Cabozantinib demonstrated a sustained benefit in progression-free survival vs placebo in patients with previously treated, radioactive iodine–refractory differentiated thyroid cancer, regardless of prior exposure to sorafenib or lenvatinib.
Cabozantinib (Cabometyx) demonstrated a sustained benefit in progression-free survival (PFS) vs placebo in patients with previously treated, radioactive iodine–refractory differentiated thyroid cancer, regardless of prior exposure to sorafenib (Nexavar) or lenvatinib (Lenvima), according to findings from the final analysis of the phase 3 COSMIC-311 trial (NCT03690388) that were presented at the 2021 ESMO Congress.1
At a median follow-up of 10.1 months, the median PFS was 11.0 months (96% CI, 7.4-13.8) with cabozantinib (n = 170) vs 1.9 months (96% CI, 1.9-3.7) with placebo (n = 88; HR, 0.22; 96% CI, 0.15-0.32; P <.0001).
The objective response rate (ORR) by blinded independent review committee (BIRC) was 11% (95% CI, 6.9%-16.9%) with cabozantinib vs 0% (95% CI, 0%-4.1%) with placebo; 1 patient had a complete response.
“All patients get the same magnitude of benefit with cabozantinib regardless of prior progression on sorafenib, lenvatinib, or both multikinase inhibitors,” said lead study author Jaume Capdevila, MD, of the Department of Medical Oncology at Vall d’Hebron University Hospital, in Barcelona, Spain, in a virtual presentation of the data.
On September 17, 2021, the FDA approved cabozantinib for the treatment of adult and pediatric patients aged 12 years and older with locally advanced or metastatic differentiated thyroid cancer that has progressed after prior VEGF-targeted therapy and who are radioactive iodine–refractory or –ineligible based on findings from the phase 3 COSMIC-311 trial.2
The COSMIC-311 trial enrolled approximately 300 patients at least 16 years of age with locally advanced or metastatic differentiated thyroid cancer who were radioactive iodine–refractory or –ineligible. Patients had to have radiographic progression during or after treatment with up to 2 prior VEGFR TKIs, including lenvatinib or sorafenib, and an ECOG performance status of 0 or 1.
Patients were stratified by prior lenvatinib exposure (yes vs no) and age (≤65 vs >65 years).
Patients were randomized 2:1 to 60 mg of cabozantinib once daily or placebo once daily. Crossover was allowed at the time of BICR–confirmed progression per RECIST v1.1 criteria.
Tumor assessment was performed every 8 weeks for 12 months and then every 12 weeks per RECIST v1.1 criteria. Treatment was continued until the loss of clinical benefit or intolerable toxicity.
The ORR in the first 100 randomized patients (OITT) and PFS in the intention-to-treat (ITT) population, both assessed per RECIST v1.1 criteria by BICR served as coprimary end points.
The primary analysis was done after a clinical data cutoff of August 19, 2020. The analysis was triggered 6 months after randomization of the 100th patient. At data cutoff, 187 patients had been randomized.
At a median follow-up of 6.2 months, cabozantinib led to a significant improvement in PFS vs placebo in the ITT population, meeting the primary end point at the interim analysis (HR, 0.22; 96% CI, 0.13-0.36; P <.0001). The ORR in the OITT population was 15% vs 0%, respectively, failing to demonstrate statistical significance (P = .028).
The final analysis, which was the focus of the presentation at the 2021 ESMO Congress, was done with a clinical data cutoff of February 8, 2021. Enrollment was stopped after a recommendation from the Independent Data Monitoring Committee.
The last patient was enrolled on February 4, 2021. At data cutoff, 258 patients had been randomized.
Regarding baseline demographics and clinical characteristics, most patients in both arms were female, White, from Europe, and had an ECOG performance status of 1, papillary histology, prior exposure to sorafenib or lenvatinib, 1 prior VEGFR TKI, and metastatic lesions other than in the bone, liver, or lung.
Additional results showed that cabozantinib improved PFS vs placebo regardless of prior exposure to sorafenib and/or lenvatinib.
Among patients who had received prior sorafenib but not lenvatinib, the median PFS was 16.6 months with cabozantinib (95% CI, 11.0-NE) vs 3.2 months (95% CI, 1.9-5.5) with placebo (HR, 0.13; 95% CI, 0.06-0.26).
Among patients who had received prior lenvatinib but not sorafenib, the median PFS was 5.8 months (95% CI, 5.1-9.3) vs 1.9 months (95% CI, 1.7-3.7), respectively (HR, 0.28; 95% CI, 0.16-0.48).
Among patients who had received both prior sorafenib and lenvatinib, the median PFS was 7.6 months (95% CI, 3.8-13.8) vs 1.9 months (95% CI, 1.8-3.8), respectively (HR, 0.27; 95% CI, 0.13-0.54).
Moreover, the median overall survival was 19.4 months (95% CI, 15.9-19.4) with cabozantinib and was not evaluable (NE; 95% CI, NE-NE) with placebo (HR, 0.76; 95% CI, 0.45-1.31).
Regarding safety, the adverse effects (AEs) were in line with the known profile of cabozantinib, said Capdevila.
Common any-grade treatment-emergent AEs (TEAEs) in the cabozantinib vs placebo arms, respectively, included diarrhea (62% vs 3%), hand-foot skin reaction (47% vs 1%), hypertension (32% vs 3%), decreased appetite (31% vs 13%), fatigue (29% vs 8%), nausea (28% vs 2%), alanine aminotransferase (ALT) increase (25% vs 2%), aspartate aminotransferase (AST) increase (25% vs 2%), hypocalcemia (25% vs 3%), weight decrease (22% vs 2%), vomiting (18% vs 8%), stomatitis (18% vs 2%), asthenia (17% vs 14%), mucosal inflammation (17% vs 0%), hypomagnesemia (16% vs 3%), and proteinuria (16% vs 2%).
Grade 3 or 4 TEAEs in the cabozantinib vs placebo arms, respectively, included diarrhea (8% vs 0%), hand-foot skin reaction (10% vs 0%), hypertension (12% vs 2%), decreased appetite (3% vs 0%), fatigue (9% vs 0%), nausea (2% vs 0%), ALT increase (1% vs 1%), AST increase (0% vs 0%), hypocalcemia (8% vs 2%), weight decrease (2% vs 0%), vomiting (2% vs 0%), stomatitis (4% vs 0%), asthenia (2% vs 0%), mucosal inflammation (2% vs 0%), hypomagnesemia (1% vs 0%), and proteinuria (2% vs 0%).
A total of 67% of patients in the cabozantinib arm vs 5% of patients in the placebo arm received dose reductions because of AEs. A total of 8.8% vs 0% of patients, respectively, discontinued treatment because of AEs unrelated to differentiated thyroid cancer. No grade 5 treatment-related AEs occurred.