Medullary Thyroid Carcinoma (MTC)

Caprelsa® (vandetanib, ZD6474) is a tyrosine kinase inhibitor (TKI) that targets rearranged during transfection receptor (RET), vascular endothelial growth factor receptor (VEGFR-2 and -3), and epidermal growth factor receptor (EGFR). On April 7, 2011, the US Food and Drug Administration (FDA) approved Caprelsa as the first systemic therapy for patients with symptomatic or progressive advanced medullary thyroid cancer (MTC).^1,2 Caprelsa is given to patients with asymptomatic, indolent, or slowly progressive disease only after a thorough consideration of the treatment-related risks. Caprelsa is administered orally; the recommended dosage is 300 mg once daily until disease progression or unacceptable toxicity. Caprelsa can be taken with or without food.³ 

Mechanism of Action

Vandetinib inhibits mainly RET, VEGFR-2, VEGFR-3, and EGFR; slight inhibition of VEGFR-1 also occurs. These receptors are involved in tumor proliferation, angiogenesis, invasion, and metastasis in MTC. Vandetanib has indirect effects on angiogenesis in vivo by interfering with the EGFR-induced production of angiogenic growth factors. The half-life (t½) of vandetanib is approximately 10 days after a single oral dose. Absorption is not affected by food. After 21 days, approximately two-thirds of the drug is eliminated in feces (44%) and urine (25%). Metabolites of the drug (N-desmethyl and N-oxide metabolites) or unchanged drug is eliminated in urine, plasma, and feces.⁴

Get detailed prescribing information on the Caprelsa monograph page at MPR.

Clinical Trial Results

A double-blind, placebo-controlled, randomized study was conducted in patients with unresectable locally advanced or metastatic MTC. Patients were randomized to receive Caprelsa at 300 mg (n = 231) or placebo (n = 100). Statistically significant improvements in progression-free survival (PFS) were noted in the patients randomized to Caprelsa (hazard ratio [HR], 0.35; 95% CI, 0.24-0.53; P <0.0001). Similar results were found in the subgroups of patients who were symptomatic or whose disease had progressed within the 6 months before enrollment in the trial (HR, 0.31; 95% CI, 0.19, 0.53 for symptomatic patients; HR, 0.41; 95% CI, 0.25, 0.66 for patients who had disease progression within 6 months before enrollment). At the time of the primary analysis of PFS, 15% of the patients had died, and no statistically significant difference in overall survival was found between the 2 treatment groups. The overall objective response rate (ORR) was 44% in the individuals randomized to Caprelsa and 1% in those randomized to placebo.³

Vandetanib Therapy in Medullary Thyroid Cancer

Very few options are available for the treatment of metastatic or unresectable MTC. In metastatic disease, a wait-and-watch protocol is followed for asymptomatic patients with no evidence of tumor progression on periodic restaging and for those with a low tumor burden. Patients with indolent metastatic disease may survive for years without systemic therapy. For patients with symptomatic or progressive metastatic disease and a high tumor burden, the National Comprehensive Cancer Network (NCCN) recommends enrollment in a clinical trial. Absent trial enrollment, systemic TKI therapy is preferred to cytotoxic chemotherapy, which is of relatively limited efficacy and associated with high rates of toxicity. Caprelsa is currently the first-line systemic therapy of choice for these cases. For patients with disease progression on vandetanib, NCCN guidelines advise treatment with a commercially available TKI such as sorafenib or sunitinib. These drugs, however, have not been approved by the FDA for the treatment of thyroid carcinoma, and phase 2 trials of sorafenib and sunitinib have specifically excluded patients previously treated with vandetanib.¹

Warnings, Precautions, and Adverse Reactions

Caprelsa should be administered with caution to patients who have asymptomatic, indolent, or slowly progressive disease because it can increase risks for prolonged QT interval, torsades de pointes, and sudden death.⁵ Cases of Stevens-Johnson syndrome and severe toxic epidermal necrolysis have been documented. The drug should be permanently discontinued in these situations, and systemic therapies such as corticosteroids may be needed. Deaths due to interstitial lung disease (ILD) have been noted. Caprelsa should be discontinued and further investigations for unexplained dyspnea, fever, and cough, along with appropriate treatments, initiated if ILD is suspected.

Heart failure, ischemic cerebrovascular events, hypertension, diarrhea, hemorrhage, hypothyroidism, and reversible posterior leukoencephalopathy syndrome have also been noted.⁵ Evidence of fetal toxicity has been noted. Therefore, women should be advised of the potential risks to the fetus, and pregnancy avoided during and for a period of 4 months after Caprelsa treatment.³

The most common adverse effects of Caprelsa are diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), tiredness (24%), upper respiratory tract infections (23%), appetite loss (21%), and abdominal pain (21%).⁶

Drug Interactions

Caprelsa is a substrate of CYP3A4; therefore, administration with a CYP3A4 inducer or inhibitor can cause drug-drug interactions.⁷ Healthy subjects were administered a single 300-mg dose of Caprelsa on day 1 or 4 of a 24-day course of itraconazole (a potent CYP3A4 inhibitor) at 200 mg daily in a phase 1 study. A mild increase (9%) in the plasma concentration of Caprelsa was noted. In another, separate arm of this phase 1 study, healthy subjects were administered a single 300-mg dose of Caprelsa on day 1 or 10 of a 31-day course of rifampicin (a potent CYP3A4 inducer) at 600 mg daily. A marked decrease (40%) in the plasma concentration of Caprelsa was noted.⁸ Therefore, the concomitant use of vandetanib and potent CYP3A4 inducers must be avoided.⁸

References

1. Chau NG, Haddad RI. Vandetanib for the treatment of medullary thyroid cancer. Clin Cancer Res. 2013;19(3):524-529. doi:10.1158:1078-0432.CCR-12-2353
2. Nick Mulcahy. FDA approves vandetanib for medullary thyroid cancer. Medscape. Published April 07, 2011. Accessed August 16, 2021.
3. CAPRELSA® (vandetanib) tablets for oral use. US Food and Drug Administration (FDA). Published March 2014. Accessed August 16, 2021.
4. Fallahi P, Ferrari SM, Elia G, et al. Evaluating vandetanib in the treatment of medullary thyroid cancer: patient-reported outcomes. Cancer Manag Res. 2019;11:7893-7907. doi: 10.2147/CMAR.S127848

5. Vandetanib (Rx), Warnings. Medscape. Accessed August 16, 2021.
6. About Caprelsa. Sanofi Genzyme Corporation. Published July 2020. Accessed August 16, 2021.
7. Cooper MR, Yi SY, Alghamdi W, Shaheen DJ, Steinberg M. Vandetanib for the treatment of medullary thyroid carcinoma. Ann Pharmacother. 2014;48(3):387-394. doi.10:1177/1060028013512791
8. Martin P, Oliver S, Robertson J, Kennedy SJ, Read J, Duvauchelle T. Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole. Drugs R D. 2011;11(1):37-51. doi:10.2165/11586980-000000000-00000

Reviewed by Debjyoti Talukdar, MD, on 8/30/2921.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.