Cabozantinib Continues to Improve PFS, Regardless of Duration of Previous Lenvatinib Therapy in RAI-Refractory DTC

Treatment with cabozantinib (Cabometyx) maintained superior progression-free survival (PFS), compared with placebo, in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC), irrespective of prior lenvatinib (Lenvima) therapy duration, according to an updated analysis of the phase 3 COSMIC-311 trial (NCT03690388) presented at the 91st Annual Meeting of the American Thyroid Association.¹

“COSMIC-311 is the first phase 3 study in RAI-refractory DTC that included lenvatinib-treated patients,” Marcia Brose, MD, PhD, Chief of Cancer Services, Jefferson University Sidney Kimmel Cancer Center, Philadelphia, said during a presentation at the meeting. “These results further support cabozantinib as a treatment option for patients with RAI-refractory DTC who have progressed on prior VEGFR-targeted therapy.”

At the meeting, Brose presented on outcomes by duration of prior lenvatinib treatment: >0 to 12 months (n = 54), >12 to 24 months (n = 48), and <24 months (n = 60).

In the overall population, median PFS was 11.0 months (95% CI, 7.4-13.8) with cabozantinib, compared with 1.9 months (95% CI, 1.9-3.7) with placebo (HR, 0.22; 96% CI, 0.15-0.32; P < .0001). In total, 162 patients received prior lenvatinib therapy. Median PFS in those who received just lenvatinib previously was 5.8 months (95% CI, 5.1-9.3) with cabozantinib vs 1.9 months (95% CI, 1.7-3.7) with placebo (HR, 0.28; 95% CI, 0.16-0.48), and was 7.6 months (95% CI, 3.8-13.8) and 1.9 months (95% CI, 1.8—3.8), respectively, in those who received prior lenvatinib and sorafenib (Nexavar) (HR, 0.27; 95% CI, 0.13-0.54).

When compared by duration of prior lenvatinib treatment, the median PFS with cabozantinib therapy, vs placebo, was 5.6 months (95% CI, 3.8-not estimable [NE]) and 1.9 months (95% CI, 1.6-5.1), respectively, with prior lenvatinib <0 to 12 months (HR, 0.32; 95% CI, 0.15-0.69); 9.2 months (95% CI, 4.3-NE) and 3.6 months (95% CI, 1.7-3.9) with prior lenvatinib <12 to 24 months (HR, 0.22; 95% CI, 0.10-0.51); and 5.8 months (95% CI, 4.4-9.3) and 1.9 months (95% CI, 1.1-3.5) with prior lenvatinib <24 months (HR, 0.28; 95% CI, 0.14-0.55).

Overall response rates (ORRs) by prior lenvatinib treatment with cabozantinib vs placebo, respectively, were 12% (95% CI, 3%-28%) vs 0% (95% CI, 0%-16%) with prior lenvatinib <0 to 12 months; 0% (95% CI, 0%-11%) vs 0% (95% CI, 0%-21%) with prior lenvatinib <12 to 24 months; and 5% (95% CI, 1%-16%) and 0% (95% CI, 0%-19%) with prior lenvatinib <24 months.

Overall survival (OS) by prior lenvatinib treatment with cabozantinib vs placebo, respectively, were NE (95% CI, 6.3-NE) vs NE (95% CI, 5.4-NE) with prior lenvatinib <0 to 12 months (HR, 1.00; 95% CI, 0.36-2.82); 19.4 months (95% CI, 10.5-NE) vs NE (95% CI, 4.6-NE) with prior lenvatinib <12 to 24 months (HR, 0.64; 95% CI, 0.18-2.19); and 14.5 months (95% CI, 10.6-NE) vs NE (3.6-NE) with prior lenvatinib <24 months (HR, 1.06; 95% CI, 0.34-3.35).

“There was no notable difference in overall survival between cabozantinib and placebo by prior lenvatinib duration, but the study was not powered to assess overall survival and patients crossed over from placebo to cabozantinib, further confounding results,” Brose explained.

COSMIC-311 Trial

In the global, randomised, double-blind, placebo-controlled, phase 3 trial, patients were randomized 2:1 to receive either 60 mg cabozantinib daily or placebo daily. Crossover was allowed at the time of blind independent review committee (BICR)-confirmed progression per RECISET v1.1.²

Patients were included if they had RAI-refractory DTC, radiographic progression, during or after treatment with up to 2 prior VEGFR MKIs (lenvatinib or sorafenib), an ECOG PS of 0-1, and aged 16 years or older.

ORR per RECIST v1.1 by BICR served as the primary end point, and PFS per RECIST v1.1 by BICR was the secondary end point.

The FDA approved cabozantinib for the treatment of patients with previously-treated RAIR-DTC aged 12 years or older who progressed after prior VEGFR-targeted therapy based on results from the phase 3 COSMIC-311 trial.

Further, an extended follow-up of a median of 10.1 months showed that cabozantinib maintained superior PFS, compared with placebo (HR, 0.22) in the intent-to-treat population. Moreover, a subgroup analysis of the extended follow-up demonstrated this benefit was maintained irrespective of prior therapy with lenvatinib, sorafenib, or both.³

_Reference:

_{1. Brose M, Krajewska J, Vaisman F, et al. Cabozantinib Versus Placebo in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer (RAIR-DTC) Who Progressed After Prior VEGFR-Targeted Therapy: Outcomes By Duration of Prior Lenvatinib Treatment. Thyroid. 2022;32(1):P-1-A-135. doi:10.1089/thy.2022.29137.abstracts.}

_{2. Brose M, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):P1126-1138. doi:10.1016/S1470-2045(21)00332-6.}

_{3. Capdevila J, Robinson B, Sherman SI, et al. Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Updated results from the phase III COSMIC-311 trial and prespecified subgroup analyses by prior therapy. Ann Oncol. 2021;32(5):S1343. doi:10.1016/j.annonc.2021.08.2148.}