Nintedanib Does Not Significantly Improve PFS in Thyroid Cancer

“[T]he impact on PFS [with nintedanib] is minimal and not clinically relevant, especially when compared [with] the efficacy demonstrated in other studies involving similar or earlier disease populations,” according to the study authors.

Nintedanib, a triple-angiokinase inhibitor, did not show a clinically significant improvement in progression-free survival (PFS) vs placebo in patients with radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC), according to phase 2 EORTC-1209 trial (NCT01788982) results published in Frontiers in Endocrinology.¹

In the intent-to-treat population within the DTC cohort (n = 70), the median PFS was 3.7 months (80% CI, 1.9-5.0) in the nintedanib arm vs 2.9 months (80% CI, 2.1-3.8) in the placebo arm (HR, 0.73; 80% CI, 0.51-1.04; P = .126). Similarly, in the MTC cohort (n = 20), the median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm vs 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR, 0.49; 95% CI, 0.16-1.53). Although nintedanib showed a numerical PFS improvement for both populations, the findings for the monotherapy did not demonstrate statical significance warranting further development of the therapy for either cohort.

“[T]he impact on PFS [with nintedanib] is minimal and not clinically relevant, especially when compared [with] the efficacy demonstrated in other studies involving similar or earlier disease populations,” Sophie Leboulleux, MD, PhD, department chief of Nuclear Medicine and assistant in the Department of Endocrine Oncology at the Gustave Roussy Cancer Institute, and study coauthors wrote.¹ “For instance, sorafenib [Nexavar] showed a PFS increase of 5 months [HR = 0.59] compared [with] placebo,² lenvatinib [Lenvima] showed an increase of almost 14.7 months [HR = 0.21],³ and cabozantinib [Cabometyx] showed an increase of 9.1 months.⁴”

The double-blind, placebo-controlled phase 2 EORTC-1209 trial enrolled and randomly assigned patients with confirmed DTC or MTC (n = 70) by 2:1 randomization from June 18, 2014, to January 31, 2018, to receive either nintedanib monotherapy (n = 45) or placebo (n = 25). Within 2 days of randomization, patients received either 200 mg nintedanib twice daily or placebo capsules as a comparator treatment. Treatment cycles lasted for 4 weeks, and treatment was administered until disease progression, unacceptable toxicity, or patient refusal at cycle end.

Patients receiving placebo were unblinded and offered to receive nintedanib if disease progression was documented. Adverse events (AE) prompted dosage decreases to 150 mg or 100 mg and included temporary treatment withholding for up to 3 weeks or permanent treatment discontinuation. No option for dose reescalation was present.

The primary end point of the study was PFS. Secondary end points included response rate, duration of response (DOR), overall survival (OS), and safety.

Within the final analysis set of the DTC cohort (n= 56), stable disease was observed in 60% of patients in the nintedanib arm (n = 22/37) and 47% of patients in the placebo arm (n = 9/19), with no objective responses recorded. Deaths occurred in 22 of the final analysis set, which included 15 in the monotherapy arm and 7 in the placebo arm. Median OS was 29.6 months (80% CI, 15.1-not reached [NR]) in the nintedanib arm vs NR in the placebo arm (HR, 1.00; 80% CI, 0.58-1.50; P = .42)

Within the final analysis set of the MTC cohort (n= 20), stable disease was observed in 13 patients, and progressive disease was observed in 6. No objective responses were recorded, and 1 patient had unevaluable activity. Median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm vs 12.3 months (80% CI, 7.1-NR) in the placebo arm (HR, 0.88; 95% CI, 0.24-3.21).

Of patients evaluable for safety in the nintedanib (n = 66) and placebo arms (n = 34), at least 1 AE was observed in 93% and 97.1% of patients, respectively. AEs of grade 3 or higher were reported in 53% of the monotherapy arm vs 35% of the placebo arm. AEs of grade 3 or higher occurring in at least 5% of patients in the nintedanib arm were diarrhea (12.1%), gamma-glutamyl transferase increase (10.6%), anorexia (9.1%), nausea (6.1%), and hypertension (6.1%).

References

1. Leboulleux S, Kapiteijn E, Litière S, et al. 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). Front Endocrinol. 2024;15. doi:10.3389/fendo.2024.1403687
2. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319–328. doi:10.1016/S0140-6736(14)60421-9
3. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621–630. doi:10.1056/NEJMoa1406470
4. Brose MS, Robinson BG, Sherman SI, et al. Cabozantinib for previous systemicly treated radioiodine-refractory differentiated thyroid cancer: update results from the phase 3 COSMIC-311 trial. Cancer. 2022;128:4203–4212. doi:10.1002/cncr.34493