OBJECTIVES: To perform an SLR of treatments for radioactive iodine (RAI)-refractory DTC after prior systemic therapy.

METHODS: Eligible studies included patients aged ≥12 years with RAI-refractory, locally advanced/metastatic DTC, who had received ≥1 prior targeted therapy. Embase, Medline, CENTRAL, CSDR and DARE were searched on 27/09/2021; peer-reviewed publications had no language or time restrictions; conference proceedings were limited to 2015 onwards. Grey literature was also searched.

RESULTS: Of 1569 unique publications screened by title/abstract, 200 were subsequently screened by full-text. Thirty-five relevant publications (including two from grey literature) reported 26 unique studies: three randomized controlled trials (RCTs); 10 non-randomized clinical studies; 13 observational studies. Of 167 excluded publications, 39 reported on mixed populations. Overall, a wide variety of interventions were assessed; safety and efficacy/effectiveness outcomes were heterogenous. RCTs were: COSMIC-311 (Phase 3), which demonstrated improved median progression-free survival (mPFS) with cabozantinib versus placebo in patients progressing on previous TKI (11.0 vs 1.9 months; hazard ratio [HR] 0.22, 96% confidence interval [CI]: 0.15–0.32; p<0.0001); SELECT (Phase 3) which showed increased mPFS in the patient subgroup (n=93) with second-line (2L) lenvatinib vs placebo (15.1 vs 3.6 months; HR 0.22, 95% CI: 0.12–0.41; p<0.0001); EORTC (Phase 2) which showed no improvement in mPFS for 2L/third-line nintedanib vs placebo (3.7 vs 2.9 months; HR 0.65, 95% CI: 0.42–0.99; p=0.095). Non-randomized trials were Phase 1–2 studies (sample size range, 10–60 patients), each investigating different therapies. Observational studies (sample size range, 11–181 patients) were mostly retrospective and typically assessed therapies across multiple treatment lines.

CONCLUSIONS: Evaluated interventions and outcomes were heterogenous, suggesting no specific standard-of-care treatment; consistent with clinical guidelines at the time the research was conducted. The lack of 2L therapy options shows significant unmet need for treatments with novel mechanisms of action that demonstrate clinical benefit in patients with RAI-refractory DTC.