Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model

Abstract

BackgroundMedullary thyroid cancer (MTC) is a rare form of cancer that affects patients’ health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq®; Ipsen, Paris, France) and vandetanib (Caprelsa®; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC.Objectives(1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England.Data sourcesPeer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers’ submissions.Review methodsA systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model.ResultsThe systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo (p < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower.LimitationsThe intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population.ConclusionsThe identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.Future research priorities(1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL.Study registrationThis study is registered as PROSPERO CRD42016050403.FundingThe National Institute for Health Research Health Technology Assessment programme.

Benefits and Limitations of TKIs in Patients with Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis

“…In the present study, we have attempted to give a view of the current status of TKI use in MTC, as reflected in the published literature. A recent, strict meta-analysis inquiring the effect of TKIs on PFS, combined with a network meta-analysis, included only the 2 phase III RCT trials [47], and showed a comparable efficacy.…”

Anlotinib in Locally Advanced or Metastatic Medullary Thyroid Carcinoma: A Randomized, Double-Blind Phase IIB Trial

“…MTC is also a highly vascularized tumor with VEGF overexpression in tumor lesions 5 . Hence, multitarget TKIs (MKIs) blocking angiogenesis and RET are the classical medicines for the systemic therapy of MTC, such as vandetanib and cabozantinib [6][7][8][9][10][11] . The potency of other TKIs, including sorafenib 12 , pazopanib 13 , lenvatinib 14,15 , and sunitinib 16 , have also been explored.…”

The added diagnostic value of complementary gadoxetic acid-enhanced MRI to 18F-DOPA-PET/CT for liver staging in medullary thyroid carcinoma

“…However, liver staging in MTC remains challenging, as small metastases may remain 18 F-DOPA-negative. A timely and comprehensive liver staging is of major importance to evaluate potential treatment options with a growing oncological toolbox including local ablative treatment, surgical, or systemic therapy [11–19]. Recent studies have shown that contrast-enhanced liver magnetic resonance imaging (MRI) is best suited for the detection of malignant liver lesions, particularly small metastases < 1.0 cm [20–24].…”