University of Michigan Health System, Department of Otolaryngology - Head and Neck Surgery , 1500 E. Medical Center Drive, 1904 Taubman Center, Ann Arbor, MI 48109-1274 , USA.
Expert Opin Drug Discov. 2014 Jan;9(1):105-14. doi: 10.1517/17460441.2014.866942. Epub 2013 Dec 4.
Thyroid cancer represents over 90% of all endocrine malignancies, with medullary thyroid carcinoma (MTC) accounting for 5 - 9% of them. Patients with early-stage disease have a favorable prognosis, but once distant metastasis develops, survival drops to 50% or less. Although surgery remains effective for early-stage disease, patients with advanced disease pose a challenge as traditional therapies have not provided long-term benefits. Vandetanib, initially developed to target other receptors, demonstrated anti-rearranged during transfection (anti-RET) kinase activity. This led to preclinical studies followed by recent human clinical trials, culminating in its FDA approval in April 2011 for application in the treatment of symptomatic or progressive MTC in patients with surgically unresectable, locally advanced or metastatic disease.
The authors provide a review of the discovery strategy and preclinical development of vandetanib. The authors also provide some insight into the clinical development and the drug's post-launch situation.
Vandetanib has been shown to improve progression-free survival in MTC patients, but its impact on overall survival is still inconclusive. Further data analysis will be needed to answer the question of whether it impacts overall survival in MTC. Despite its advancements, vandetanib still lacks durable efficacy, carries moderate toxicity and has issues with drug resistance over time, not to mention issues of cost. There is a significant need for additional research to discover and develop improved therapeutic strategies for this difficult disease.
甲状腺癌占所有内分泌恶性肿瘤的 90%以上，其中髓样甲状腺癌（MTC）占 5-9%。早期疾病患者预后良好，但一旦发生远处转移，生存率降至 50%以下。尽管手术对早期疾病仍然有效，但晚期疾病患者仍存在挑战，因为传统疗法并未提供长期益处。凡德他尼最初是为了靶向其他受体而开发的，具有抗重排的转化（anti-RET）激酶活性。这导致了临床前研究，随后进行了最近的人类临床试验，最终于 2011 年 4 月获得 FDA 批准，用于治疗手术不可切除、局部晚期或转移性疾病的有症状或进展性 MTC 患者。
作者回顾了凡德他尼的发现策略和临床前开发。作者还对该药的临床开发和上市后的情况提供了一些见解。
凡德他尼已被证明可改善 MTC 患者的无进展生存期，但对总生存期的影响仍不确定。还需要进一步的数据分析来回答它是否影响 MTC 患者的总生存期的问题。尽管取得了进展，但凡德他尼仍缺乏持久的疗效，具有中度毒性，随着时间的推移会产生耐药性问题，更不用说成本问题了。需要进一步研究，以发现和开发针对这种难治性疾病的改良治疗策略。
