATATE arm and 36.3 months (95% CI: 25.9, 51.7) in the control arm. HR was 0.84 (95% CI: 0.60, 1.17) with p = 0.30 (unstratified 2-sided log-rank test). A total of 2/111 (1.8%) 177Lu-DOTATATE treated patients developed myelodysplastic syndrome (MDS). No new cases of MDS or acute leukemia were reported in the long-term follow-up. Conclusions Median OS was 11.7 months longer with 177Lu-DOTATATE compared to high-dose octreotide in the NETTER-1 trial (48 vs. 36.3 months). This difference was not statistically significant, potentially impacted by a high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. In overall conclusion, the NETTER-1 study demonstrated a clinically and statistically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001) as well as a clinically meaningful trend towards improvement in median OS in 177Lu-DOTATATE treatment arm. No new safety signals emerged during the median 6.3 year long-term follow-up. Legal entity responsible for the study The author. Funding Has not received any funding. Disclosure J. Strosberg: Advisory / Consultancy: Novartis. Speaker Bureau / Expert testimony: Ipsen, Lexicon. Research grant / Funding (institution): Novartis. M. Chaplin: Advisory / Consultancy: Advanced Accelerator Applications, a Novartis company, Ipsen, Sirtex Medical, Novartis Speaker Bureau / Expert testimony: Advanced Accelerator Applications, a Novartis company, Ipsen, Sirtex Medical, Pfizer Research grant / Funding (institution): Advanced Accelerator Applications, a Novartis company. P. Kunz: Advisory / Consultancy: Ipsen, Lexicon, Advanced Accelerator Applications, a Novartis company. Research grant / Funding (institution): Advanced Accelerator Applications, a Novartis company, Lexicon, Ipsen, Xencor, Brahms. Shareholder / Stockholder / Stock options: Guardant Health. P. Ruszniewski: Advisory / Consultancy: Ipsen, Advanced Accelerator Applications, a Novartis company, ITM, Novartis. Research grant / Funding (institution): Advanced Accelerator Applications, a Novartis company, Ipsen, ITM. Travel / Accommodation / Expenses: Ipsen. L. Bodei: Advisory / Consultancy: Advanced Accelerator Applications, a Novartis company, ITM, Clovis Oncology, Curium, Iba. Speaker Bureau / Expert testimony: Advanced Accelerator Applications, a Novartis company, ITM, Iba. Research grant / Funding (institution): Advanced Accelerator Applications, a Novartis company. A. Hendifar: Advisory / Consultancy: Novartis, Ipsen, Perthera, Celgene, AbbVie. Travel / Accommodation / Expenses: Halozyme. Research funding: Ipsen. E. Mittra: Honoraria (Institution): Advanced Accelerator Applications, a Novartis company, Curium. Advisory / Consultancy: Ipsen, Advanced Accelerator Applications, a Novartis company. Research grant / Funding (institution): Advanced Accelerator Applications, a Novartis company, Nordic Nanovector. E. Wolin: Advisory / Consultancy: Advanced Accelerator Applications, a Novartis company, Lexicon, Progenics. J. Yao: Advisory / Consultancy: Advanced Accelerator Applications, a Novartis company, Ipsen, Chiasma, Crinetics, Hutchinson Medi Pharma. Research grant / Funding (institution): Advanced Accelerator Applications, a Novartis company., Novartis. M. Pavel: Honoraria (self): AAA, Novartis, Ipsen, Pfizer, Boehringer Ingelheim, Riemser, Hutchison Honoraria (Institution): Ipsen, Hutchison MediPharma, Advanced Accelerator Applications, a Novartis company, Riemser, Boehringer Ingelheim. Advisory / Consultancy: AAA, Novartis, Ipsen, Riemser, Hutchison, Boehringer-Ingelheim Travel / Accommodation / Expenses: Ipsen, Hutchison. E. Grande Pulido: Honoraria (Institution): Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Advanced Accelerator Applications, a Novartis company, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma, AstraZeneca, Lilly. Advisory / Consultancy: MSD, Pfizer, Ipsen, Roche, Bristol-Myers Squibb. Research grant / Funding (institution): Roche, Pfizer, AstraZeneca, Ipsen, Molecular Templates, Lexicon, Astellas Pharma. Travel / Accommodation / Expenses: Bristol-Myers Squibb, Roche/Genentech, Pfizer, Janssen-Cilag, Ipsen. E. Van Cutsem: Advisory / Consultancy: Bayer, Lilly, Roche, Servier, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, Novartis, AstraZeneca, Halozyme, Array BioPharma, Biocartis, GlaxoSmithKline, Daiichi Sankyo, Pierre Fabre, Sirtex Medical, Taiho Pharmaceutical, Incyte. Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. E. Seregni: The author has declared no conflicts of interest. H. Duarte: The author has declared no conflicts of interest. G. Gericke: Travel / Accommodation / Expenses: Novartis. Shareholder / Stockholder / Stock options: Novartis. Full / Part-time employment: Novartis. A. Bartalotta: Travel / Accommodation / Expenses: Novartis Shareholder / Stockholder / Stock options: Novartis Full / Part-time employment: Novartis. A. Demange: Shareholder / Stockholder / Stock options: Novartis. Full / Part-time employment: Novartis. S. Mutevelic: Shareholder / Stockholder / Stock options: Novartis. Full / Part-time employment: Novartis. E. Krenning: Travel / Accommodation / Expenses: Advanced Accelerator Applications, a Novartis company, Shareholder / Stockholder / Stock options: AAA Adacap Licensing / Royalties: AAA. Non-remunerated activity/ies: AAA adacap.