A Comprehensive Monograph on Vandetanib (Caprelsa)

This report has been compiled by a PhD researcher specializing in the authoring of technical papers and clinical pharmacology reviews. The content is intended for an audience of clinical oncologists, pharmacologists, regulatory affairs specialists, and other healthcare professionals with advanced knowledge in oncology and drug development.

1.0 Executive Summary

Vandetanib is an orally administered, once-daily, small-molecule antineoplastic agent that represents a significant therapeutic advance in the management of a rare and aggressive malignancy. It is classified as a multi-targeted tyrosine kinase inhibitor (TKI), a pharmacological class of drugs designed to interfere with specific cellular signaling pathways that drive cancer growth and survival. The core mechanism of action of Vandetanib is distinguished by its simultaneous inhibition of three key receptor tyrosine kinases: the Vascular Endothelial Growth Factor Receptor (VEGFR), the Epidermal Growth Factor Receptor (EGFR), and the REarranged during Transfection (RET) proto-oncogene.[1] This tripartite blockade provides a dual-pronged attack on tumors, directly inhibiting cancer cell proliferation and survival while concurrently disrupting the tumor's ability to form new blood vessels (angiogenesis), a process essential for its growth and metastasis.

The primary clinical indication for Vandetanib is the treatment of symptomatic or progressive medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease.[4] This approval was based on the pivotal results of the Phase III ZETA trial, which demonstrated a statistically significant and clinically meaningful improvement in Progression-Free Survival (PFS) for patients treated with Vandetanib compared to those receiving placebo.[6] This established Vandetanib as the first therapeutic agent specifically approved for this challenging indication.

The clinical utility of Vandetanib is defined by a significant and complex safety profile, which is dominated by a Boxed Warning from the U.S. Food and Drug Administration (FDA) regarding the risk of QT interval prolongation, the potentially fatal arrhythmia Torsades de Pointes, and sudden death.[8] This profound cardiotoxicity necessitates a highly controlled approach to its use, mandated through a Risk Evaluation and Mitigation Strategy (REMS) program known as the CAPRELSA REMS Program. This program restricts prescribing and dispensing to certified healthcare providers and pharmacies and requires strict patient selection and intensive monitoring protocols.[6]

A hallmark of Vandetanib's clinical pharmacology is its exceptionally long terminal elimination half-life of approximately 19 days at steady state.[11] This pharmacokinetic characteristic has profound clinical implications, dictating a long period of approximately three months to reach steady-state plasma concentrations and, critically, a slow resolution of adverse events, including cardiotoxicity, upon dose interruption or discontinuation.

In conclusion, Vandetanib is an important, albeit niche, therapeutic agent for a difficult-to-treat cancer. Its proven efficacy in delaying disease progression in advanced MTC is counterbalanced by a significant and potentially life-threatening safety profile. Its successful use in the clinic is contingent upon meticulous patient selection, a comprehensive understanding of its complex pharmacokinetics and drug interaction profile, and strict adherence to the mandated risk management and monitoring protocols. Vandetanib thus serves as a key example of a modern targeted therapy where substantial clinical benefit is achieved within a framework of carefully managed risk.

2.0 Chemical Identity and Physicochemical Properties

A precise understanding of a drug's chemical and physical nature is foundational to its pharmacology, formulation, and analytical characterization. This section provides a comprehensive consolidation of the identifying and physicochemical data for Vandetanib.

2.1 Nomenclature and Identifiers

Vandetanib is a small molecule drug belonging to the quinazoline class of compounds.[4] Its development and regulatory history are reflected in its various names and identifiers.

• Drug Type: Small Molecule [1]
• International Union of Pure and Applied Chemistry (IUPAC) Name: N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine [4]
• Synonyms and Code Names: The drug is most commonly known by its generic name, Vandetanib, and its primary brand name, Caprelsa.[15] During its development by AstraZeneca, it was referred to by the code ZD6474 or AZD6474.[13] The name Zactima was a proposed brand name associated with its investigational use in non-small cell lung cancer, an indication for which it was not ultimately approved.[13] These different names serve as historical markers of the drug's journey from a research compound (ZD6474) through an unsuccessful attempt at a large-market indication (Zactima for NSCLC) to its final approval in a niche, orphan disease setting (Caprelsa for MTC).
• Key Registry Numbers:
• CAS Number: 443913-73-3 (for the free base).[4] A deprecated CAS number, 338992-00-0, corresponds to the fumarate salt form.[4]
• DrugBank ID: DB05294 [1]
• Other Key Identifiers:
• UNII (Unique Ingredient Identifier): YO460OQ37K [4]
• ChEBI ID: 49960 [4]
• ChEMBL ID: CHEMBL24828 [4]
• European Community (EC) Number: 669-841-4 [4]

2.2 Molecular and Structural Formulae

The molecular composition and structure of Vandetanib are precisely defined by the following parameters.

• Molecular Formula: C22​H24​BrFN4​O2​ [4]
• Molecular Weight: 475.35 g/mol (also cited as 475.354 g/mol) [13]
• Monoisotopic / Exact Mass: 474.1067 Da (also cited as 474.106666884 Da) [1]
• Structural Identifiers:
• SMILES (Simplified Molecular-Input Line-Entry System): CN1CCC(CC1)COC2=C(C=C3C(=C2)N=CN=C3NC4=C(C=C(C=C4)Br)F)OC [4]
• InChIKey (International Chemical Identifier Key): UHTHHESEBZOYNR-UHFFFAOYSA-N [4]

2.3 Physicochemical Characteristics

The physical properties of Vandetanib influence its formulation, stability, and absorption characteristics.

• Appearance: Light yellow to yellow solid powder [13]
• Solubility: Vandetanib is described as having 'low solubility' with an aqueous solubility that is pH-dependent.[14] This property necessitates specific instructions for administration if the tablet cannot be swallowed whole.
• Hygroscopicity: The compound is non-hygroscopic.[14]
• Melting Point: Approximately 235°C [14]
• pKa Values: The molecule possesses two ionization constants (pKa values), reflecting its basic nature at two different sites: a value of 5.2 is attributed to the aminoquinazolone moiety, and a value of 9.4 is attributed to the piperidine moiety.[14]

2.4 Pharmaceutical Formulation

Vandetanib is formulated for oral administration as film-coated tablets.

• Dosage Forms and Strengths: It is commercially available as 100 mg and 300 mg film-coated tablets.[11]
• Tablet Description: The 100 mg tablet is described as a round, biconvex, white film-coated tablet with 'Z100' impressed on one side.[11]
• Excipients: The tablet formulation includes several inactive ingredients that aid in its manufacture, stability, and delivery. These include: calcium hydrogen phosphate, microcrystalline cellulose, crospovidone, povidone, magnesium stearate, hypromellose, macrogol 300, and titanium dioxide.[14]

Table 2.1: Chemical and Physical Identifiers of Vandetanib

Property	Value	Source(s)
Drug Type	Small Molecule	1
IUPAC Name	N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	4
Brand Name	Caprelsa	15
Developmental Code	ZD6474, AZD6474	13
CAS Number	443913-73-3 (free base)	4
DrugBank ID	DB05294	1
Molecular Formula	C22​H24​BrFN4​O2​	4
Molecular Weight	475.35 g/mol	15
Appearance	Light yellow to yellow solid powder	13
Melting Point	Approx. 235°C	14
pKa Values	5.2 (aminoquinazolone), 9.4 (piperidine)	14
Solubility	Low, pH-dependent aqueous solubility	14

3.0 Pharmacology: A Multi-Targeted Kinase Inhibition Strategy

Vandetanib's clinical activity is derived from its ability to simultaneously modulate multiple critical signaling pathways involved in tumor growth, survival, and angiogenesis. This multi-targeted approach is central to both its efficacy and its distinct toxicity profile.

3.1 Overview of Pharmacological Class

Vandetanib is classified as an antineoplastic agent and, more specifically, a multi-targeted tyrosine kinase inhibitor (TKI).[1] Tyrosine kinases are enzymes that function as critical "on/off" switches in a multitude of cellular processes, including cell growth, differentiation, and death. In many cancers, these kinases become constitutively "on" due to mutations, leading to uncontrolled cell proliferation. Vandetanib functions by competitively binding to the adenosine triphosphate (ATP) binding pocket of specific tyrosine kinases, thereby blocking their activity and disrupting the downstream signaling cascades that promote tumorigenesis.[3] Its primary pharmacological effects are the inhibition of tumor cell proliferation and the inhibition of tumor angiogenesis.[1]

3.2 Detailed Mechanism of Action

The unique profile of Vandetanib stems from its potent and selective inhibition of three distinct receptor tyrosine kinases: VEGFR, EGFR, and RET. The simultaneous blockade of these targets creates a synergistic anti-cancer effect by attacking the tumor cell directly and also cutting off its essential blood supply.

A. Inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR)

Vandetanib's anti-angiogenic properties are mediated primarily through its blockade of the VEGFR family, which is crucial for the formation of new blood vessels (angiogenesis) that tumors require to grow and metastasize.

• Primary Target: Vandetanib is a potent inhibitor of VEGFR-2 (also known as Kinase insert Domain Receptor, or KDR), which is the principal mediator of the pro-angiogenic signals initiated by its ligand, VEGF.[13] The half-maximal inhibitory concentration ( IC50​) for VEGFR-2 tyrosine kinase activity is approximately 40 nM.[13] The drug also demonstrates inhibitory activity against VEGFR-3 and, to a lesser degree, VEGFR-1.[2]
• Mechanism and Downstream Effect: By binding to the ATP-binding site within the intracellular kinase domain of VEGFR-2, Vandetanib prevents the receptor's autophosphorylation and subsequent activation.[3] This action directly blocks VEGF-stimulated proliferation and migration of endothelial cells, reduces the permeability of tumor blood vessels, and ultimately suppresses the formation of a new vascular network, effectively starving the tumor of oxygen and nutrients.[3] This targeting of the tumor microenvironment represents a critical, albeit indirect, anti-tumor strategy.

B. Inhibition of Epidermal Growth Factor Receptor (EGFR)

In addition to its anti-angiogenic effects, Vandetanib directly targets the tumor cells by inhibiting the EGFR signaling pathway, a well-validated target in oncology.

• Mechanism and Downstream Effect: Vandetanib binds to the ATP-binding site of the EGFR tyrosine kinase domain, preventing its phosphorylation and activation upon ligand binding.[3] This blockade disrupts critical downstream signaling pathways that are essential for cell survival and proliferation, most notably the Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT) and the Ras/Raf/MEK/ERK (MAPK) pathways.[3] EGFR signaling is a known mediator of tumor cell proliferation, migration, and angiogenesis, and its overexpression or mutation is common in various cancers, including thyroid cancer and non-small-cell lung cancer (NSCLC).[1]

C. Inhibition of REarranged during Transfection (RET) Proto-Oncogene

The inhibition of the RET proto-oncogene is the most critical component of Vandetanib's mechanism for its approved indication in medullary thyroid cancer (MTC).

• Primary Relevance: Activating mutations in the RET proto-oncogene are the primary oncogenic drivers in the vast majority of hereditary MTC cases (found in >98% of Multiple Endocrine Neoplasia type 2A and 2B syndromes) and are also present in approximately 50% of sporadic (non-hereditary) MTC cases.[22] These mutations lead to constitutive, ligand-independent activation of the RET tyrosine kinase.
• Mechanism and Downstream Effect: Vandetanib potently and selectively inhibits the tyrosine kinase activity of both wild-type and various mutated forms of the RET receptor.[1] By blocking the constitutively active RET kinase, Vandetanib directly shuts down the aberrant downstream signaling that drives the uncontrolled proliferation and survival of MTC cells.[3] This direct targeting of the core genetic driver of the disease is fundamental to its clinical efficacy in this specific patient population.

The ability of Vandetanib to inhibit these three pathways simultaneously provides a multifaceted attack. It not only suppresses tumor cell proliferation directly via EGFR and RET inhibition but also impedes the supportive tumor microenvironment by inhibiting angiogenesis via VEGFR blockade. This combination helps to combat tumor growth more effectively than agents that target only a single pathway.

3.3 Pharmacodynamic Effects and Clinical Correlates

The mechanistic actions of Vandetanib translate into measurable effects both in laboratory models and in the clinical setting.

• In Vitro Activity: Vandetanib demonstrates potent anti-proliferative activity in MTC cell lines, with reported IC50​ values in the range of 5–30 nM.[17] Further studies have shown that it can induce apoptosis (programmed cell death) and cause cell cycle arrest at the G2/M phase in various cancer cell lines, contributing to its growth-inhibitory effects.[13]
• In Vivo Activity: In preclinical animal models, administration of Vandetanib has been shown to decrease tumor cell mass, markedly suppress the phosphorylation of EGFR and VEGFR, reduce tumor-induced angiogenesis, and inhibit overall tumor growth and metastasis.[13]
• Resistance Mechanisms: A key clinical challenge in targeted therapy is the development of resistance. For Vandetanib, specific mutations within the RET kinase domain, notably substitutions at the valine 804 residue (V804M and V804L), have been shown to confer significant resistance to its anti-RET activity.[15] The presence of these mutations can predict a lack of response to therapy and is a critical consideration for patient management and the development of next-generation inhibitors.

The drug's efficacy and its toxicity profile are inextricably linked, both stemming directly from its multi-targeted mechanism. The well-known class effects of VEGFR inhibitors, such as hypertension, hemorrhage, and impaired wound healing, are prominent in Vandetanib's safety profile.[9] Similarly, the hallmark toxicities of EGFR inhibitors, including rash, acneiform dermatitis, and diarrhea, are among the most common adverse events experienced by patients.[23] The dermatological adverse events, for instance, are a direct consequence of inhibiting EGFR, which is highly expressed in the epidermis and its appendages, leading to effects like hyperkeratosis and inflammation.[26] This direct link between the intended pharmacology and the observed side effects provides a rational basis for predicting, monitoring, and managing the drug's toxicity.

3.4 Other Minor Targets

In addition to its three primary targets, in vitro studies have suggested that Vandetanib may possess inhibitory activity against other kinases, including breast tumour kinase (BRK) and the TIE2 receptor.[14] It has also been shown to act as an antagonist at histamine H1 and H2 receptors and the adrenergic α2A receptor.[14] The clinical significance of these off-target activities is not well characterized but may contribute to certain aspects of its overall pharmacological and toxicological profile.

4.0 Pharmacokinetic Profile: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Vandetanib is characterized by slow absorption, extensive tissue distribution, and a remarkably long elimination half-life. These properties are fundamental to its clinical use, dictating its dosing schedule, the time required to achieve therapeutic effect, and the management of its adverse events.

4.1 Absorption

• Rate and Extent: Following oral administration, Vandetanib is absorbed slowly, with the time to reach maximum plasma concentration (Tmax​) occurring at a median of 6 to 10 hours post-dose.[1]
• Food Effect: The presence of food does not significantly affect the overall extent of absorption (as measured by Area Under the Curve, AUC) or the peak plasma concentration (Cmax​).[28] This allows the drug to be administered with or without food, providing convenience and flexibility for patients.[20]
• Accumulation and Steady State: The most critical feature of Vandetanib's absorption and elimination kinetics is its substantial accumulation with repeated dosing. Due to its very long half-life, the drug accumulates approximately 8-fold in the body, and steady-state plasma concentrations are not reached until after about 3 months of continuous daily administration.[1] This long lead-in period has major implications for clinical monitoring, as the full extent of both efficacy and toxicity may not be apparent for several months.

4.2 Distribution

• Volume of Distribution (Vd​): Vandetanib exhibits a very large apparent volume of distribution, estimated to be around 7450 L.[1] This large value indicates that the drug distributes extensively into tissues throughout the body, with only a small fraction remaining in the systemic circulation at any given time.
• Plasma Protein Binding: The drug is highly bound to plasma proteins in the blood. In vitro studies report binding of approximately 90%, while ex vivo measurements from patient plasma samples at steady state show a mean protein binding of 93.7% (range 92.2% to 95.7%).[1] It binds primarily to human serum albumin and α1-acid-glycoprotein.[14] This high degree of protein binding means that only a small fraction of the drug is "free" and pharmacologically active.

4.3 Metabolism

Vandetanib is metabolized in the liver through multiple enzymatic pathways.

• Primary Enzymes: In vitro studies have established that the main cytochrome P450 enzyme responsible for Vandetanib's metabolism is CYP3A4.[14] In addition to the CYP450 system, flavin-containing monooxygenase enzymes, specifically FMO1 and FMO3, also play a significant role in its biotransformation.[12]
• Active Metabolites: The metabolic process generates two primary metabolites that are also pharmacologically active and have been detected in plasma, urine, and feces [15]:

1. N-desmethyl-vandetanib: This metabolite is produced mainly through the action of CYP3A4. It circulates in the plasma at concentrations that are approximately 11% of those of the parent Vandetanib compound.[14]
2. Vandetanib-N-oxide: This metabolite is formed primarily by the FMO1 and FMO3 enzymes. It is present in plasma at much lower concentrations, approximately 1.4% of the parent drug.[14]

• Minor Metabolites: A glucuronide conjugate of Vandetanib has also been identified as a minor metabolite, found in trace amounts in urine and feces.[28]

4.4 Elimination

The elimination of Vandetanib from the body is a slow process, consistent with its long half-life.

• Routes of Excretion: Elimination occurs through both fecal and renal pathways. Following a single radiolabeled dose, approximately 69% of the dose was recovered over a 21-day collection period. Of this, 44% was excreted in the feces and 25% was excreted in the urine, primarily as unchanged drug and the N-desmethyl and N-oxide metabolites.[12]
• Half-Life (t1/2​): This is the most clinically significant pharmacokinetic parameter for Vandetanib. While studies after a single dose reported a half-life of around 10 days [28], the mean elimination half-life at steady state in patients is approximately 19 days.[11] This exceptionally long half-life is the central organizing principle of the drug's clinical pharmacology. It directly explains the 3-month period required to reach steady state, the relaxed rule for managing missed doses, and, most importantly, the slow resolution of adverse events upon dose modification or cessation. A clinician must recognize that stopping the drug does not lead to a rapid disappearance of its effects or risks.
• Clearance: The apparent oral clearance (CL/F) of Vandetanib is approximately 13.2 L/h.[29]
• Role of Transporters: Vandetanib is an inhibitor of the organic cation transporter 2 (OCT2), a transporter protein involved in the renal secretion of various drugs. This inhibition can lead to drug-drug interactions by decreasing the clearance of co-administered OCT2 substrates.[14]

Table 4.1: Key Pharmacokinetic Parameters of Vandetanib

Parameter	Value	Clinical Implication / Note
Time to Peak (Tmax​)	6–10 hours	Slow absorption profile.
Food Effect	Not significant	Dosing is permitted with or without food, enhancing patient convenience.
Accumulation	~8-fold	Significant accumulation occurs with daily dosing.
Time to Steady State	~3 months	Full therapeutic and toxic effects may not be evident for several months.
Volume of Distribution (Vd​)	~7450 L	Indicates extensive distribution into body tissues.
Plasma Protein Binding	~90–96%	High binding to albumin and α1-acid-glycoprotein; small free fraction.
Metabolism	Hepatic: CYP3A4, FMO1, FMO3	Multiple pathways involved; produces two active metabolites.
Elimination Half-Life (t1/2​)	~19 days (at steady state)	CRITICAL PARAMETER: Explains long time to steady state, long duration of action, and slow resolution of adverse events.
Excretion	44% feces, 25% urine (over 21 days)	Both hepatic and renal routes are important for elimination.
Clearance (CL/F)	~13.2 L/h	Slow clearance rate consistent with the long half-life.

5.0 Clinical Efficacy in Medullary Thyroid Carcinoma (MTC)

Vandetanib was the first drug to receive regulatory approval specifically for the treatment of advanced medullary thyroid carcinoma, representing a major milestone for patients with this rare and often aggressive disease. Its approval was based on robust evidence of clinical benefit from a large, well-designed Phase III clinical trial.

5.1 Overview of the Indication

Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease.[4] This indication is carefully worded to guide its use toward patients who are most likely to derive a meaningful benefit that outweighs the drug's considerable risks. The prescribing information specifically advises that for patients with MTC that is indolent (slow-growing), asymptomatic, or progressing slowly, the decision to initiate therapy should be made only after careful consideration of the treatment-related risks.[6] This reflects a sophisticated risk-benefit calculation embedded within the regulatory approval, acknowledging that not all patients with advanced MTC require immediate systemic therapy and pushing clinicians to reserve this potent but toxic drug for those whose disease trajectory justifies the risks.

5.2 The Pivotal Phase III ZETA Trial (NCT00410761)

The cornerstone of Vandetanib's approval is the ZETA (Zactima Efficacy in Thyroid Cancer Assessment) trial, an international, randomized, double-blind, placebo-controlled study that definitively established its efficacy.

• Study Design and Population: The trial enrolled 331 patients with unresectable locally advanced or metastatic MTC. Patients were randomized in a 2:1 ratio to receive either Vandetanib 300 mg once daily (n=231) or a matching placebo (n=100).[6] The study population was representative of advanced MTC, including patients with both sporadic (90%) and hereditary (10%) disease, with the vast majority (95%) having metastatic disease at study entry.[7]
• Primary Endpoint: The primary objective was to demonstrate an improvement in Progression-Free Survival (PFS), defined as the time from randomization until objective tumor progression or death, as determined by independent central radiological review.[6]
• Key Efficacy Results:
• Progression-Free Survival (PFS): The ZETA trial successfully met its primary endpoint. Vandetanib demonstrated a statistically significant and clinically meaningful prolongation of PFS compared to placebo. The analysis showed a 54% reduction in the risk of disease progression, with a hazard ratio (HR) of 0.46 (95% confidence interval [CI], 0.31 to 0.69; P <.001).[7] The FDA's review cited a similar HR of 0.35.[6] The median PFS was 19.3 months in the placebo arm, while the median PFS in the Vandetanib arm had not yet been reached at the time of analysis but was predicted to be 30.5 months, representing a substantial delay in tumor growth.[23]
• Objective Response Rate (ORR): Vandetanib produced a significantly higher rate of tumor shrinkage. The ORR was 44–45% in the Vandetanib arm (consisting entirely of partial responses) compared to just 1–13% in the placebo arm (P <.001).[6]
• Disease Control Rate (DCR): The DCR (defined as the percentage of patients with a complete response, partial response, or stable disease) was also significantly higher in the Vandetanib group (P =.001).[7]
• Overall Survival (OS): At the time of the primary analysis, the data for overall survival were immature, with only 15% of patients having died. There was no statistically significant difference in OS between the two treatment arms (HR 0.89; 95% CI, 0.48 to 1.65).[7] This lack of an OS benefit is a critical point of interpretation. The trial's ethical design allowed patients in the placebo group to cross over and receive open-label Vandetanib upon documented disease progression.[33] A very high proportion of placebo patients (93% in one report) did, in fact, receive Vandetanib after their cancer worsened.[33] This crossover effectively "contaminates" the OS analysis, making it statistically very difficult to demonstrate a survival difference between a group that received the drug from the start and a group that received it later. Therefore, the robust and highly significant PFS benefit is considered the most accurate measure of Vandetanib's clinical activity in this setting.

5.3 Efficacy in Patient Subgroups

• RET Mutation Status: While the biological rationale for Vandetanib is strongest in patients with RET-mutant MTC, the clinical benefit observed in the ZETA trial was not limited to this subgroup. The European label notes that patients benefit from treatment regardless of their RET mutation status (known positive, known negative, or unknown), although it advises that a possible lower benefit should be considered for patients who are RET-negative or whose status is unknown.[11]
• Disease Aggressiveness: A post-hoc analysis of the ZETA trial provided further insight into which patients benefit most. The analysis stratified patients based on whether they had symptomatic disease, progressive disease, both, or neither at baseline. The greatest PFS benefit was observed in the subgroup of patients whose disease was both progressive and symptomatic at the start of the trial (HR for PFS 0.43).[37] This finding reinforces the label's guidance to use the drug in patients with "symptomatic or progressive" disease.

5.4 Long-Term Efficacy and Durability of Response

Follow-up and real-world studies have provided valuable data on the long-term outcomes for patients treated with Vandetanib. These studies have identified a significant subset of patients who derive prolonged clinical benefit.

• Long-Term Users: One retrospective analysis identified a cohort of "long-term users," defined as patients who received Vandetanib for more than 48 months. This group constituted 27.6% of the total patient population studied.[38]
• Durable Responses: Within this long-term user group, the median duration of treatment was an impressive 68.1 months. The objective response rate was 85.7%, and the median PFS was 73.2 months, indicating a highly durable anti-tumor effect in these select patients.[38]
• Predictors of Durable Response: The same study found that a younger age at diagnosis and the absence of confirmed tumor progression immediately prior to starting treatment were significantly associated with a more durable response.[38] This suggests that earlier intervention in patients with high-risk disease may lead to better long-term outcomes.

Table 5.1: Summary of Efficacy Results from the Pivotal ZETA Trial

Endpoint	Vandetanib 300 mg (n=231)	Placebo (n=100)	Hazard Ratio / Odds Ratio (95% CI)	P-value	Source(s)
Progression-Free Survival (PFS)	Median Not Reached (Predicted 30.5 mo)	Median 19.3 mo	HR: 0.46 (0.31–0.69)	< 0.001	7
Objective Response Rate (ORR)	45%	13%	OR: 5.48 (2.99–10.79)	< 0.001	7
Disease Control Rate (DCR)	87%	71%	OR: 2.64 (1.48–4.69)	0.001	7
Overall Survival (OS)	Data Immature	Data Immature	HR: 0.89 (0.48–1.65)	Not Significant	7

6.0 Investigational and Off-Label Applications

While Vandetanib found its niche in medullary thyroid cancer, its development program explored its potential in several other malignancies. The results of these trials have been instrumental in defining the drug's therapeutic boundaries and reinforcing the principle of targeted therapy. The collective outcomes from these investigations solidify Vandetanib's identity as a highly specific agent whose major clinical utility is confined to RET-driven MTC. The broader anti-angiogenic (VEGFRi) and anti-proliferative (EGFRi) effects, while biologically active, appear insufficient on their own to drive significant clinical benefit in cancers that are not "addicted" to the RET pathway.

6.1 Differentiated Thyroid Cancer (DTC): The VERIFY Trial (NCT01876784)

Given the involvement of VEGFR and EGFR pathways in differentiated thyroid cancer (papillary and follicular types), Vandetanib was investigated as a potential treatment for patients who had become refractory to standard radioiodine (RAI) therapy.

• Study Aim: The VERIFY study was a large, Phase III, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of Vandetanib in patients with locally advanced or metastatic RAI-refractory DTC.[40]
• Outcome: The trial failed to meet its primary endpoint. Vandetanib did not produce a statistically significant improvement in progression-free survival compared to placebo. The median PFS was 10.0 months in the Vandetanib arm versus 5.7 months in the placebo arm, which corresponded to a hazard ratio of 0.75 but with a P-value of 0.080, falling short of the threshold for statistical significance.[40]
• Safety Findings: Consistent with its known profile, active treatment with Vandetanib was associated with a higher incidence of adverse events and a greater number of deaths compared to the placebo arm, although the difference in overall survival was not statistically significant.[40]
• Exploratory TSH Analysis: A critical post-hoc analysis from the VERIFY trial provided a potential explanation for the negative result and serves as a key lesson for TKI trials in endocrine cancers. Vandetanib is known to cause hypothyroidism, which leads to an elevation in thyroid-stimulating hormone (TSH) if not adequately managed. Since TSH is a known growth factor for DTC, it was hypothesized that drug-induced TSH elevation could have stimulated tumor growth, thereby confounding and masking an underlying anti-tumor effect of Vandetanib. An exploratory analysis that adjusted for TSH levels during the trial revealed a statistically significant treatment effect, with an HR for PFS of 0.62 (P = 0.005).[40] This suggests that the drug's own side effect may have contributed to the trial's failure and underscores the critical importance of aggressive TSH suppression as a component of the study protocol in future trials of TKIs in DTC.

6.2 Non-Small Cell Lung Cancer (NSCLC)

The dual inhibition of VEGFR and EGFR made Vandetanib a theoretically attractive candidate for NSCLC, a major cancer type where both pathways are clinically validated targets.

• Historical Context and Outcome: AstraZeneca pursued an extensive clinical development program for Vandetanib in NSCLC and submitted a New Drug Application (NDA) to the FDA for its use in the second-line treatment setting, under the proposed brand name Zactima.[19] However, the clinical trials ultimately failed to demonstrate a sufficient clinical benefit when Vandetanib was added to standard chemotherapy. Consequently, the application was withdrawn from the European Medicines Agency (EMA) in October 2009, and the drug was not approved for this indication.[15] This failure in a large potential market was a pivotal moment that redirected the drug's development path toward the rare disease space.

6.3 Other Investigational Settings

Vandetanib has been explored in several other contexts with limited success, further defining its narrow spectrum of major activity.

• Pediatric MTC (NCT00514046): The most successful expansion of Vandetanib's use was in pediatric patients. A Phase I/II study sponsored by the National Cancer Institute (NCI) evaluated the activity, safety, and pharmacokinetics of Vandetanib in children and adolescents (ages 5 to 18) with hereditary MTC, a population that shares the same core RET-driven biology as adult MTC.[43] The positive results from this trial led to the expansion of the approved indication to include pediatric patients aged 5 years and older.[26]
• Biliary Tract Cancer (VanGogh Study, NCT00753675): A randomized Phase II trial was conducted in patients with advanced biliary tract cancer. It compared three arms: Vandetanib monotherapy, Vandetanib in combination with gemcitabine, and gemcitabine plus placebo. The study found no improvement in PFS for either of the Vandetanib-containing arms compared to the standard gemcitabine/placebo arm.[46]
• Renal Cell Carcinoma (NCT02495103): A Phase I/II trial was initiated to investigate Vandetanib in combination with metformin for specific subtypes of renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer, succinate dehydrogenase-associated, or sporadic papillary RCC). However, the trial was terminated prematurely because the manufacturer, Sanofi, decided not to provide additional drug for the study.[47]

7.0 Comprehensive Safety Profile and Risk Management

The clinical use of Vandetanib is fundamentally defined by its extensive and serious safety profile. The management of its toxicities, particularly its profound cardiotoxicity, is paramount and is governed by a strict regulatory framework. The entire clinical management strategy for Vandetanib is built around mitigating this risk. This is exemplified by the REMS program, which is not an ancillary measure but a central, legally mandated component of its approval, representing a modern paradigm of drug regulation for agents with significant but manageable risks.

7.1 Boxed Warning: QT Prolongation, Torsades de Pointes, and Sudden Death

Vandetanib carries a Boxed Warning, the most stringent warning issued by the FDA, for its potential to cause life-threatening cardiac events.

• The Central Risk: The primary safety concern is Vandetanib's ability to cause a substantial and concentration-dependent prolongation of the QT interval on an electrocardiogram (ECG).[5] The QT interval represents the time it takes for the heart's ventricles to repolarize after a contraction; its prolongation increases the risk of dangerous arrhythmias.
• Clinical Events: Cases of Torsades de Pointes (a specific, life-threatening form of polymorphic ventricular tachycardia), other ventricular tachycardias, and sudden death have been reported in patients treated with Vandetanib.[9]
• Magnitude of Effect: The effect on the QT interval is significant. In the pivotal ZETA trial, the mean increase in the Fridericia-corrected QT interval (QTcF) from baseline was 35 milliseconds. A QTcF interval greater than 500 ms was observed in 11% of patients, and an increase of more than 60 ms from baseline occurred in 36% of patients.[10]
• Impact of Half-Life: This risk is critically exacerbated by Vandetanib's long 19-day elimination half-life. This means that upon dose interruption or discontinuation, the drug is cleared very slowly, and the prolongation of the QT interval may not resolve quickly, prolonging the period of risk.[10]

7.2 Contraindications

To mitigate the severe cardiac risk, patient selection is of utmost importance. Vandetanib is strictly contraindicated in patients with any of the following conditions [1]:

• Congenital long QT syndrome
• A history of Torsades de Pointes
• A baseline QTcF interval greater than 450 ms (per the US label) or greater than 480 ms (per the EU label)
• Uncorrected baseline electrolyte abnormalities, specifically hypocalcemia, hypokalemia, or hypomagnesemia
• Pre-existing bradyarrhythmias or uncompensated heart failure

7.3 Other Serious Warnings and Precautions

Beyond its cardiotoxicity, Vandetanib is associated with a range of other serious and potentially fatal adverse events.

• Severe Skin Reactions: Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Vandetanib must be permanently discontinued if a patient develops a severe skin reaction.[21] Photosensitivity reactions are also common and can occur during treatment and for up to 4 months after discontinuation.[5]
• Interstitial Lung Disease (ILD): Cases of ILD, including some with fatal outcomes, have occurred. Any patient who develops unexplained, non-specific respiratory symptoms such as dyspnea, cough, or fever should have Vandetanib therapy interrupted pending investigation. If ILD is confirmed, the drug should be permanently discontinued.[21]
• Hemorrhage: Serious and sometimes fatal hemorrhagic events have been observed. The drug should not be administered to patients with a recent history of hemoptysis (coughing up blood).[24]
• Heart Failure: Cases of heart failure, some of which have been fatal, have been reported. Discontinuation of Vandetanib may be necessary, and the heart failure may not be reversible upon stopping the drug.[9]
• Ischemic Cerebrovascular Events: Events such as stroke have been reported, and the drug should be discontinued if a severe event occurs.[21]
• Hypertension: Hypertension, including hypertensive crisis, is a common on-target effect of VEGFR inhibition. Blood pressure must be monitored and managed appropriately. If hypertension cannot be controlled, Vandetanib should not be resumed.[9]
• Diarrhea: Severe diarrhea is a very common adverse event. It requires proactive management with antidiarrheal agents to prevent dehydration and subsequent electrolyte disturbances (e.g., hypokalemia, hypomagnesemia), which can further exacerbate the risk of QT prolongation.[9]
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): This rare neurological syndrome, characterized by headache, seizures, and visual disturbances, has been reported in patients treated with Vandetanib.[21]
• Impaired Wound Healing: As a class effect of VEGFR inhibitors, Vandetanib can interfere with wound healing. It is recommended to withhold therapy for at least 1 month prior to elective surgery. The drug should not be administered for at least 2 weeks following major surgery and until the wound is adequately healed.[21]
• Embryo-Fetal Toxicity: Vandetanib can cause fetal harm. Animal studies have shown it to be embryotoxic and fetotoxic. Females of reproductive potential must be advised of the risk and must use effective contraception during treatment and for at least 4 months after the final dose.[15]

7.4 Common Adverse Reactions

The most frequently reported adverse reactions (occurring in >20% of patients) in clinical trials are direct consequences of the drug's inhibition of EGFR and VEGFR pathways. These include [5]:

• Gastrointestinal: Diarrhea, nausea, abdominal pain, decreased appetite, vomiting
• Dermatologic: Rash (including acneiform dermatitis), dry skin, photosensitivity reaction, pruritus
• Cardiovascular: Hypertension, QT prolongation
• General: Fatigue, headache
• Infections: Upper respiratory tract infections

7.5 The CAPRELSA REMS Program

Due to the severity of the risks associated with QT prolongation, Torsades de Pointes, and sudden death, Vandetanib is only available in the United States through a restricted distribution program known as the CAPRELSA Risk Evaluation and Mitigation Strategy (REMS) Program.[5]

• Mandate and Goals: The REMS program is mandated by the FDA. Its goals are to mitigate the serious cardiac risks by ensuring that prescribers are educated about these risks, that patients are informed, and that the necessary safety monitoring is conducted.[9]
• Requirements: Only healthcare providers and pharmacies that are certified with the CAPRELSA REMS Program are able to prescribe and dispense the drug. This creates a closed-loop system designed to enforce safe-use conditions.[9]

Table 7.1: Summary of Key Adverse Reactions from the ZETA Trial (Vandetanib vs. Placebo)

System Organ Class	Adverse Reaction	Vandetanib (All Grades %)	Vandetanib (Grade 3/4 %)	Placebo (All Grades %)	Source(s)
Gastrointestinal	Diarrhea / Colitis	56-57%	9-11%	26%	7
	Nausea	33%	-	16%	7
	Decreased Appetite	21%	-	-	25
	Abdominal Pain	21%	-	-	25
Dermatologic	Rash / Acneiform Dermatitis	45-53%	-	11%	7
Cardiovascular	Hypertension	32-33%	9%	5%	7
	QT Prolongation	14%	8%	-	25
General	Fatigue	24%	6%	-	29
	Headache	26%	-	9%	7
Endocrine	Hypocalcemia	11-57%	-	-	25
Infections	Upper Respiratory Tract Infections	23%	-	-	25

Note: Data compiled from multiple sources reporting on the ZETA trial; percentages may vary slightly based on specific analyses and reporting criteria. Grade 3/4 data for placebo were often not specified in the provided materials.

8.0 Dosage, Administration, and Clinical Monitoring

The clinical management of Vandetanib therapy requires strict adherence to prescribed dosing, administration, and monitoring schedules. These protocols are designed to maximize efficacy while proactively managing the drug's significant safety risks, particularly cardiotoxicity. The unusually intensive and prolonged monitoring schedule is a direct clinical manifestation of Vandetanib's challenging pharmacokinetic (long half-life) and safety (cardiotoxicity) profiles. The protocol is not arbitrary; every time point and every test represents a rational response to the drug's known behavior in the body and its associated risks.

8.1 Recommended Dosing

• Standard Adult Dose: The recommended starting dose of Vandetanib is 300 mg taken orally once daily.[20]
• Duration of Therapy: Treatment should be continued until the patient experiences disease progression or develops unacceptable toxicity.[20]
• Dose Comparison Study (NCT01496313): A Phase IV study was specifically designed to compare the efficacy and safety of a 150 mg daily dose versus the standard 300 mg daily dose. The results showed a more favorable trend in objective response rate for the 300 mg dose. This confirmed that 300 mg is the most appropriate starting dose for the majority of patients, with the 150 mg dose (and other reductions) being reserved for managing toxicities or for use in patients with specific comorbidities that might increase their risk.[36]

8.2 Administration Instructions

• General Administration: Vandetanib can be taken with or without food, but it should be taken at approximately the same time each day to maintain consistent plasma levels.[5]
• Tablet Integrity: The tablets should be swallowed whole with water and should not be crushed or cut.[20]
• Instructions for Dispersion: For patients who are unable to swallow tablets whole, a specific dispersion method is provided. The tablet should be placed in a glass containing 2 ounces (60 mL) of plain, non-carbonated drinking water. It should be stirred for approximately 10 minutes. The tablet will disperse into very small pieces but will not dissolve completely. The patient should drink the mixture immediately. To ensure the full dose is consumed, the glass should be rinsed with an additional 4 ounces (120 mL) of non-carbonated water, and the rinse water should also be drunk. This dispersion can also be administered through nasogastric or gastrostomy tubes.[5]
• Missed Dose Management: The long half-life of Vandetanib allows for a flexible approach to missed doses. If a patient misses a dose, they should take it as soon as they remember. However, if it is less than 12 hours until the next scheduled dose, the patient should skip the missed dose and take the next dose at the regular time. Patients should be instructed not to take a double dose to make up for a missed one.[11]

8.3 Dose Modification Schedules

Dose adjustments are a critical component of managing Vandetanib-related toxicities.

• For General Toxicity: If a patient experiences a Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher toxicity, therapy should be interrupted. Once the toxicity has resolved or improved to CTCAE Grade 1, treatment can be resumed at a reduced dose. The 300 mg daily dose can be reduced first to 200 mg, and then to 100 mg if further reduction is necessary.[11]
• For QT Prolongation: If the QTcF interval exceeds 500 ms, Vandetanib therapy must be interrupted immediately. Treatment may be resumed at a reduced dose only after the QTcF interval has returned to a value of less than or equal to 450 ms.[9]

8.4 Dosing in Special Populations

• Renal Impairment: Vandetanib exposure is increased in patients with renal impairment, necessitating dose adjustments.
• Mild Impairment (Creatinine Clearance [CrCl] ≥50 mL/min): No dose adjustment is required.[20]
• Moderate Impairment (CrCl 30 to <50 mL/min): The recommended starting dose should be reduced to 200 mg once daily.[9]
• Severe Impairment (CrCl <30 mL/min): Use of Vandetanib is not recommended in this population.[9]
• Hepatic Impairment:
• Mild Impairment (Child-Pugh Class A): No specific dose adjustment is described in the manufacturer's labeling.[31]
• Moderate to Severe Impairment (Child-Pugh Class B or C): Use of Vandetanib is not recommended, as its safety and efficacy have not been established in these populations.[24]

8.5 Mandatory and Recommended Clinical Monitoring

The intensive monitoring schedule for Vandetanib is a direct reflection of its pharmacokinetic and safety profiles. The front-loaded schedule is designed to detect issues during the critical 3-month drug accumulation phase, while the long-term monitoring addresses the sustained risk at steady state.

• Baseline Assessment: Before initiating therapy, a comprehensive baseline assessment is mandatory. This must include:
• An ECG to determine the baseline QTcF interval.
• Serum levels of potassium, calcium, magnesium, and TSH.[9]
• Electrolyte abnormalities must be corrected prior to starting Vandetanib, and serum potassium should be maintained at 4.0 mEq/L or higher (within the normal range).[25]
• Monitoring During Treatment:
• ECG and Electrolytes (K, Ca, Mg): These must be re-checked at 2–4 weeks, at 8–12 weeks, and then every 3 months thereafter.[9] More frequent monitoring of electrolytes and ECGs is clinically indicated for patients who develop conditions that could alter electrolyte balance, such as severe diarrhea.[9]
• Thyroid-Stimulating Hormone (TSH): TSH levels should be monitored on the same schedule as the ECG and electrolytes (2–4 weeks, 8–12 weeks, and every 3 months thereafter) to detect drug-induced hypothyroidism and allow for timely adjustment of thyroid hormone replacement therapy.[20]
• Blood Pressure: Blood pressure should be monitored regularly for the development of hypertension.[9]

Table 8.1: Dose Adjustment and Monitoring Guidelines for Vandetanib

Part A: Dose Adjustment Guidelines
Clinical Scenario	Action
CTCAE Grade ≥3 Toxicity	Interrupt therapy. Resume at a reduced dose (200 mg, then 100 mg) once toxicity resolves to ≤ Grade 1.
QTcF Interval > 500 ms	Interrupt therapy. Resume at a reduced dose only after QTcF returns to ≤ 450 ms.
Moderate Renal Impairment (CrCl 30 to <50 mL/min)	Reduce starting dose to 200 mg once daily.
Severe Renal Impairment (CrCl <30 mL/min)	Use is not recommended.
Moderate-to-Severe Hepatic Impairment	Use is not recommended.
Part B: Clinical Monitoring Schedule
Parameter	Baseline
ECG (for QTcF)	Required
Serum Potassium	Required
Serum Calcium	Required
Serum Magnesium	Required
Serum TSH	Required
Blood Pressure	Required

9.0 Significant Drug-Drug Interactions (DDIs)

Vandetanib is subject to several clinically significant drug-drug interactions (DDIs) that can alter its efficacy or increase its toxicity. These interactions can be pharmacodynamic (affecting the drug's action) or pharmacokinetic (affecting the drug's concentration). A thorough medication review is essential before initiating and during Vandetanib therapy.

9.1 Interactions with QT-Prolonging Agents (Pharmacodynamic)

This represents the most critical and potentially dangerous drug interaction.

• Primary Concern: Due to Vandetanib's own substantial effect on QT interval prolongation, its co-administration with other drugs that share this property creates an additive risk of inducing Torsades de Pointes and sudden death. Therefore, concomitant use should be avoided whenever possible.[10]
• Examples of Interacting Drugs: The list of drugs that can prolong the QT interval is extensive. Key examples include, but are not limited to:
• Class IA and Class III Antiarrhythmics: amiodarone, sotalol, dofetilide, procainamide, disopyramide.[10]
• Certain Antibiotics: Macrolides (e.g., clarithromycin, erythromycin IV) and fluoroquinolones (e.g., moxifloxacin).[10]
• Antipsychotics: haloperidol, pimozide.[10]
• Other Agents: methadone, chloroquine, ondansetron, granisetron.[10]
• Management: If the co-administration of a QT-prolonging agent is deemed medically necessary and cannot be avoided, more frequent ECG monitoring of the QT interval is required.[10]

9.2 Interactions with CYP3A4 Modulators (Pharmacokinetic)

Vandetanib's metabolism via CYP3A4 makes it susceptible to interactions with drugs that induce or inhibit this enzyme. Interestingly, the interaction profile is asymmetric, with inducers posing a much greater clinical risk than inhibitors. This is explained by Vandetanib's parallel metabolic clearance by FMO enzymes. This dual-pathway metabolism acts as a safety valve; when the CYP3A4 pathway is inhibited, the FMO pathway can still clear the drug, preventing a dangerous surge in plasma levels. Conversely, strong induction of CYP3A4 creates such a powerful clearance mechanism that the FMO pathway cannot compensate, leading to a clinically significant drop in drug levels and a risk of therapeutic failure.

• Strong CYP3A4 Inducers:
• Effect: Strong inducers of CYP3A4 can significantly increase the metabolism of Vandetanib, leading to lower plasma concentrations and a potential loss of efficacy. A clinical study showed that co-administration of the potent inducer rifampicin decreased the AUC of Vandetanib by approximately 40%.[18]
• Management: Concomitant use of strong CYP3A4 inducers should be avoided. This includes drugs like rifampicin, carbamazepine, phenytoin, phenobarbital, and the herbal supplement St. John's Wort.[18]
• Strong CYP3A4 Inhibitors:
• Effect: Strong inhibitors of CYP3A4 have a surprisingly minimal impact on Vandetanib exposure. A clinical study with the potent inhibitor itraconazole showed only a 9% increase in the AUC of Vandetanib.[18]
• Management: While caution is still warranted, no routine contraindication or dose adjustment is typically required when Vandetanib is co-administered with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir).[14]

9.3 Interactions Involving Drug Transporters

Vandetanib can both be affected by and affect the function of various drug transporter proteins.

• Vandetanib as an Inhibitor:
• OCT2 (Organic Cation Transporter 2): Vandetanib is an inhibitor of the renal transporter OCT2.[14] This can decrease the renal excretion and thereby increase the plasma concentrations of co-administered drugs that are OCT2 substrates. For example, co-administration of Vandetanib with metformin (a common OCT2 substrate) increased metformin's AUC by 74% and its Cmax​ by 50%.[30] Therefore, caution and close monitoring for toxicities of the co-administered drug are advised.
• P-glycoprotein (P-gp): Vandetanib can modestly inhibit the efflux transporter P-gp. It has been shown to increase the exposure of the P-gp substrate digoxin, raising its AUC by 23% and its Cmax​ by 29%.[30] Clinical monitoring for digoxin toxicity is recommended.
• Vandetanib as a Substrate:
• Efflux Transporters: Vandetanib itself is a substrate for the efflux transporters P-gp and BCRP (Breast Cancer Resistance Protein). The activity of these transporters may limit Vandetanib's penetration across the blood-brain barrier.[29]
• Uptake Transporters: Vandetanib is also a substrate for the hepatic uptake transporters OATP1B1 and OATP1B3, which may influence its hepatic disposition and create the potential for other transporter-mediated DDIs.[15]

10.0 Regulatory and Commercial Landscape

The regulatory and commercial history of Vandetanib is a direct reflection of its clinical development journey, which ultimately defined its market position as a valuable but highly specialized orphan drug. This history serves as an illustrative case study in modern pharmaceutical portfolio management, where a drug that is a poor strategic fit for a blockbuster-focused company can become a key asset for a company specializing in rare diseases.

10.1 Development and Initial Marketing

• Developer: Vandetanib (originally coded ZD6474) was discovered and developed by the global biopharmaceutical company AstraZeneca.[15]
• Orphan Drug Designation: Recognizing the high unmet need in a rare disease, the U.S. FDA granted Vandetanib Orphan Drug Designation in 2005 for the treatment of medullary thyroid carcinoma.[54] This designation provides incentives to encourage the development of drugs for rare conditions.

10.2 Global Regulatory Approval History

Vandetanib underwent rigorous review by major global regulatory agencies, leading to its approval for advanced MTC.

• U.S. Food and Drug Administration (FDA): Vandetanib, under the brand name Caprelsa, was approved by the FDA on April 6, 2011. The approved indication was for the treatment of symptomatic or progressive MTC in patients with unresectable, locally advanced, or metastatic disease.[6]
• European Medicines Agency (EMA): Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in November 2011, the European Commission granted marketing authorisation for Caprelsa on February 21, 2012. The European indication was for the treatment of aggressive and symptomatic MTC in patients with unresectable locally advanced or metastatic disease.[35]
• Other Regions: The drug was also approved in Canada and subsequently underwent regulatory review in other countries, including Russia, Switzerland, and Australia.[35]

10.3 Corporate Divestment and Current Marketer

The commercial trajectory of Vandetanib shifted significantly after its initial approvals, driven by strategic corporate decisions based on its market potential.

• The Transaction: After failing to secure approval for larger indications like NSCLC, Vandetanib was positioned as a niche, orphan drug. In July 2015, AstraZeneca announced a definitive agreement to divest the global rights to sell and develop Caprelsa to Genzyme, a Sanofi company.[15] Genzyme, a company with a long-standing focus and expertise in rare and debilitating diseases, was seen as a more strategic home for the product.
• Current Marketer/Manufacturer: As a result of this transaction, Vandetanib (Caprelsa) is now marketed globally by Genzyme/Sanofi.[4] Genzyme manages the product, including the critical CAPRELSA REMS Program in the United States.

10.4 Patent Information

The intellectual property for Vandetanib remains with its original developer.

• Key Patents: Key patents covering the drug, such as U.S. Patent 8,067,427 for "Pharmaceutical compositions comprising ZD6474," are assigned to AstraZeneca AB. These patents provide market exclusivity, with expiration dates extending into the late 2020s (e.g., August 8, 2028, for the aforementioned patent).[58] This ensures that while Genzyme/Sanofi markets the drug, the foundational intellectual property is controlled by AstraZeneca.

11.0 Expert Synthesis and Concluding Remarks

Vandetanib occupies a distinct and important place in the history of targeted therapy for endocrine malignancies. As the first agent approved specifically for advanced medullary thyroid cancer (MTC), it fundamentally changed the treatment landscape for a disease that previously had no effective systemic options. Its clinical profile, however, is one of profound duality, where significant efficacy is inextricably bound to a challenging and complex safety profile.

Vandetanib's Place in Therapy: Vandetanib established the principle of effective targeted therapy in advanced MTC, demonstrating that inhibiting the core oncogenic driver—the RET proto-oncogene—along with key supportive pathways like VEGFR and EGFR could lead to substantial and durable delays in disease progression. The data from the pivotal ZETA trial and subsequent long-term follow-up studies confirm its role as a valuable therapeutic option. For a subset of patients, particularly younger individuals and those treated before significant disease progression, Vandetanib can provide years of disease control.

The Duality of a Multi-Targeted Agent: The core theme of Vandetanib is that its greatest strength—the ability to hit multiple critical pathways simultaneously—is also the source of its greatest weakness. The inhibition of VEGFR and EGFR contributes to its anti-tumor effect but is also directly responsible for its most common and burdensome toxicities, such as hypertension, diarrhea, and rash. This broad activity profile stands in contrast to the next generation of more selective RET inhibitors (e.g., selpercatinib, pralsetinib), which were designed to target the RET kinase with greater precision and fewer off-target effects, often resulting in a more favorable safety profile.[59] The evolution from multi-targeted agents like Vandetanib to highly selective agents represents a key progression in the field of precision oncology.

The Primacy of the Safety Profile: The clinical management of Vandetanib is overwhelmingly dominated by the need to mitigate its risk of cardiotoxicity. The Boxed Warning for QT prolongation and sudden death is the central fact around which all other clinical considerations—pharmacokinetics, dosing, drug interactions, and monitoring—revolve. The 19-day half-life, the intensive ECG and electrolyte monitoring schedule, the strict contraindications, the critical DDI warnings, and the mandated CAPRELSA REMS program are not disparate elements but rather a single, integrated risk management strategy. Vandetanib serves as a premier case study in modern pharmacovigilance, demonstrating how a drug with a narrow therapeutic index can be safely used in a high-unmet-need population, but only within a tightly controlled system.

Lessons from Clinical Development: The Vandetanib story offers several important lessons. Its success in MTC underscores the power of targeting a specific, dominant oncogenic driver. Its failures in more heterogeneous diseases like DTC and NSCLC highlight the limitations of a less-targeted approach, suggesting that the anti-VEGFR/EGFR activity alone was insufficient to overcome the complex biology of those cancers. Furthermore, the confounding effect of TSH elevation in the VERIFY trial in DTC is a crucial reminder of the potential for complex drug-disease interactions in clinical research, with major implications for the design of future trials in endocrine cancers.

Future Outlook: In an era of increasingly selective and potent RET inhibitors, Vandetanib's role in the frontline treatment of RET-mutant MTC will likely evolve. The newer agents may be preferred for their superior safety profiles and potentially higher response rates. However, Vandetanib is unlikely to disappear. Its established track record, extensive long-term efficacy and safety data, and potentially different resistance profile may ensure it retains a valuable place in the MTC treatment armamentarium, perhaps as a later-line option, for patients with RET-negative disease, or in specific healthcare systems based on access and cost considerations. It remains a landmark drug, a potent but challenging therapeutic agent that brought the hope of targeted therapy to patients with a rare and difficult cancer.

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