A multicentre, randomised, double-blind, parallel-group, placebo-controlled trial of apatinib in local progressive or metastatic radioactive iodine-refractory differentiated thyroid cancer

LBA6008 Background: Lenvatinib (LEN) is an oral tyrosine kinase inhibitor of the VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT signaling networks. Based on efficacy results of the phase 2 study of patients (pts) with 131I-refractory differentiated thyroid cancer (RR-DTC), this phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) was developed. Methods: This randomized, double-blind, placebo (PBO)-controlled study enrolled pts with RR-DTC with documented disease progression within 13 months (mo). Pts were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and randomized 2:1 to LEN or PBO (24mg/d, 28-d cycle). Upon progression, pts receiving PBO could crossover to open-label LEN. The primary endpoint was PFS assessed by Independent Radiologic Review; secondary endpoints included overall response rate (ORR; complete response [CR] + PR), overall survival (OS) and safety. Results: 392 pts (63.0 years median age; 51.0% male) were randomized. Pts on LEN had a significantly prolonged PFS vs PBO (hazard ratio 0.21, 95% confidence interval [CI] 0.14–0.31; P <.0001); median PFS was LEN: 18.3 mo (95% CI 15.1–not evaluable), PBO: 3.6 mo (95% CI 2.2–3.7). A LEN PFS benefit was observed in all predefined subgroups; median LEN PFS for pts with prior vs no prior VEGF-therapy was 15.1 mo (n=66) and 18.7 mo (n=195), respectively. Rates (n) of CRs were LEN: 1.5% (4), PBO: 0; PRs were LEN: 63.2% (165), PBO: 1.5% (2).Median exposure duration was LEN: 13.8 mo, PBO: 3.9 mo; median time to LEN response was 2.0 mo. Median OS has not been reached; deaths per arm were LEN: 71 (27.2%), PBO: 47 (35.9%). The 5 most common LEN treatment-related adverse events (TRAEs; any grade) were hypertension (68%), diarrhea (59%), appetite decreased (50%), weight loss (46%), nausea (41%). LEN grade ≥3 TRAEs (≥5%) were hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea (8%), appetite decreased (5%). The dose was reduced in 78.5% of pts and discontinued due to adverse events (AEs) in 14.2% of pts. Conclusions: LEN significantly improved PFS compared with PBO in pts with progressive RR-DTC. There were no unexpected toxicities and AEs were manageable. Clinical trial information: NCT01321554.

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A phase 3 (COSMIC-311), randomized, double-blind, placebo-controlled study of cabozantinib in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps6097 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS6097-TPS6097 ◽

Cited By ~ 2

Author(s):

Marcia S. Brose ◽

Bruce Robinson ◽

Candy Bermingham ◽

Soham Puvvada ◽

Anne E. Borgman ◽

...

Keyword(s):

Thyroid Cancer ◽

Targeted Therapy ◽

Differentiated Thyroid Cancer ◽

Controlled Trial ◽

Objective Response ◽

Controlled Study ◽

Clinical Activity ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo

TPS6097 Background: Treatment options are limited for patients with RAI-refractory DTC that is resistant to VEGFR-targeted therapy. Cabozantinib inhibits receptor tyrosine kinases including VEGFR2, MET, AXL, and RET, which are implicated in the development of DTC, and has shown clinical activity in early-phase studies of patients with RAI-refractory DTC. This study evaluates the efficacy and safety of cabozantinib in patients with RAI-refractory DTC who have progressed during or after prior VEGFR-targeted therapy. Methods: This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT03690388). The co-primary endpoints are progression-free survival and objective response rate evaluated by blinded independent radiology committee (BIRC) per RECIST v 1.1. Additional endpoints include safety, overall survival, quality of life, and changes in relevant biomarker levels (eg, thyroglobulin). Approximately 300 patients will be randomized in a 2:1 ratio to receive either cabozantinib (60 mg QD orally) or placebo. Randomization is stratified by prior treatment with lenvatinib and age (≤ 65 yrs vs > 65 yrs). Eligible patients must have a pathologic diagnosis of DTC and must have been previously treated with or deemed ineligible for treatment with iodine-131 for DTC. Patients must have received lenvatinib or sorafenib for DTC and progressed during or following treatment with a VEGFR inhibitor. Up to 2 prior VEGFR-targeting TKI agents are allowed. Patients randomized to placebo may be eligible for real time on-study crossover to cabozantinib based on BIRC confirmation of disease progression. Unblinded patients randomized to cabozantinib may continue on study treatment if there is clinical benefit per investigator. Key words: Radioiodine-refractory differentiated thyroid cancer, cabozantinib, VEGFR-targeted therapy, trial-in-progress. Clinical trial information: NCT03690388.

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