Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF).

Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC).
Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety.
Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo.
Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.
Competing Interests: JC: None related to nintedanib/Boehringer Ingelheim; scientific consultancy role from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, ITM, Sirlex, Lilly, and Merck Serono. Research grants from Novartis, Pfizer, Astrazeneca, Advanced Accelerator Applications, Eisai, and Bayer. FC: None related to nintedanib/Boehringer Ingelheim; scientific consultancy role from Eisai and Bayer. YG: None related to nintedanib/Boehringer Ingelheim; scientific consultancy role from Eisai, Lilly, Sanofi, and Bayer. EK: None related to nintedanib/Boehringer Ingelheim; scientific consultancy role from Eisai, Bayer, and Genzyme; research grant from Novartis. YL: None related to nintedanib/Boehringer Ingelheim; scientific consultancy role from Eisai, Merck, MSD, and Roche. SLe: None related to nintedanib/Boehringer Ingelheim; scientific consultancy role from Eisai, Bayer, and Lilly; research grant from Novartis and Genzyme. PS: None related to nintedanib/Boehringer Ingelheim; have received institutional research support and biological material from Eisai. TL: None related to nintedanib/Boehringer Ingelheim; advisory board from EISAI, Bayer, and Genzyme-Sanofi. DLL: None related to nintedanib/Boehringer Ingelheim; advisory board from EISAI, IPSEN, MSD, Merck Serono, Bayer, Roche, Lilly, Seagen, Gilead, Novartis, Gentili SrL, and New Bridge. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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