Increased Progression-Free Survival with Cabozantinib Versus Placebo in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Irrespective of Prior Vascular Endothelial Growth Factor Receptor-Targeted Therapy and Tumor Histology: A Subgroup Analysis of the COSMIC-311 Study

Abstract

Background: Lenvatinib and sorafenib are standard of care first-line treatments for advanced, radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC). However, most patients eventually become treatment-resistant and require additional therapies. The phase 3 COSMIC-311 study investigated cabozantinib in patients with RAIR DTC who progressed on lenvatinib, sorafenib, or both and showed that cabozantinib provided substantial clinical benefit. Presented in this study is an analysis of COSMIC-311 based on prior therapy and histology. Methods: Patients were randomized 2:1 (stratification: prior lenvatinib [yes/no]; age [≤65, >65 years]) to oral cabozantinib (60 mg tablet/day) or matched placebo. Eligible patients received 1-2 prior vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors for DTC (lenvatinib or sorafenib required), had a confirmed DTC diagnosis, and were refractory to or ineligible for radioiodine therapy. For this analysis, progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by a blinded independent radiology committee were evaluated by prior therapy (lenvatinib only, sorafenib only, both) and histology (papillary, follicular, oncocytic, poorly differentiated). Results: Two hundred fifty-eight patients were randomized (170 cabozantinib/88 placebo) who previously received sorafenib only (n = 96), lenvatinib only (n = 102), or both (n = 60). The median follow-up was 10.1 months. The median PFS (months) with cabozantinib/placebo was 16.6/3.2 (sorafenib only: hazard ratio [HR] 0.13 [95% confidence interval, CI, 0.06-0.26]), 5.8/1.9 (lenvatinib only: HR 0.28 [95% CI 0.16-0.48]), and 7.6/1.9 (both: HR 0.27 [95% CI 0.13-0.54]). The ORR with cabozantinib/placebo was 21%/0% (sorafenib only), 4%/0% (lenvatinib only), and 8%/0% (both). Disease histology consisted of 150 papillary and 113 follicular, including 43 oncocytic and 36 poorly differentiated. The median PFS (months) with cabozantinib/placebo was 9.2/1.9 (papillary: HR 0.27 [95% CI 0.17-0.43]), 11.2/2.5 (follicular: HR 0.18 [95% CI 0.10-0.31]), 11.2/2.5 (oncocytic: HR 0.06 [95% CI 0.02-0.21]), and 7.4/1.8 (poorly differentiated: HR 0.18 [95% CI 0.08-0.43]). The ORR with cabozantinib/placebo was 15%/0% (papillary), 8%/0% (follicular), 11%/0% (oncocytic), and 9%/0% (poorly differentiated). Safety outcomes evaluated were consistent with those previously observed for the overall population. Conclusions: Results indicate that cabozantinib benefits patients with RAIR DTC, regardless of prior lenvatinib or sorafenib treatments or histology. Clinical Trial Registration Number: NCT03690388.

Keywords: COSMIC-311; cabozantinib; follicular; lenvatinib; papillary; radioiodine-refractory differentiated thyroid cancer.

FIG. 1.

Kaplan–Meier estimates of PFS based on prior sorafenib/lenvatinib treatment. Disease progression was assessed with the use of Response Evaluation Criteria in Solid Tumors version 1.1 and was confirmed by BIRC. BIRC, blinded independent radiology committee; CI, confidence interval; HR, hazard ratio; NE, not estimable; PFS, progression-free survival; Pts, patients.

FIG. 2.

Best change from baseline in sum of target lesions per BIRC with cabozantinib based on prior sorafenib/lenvatinib treatment. Data are included for patients before or on the date of first progression and before or on the date of first systemic non-radiation therapy. Only ITT patients with at least one baseline and one post-baseline assessment are shown. If the percent change was in the interval 0 to 5 (including 0), then the percent change is shown as 5%; if the percent change is in the interval −5 to 0, then it is shown as −5% for visual clarity. The bars that are shown as 5% and −5% for visual clarity are indicated with an asterisk and the bars that represent 0 are indicated with a 0. ITT, intent-to-treat; SoD, sum of diameters.

FIG. 3.

Kaplan–Meier estimates of PFS based on DTC histology. Disease progression was assessed with the use of Response Evaluation Criteria in Solid Tumors version 1.1 and was confirmed by blinded independent radiology committee. DTC, differentiated thyroid cancer.

FIG. 4.

Best change from baseline in sum of target lesions per BIRC with cabozantinib based on DTC histology. Data are included for patients before or on the date of first progression and before or on the date of first systemic non-radiation therapy. Only ITT patients with at least one baseline and one post-baseline assessment are shown. If the percent change was in the interval 0 to 5 (including 0), then the percent change is shown as 5%; if the percent change is in the interval −5 to 0, then it is shown as −5% for visual clarity. The bars that are shown as 5% and −5% for visual clarity are indicated with an asterisk, and the bars which represent 0 are indicated with a 0.

FIG. 5.

Best change from baseline in sum of target lesions per BIRC with cabozantinib for patients with oncocytic and poorly differentiated DTC. Data are included for patients before or on the date of first progression and before or on the date of first systemic non-radiation therapy. Only ITT patients with at least one baseline and one post-baseline assessment are shown. If the percent change was in the interval 0 to 5 (including 0), then the percent change is shown as 5%; if the percent change is in the interval −5 to 0, then it is shown as −5% for visual clarity. The bars that are shown as 5% and −5% for visual clarity are indicated with an asterisk, and the bars that represent 0 are indicated with a 0.