Cabozantinib in Progressive Medullary Thyroid Cancer

PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

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Vandetanib (100 mg) in Patients with Locally Advanced or Metastatic Hereditary Medullary Thyroid Cancer

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2461 ◽

2010 ◽

Vol 95 (6) ◽

pp. 2664-2671 ◽

Cited By ~ 148

Author(s):

Bruce G. Robinson ◽

Luis Paz-Ares ◽

Annetta Krebs ◽

James Vasselli ◽

Robert Haddad

Keyword(s):

Thyroid Cancer ◽

Growth Factor ◽

Medullary Thyroid Cancer ◽

Response Rate ◽

Objective Response ◽

Locally Advanced ◽

Growth Factor Receptor ◽

Once Daily ◽

Medullary Thyroid ◽

Hereditary Medullary Thyroid Cancer

Abstract Purpose: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases that also inhibits rearranged during transfection kinase activity. Vandetanib (300 mg/d) has previously demonstrated antitumor activity in patients with advanced hereditary medullary thyroid cancer (MTC). This study investigated the efficacy and safety of 100 mg/d vandetanib in patients with advanced hereditary MTC. Patients and Methods: Eligible patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC received 100 mg/d vandetanib. Upon disease progression, eligible patients could enter postprogression treatment with 300 mg/d vandetanib until a withdrawal criterion was met. The primary objective was to assess the objective response rate by response evaluation criteria in solid tumors. Results: The study comprised 19 patients (13 males, six females; mean age 45 yr). Confirmed objective partial responses were observed in three patients, yielding an objective response rate of 16% (95% confidence interval 3.4–39.6). Stable disease lasting 24 wk or longer was reported in a further 10 patients (53%); the disease control rate was therefore 68% (95% confidence interval 43.4–87.4). Serum levels of calcitonin and carcinoembryonic antigen showed a sustained 50% or greater decrease from baseline in 16% (three of 19) and 5% (one of 19) of patients, respectively. Adverse events were predominantly grade 1 or 2 and consistent with previous vandetanib monotherapy studies. Conclusions: Vandetanib at a once-daily dose of 100 mg has clinically relevant antitumor activity in patients with locally advanced or metastatic hereditary MTC and an overall acceptable safety profile.

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Multikinase Inhibitors for the Treatment of Progressive, Metastatic Medullary Thyroid Cancer – An Evolving Paradigm

European Endocrinology ◽

10.17925/ee.2014.10.02.145 ◽

2014 ◽

Vol 10 (2) ◽

pp. 145

Author(s):

Barbara Jarzab ◽

Jolanta Krajewska ◽

◽

Keyword(s):

Thyroid Cancer ◽

Growth Factor ◽

Medullary Thyroid Cancer ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Phase Iii ◽

Medullary Thyroid ◽

Modes Of Action ◽

Phase Iii Trials ◽

Endothelial Growth Factor

Medullary thyroid cancer (MTC) is an uncommon type of thyroid cancer, representing around 4 % of the all thyroid cancers, and is a challenging malignancy. So far, surgery has been the only curative treatment and until recently there have been no effective medications. Within the past 5 years, multi-targeted kinase inhibitors have emerged that have shown convincing efficacy against such tumours. These drugs have changed the landscape in MTC treatment by providing effective medication for the first time. The modes of action of these drugs differ, but most target RET, a tyrosine kinase shown to play an important role in the pathobiology of MTC, as well as other receptors including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor MET. Two agents in this class, vandetanib and cabozantinib, have demonstrated efficacy and safety in phase III trials and have consequently received regulatory approval. Other therapies for MTC treatment, including some with similar modes of action, are also in early development.

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NTRK3 receptor expression is strictly associated with medullary thyroid cancer RET mutation status

Endocrine Abstracts ◽

10.1530/endoabs.35.oc3.5 ◽

2014 ◽

Author(s):

Malgorzata Oczko-Wojciechowska ◽

Michal Swierniak ◽

Malgorzata Kowalska ◽

Agnieszka Pawlaczek ◽

Monika Kowal ◽

...

Keyword(s):

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Receptor Expression ◽

Mutation Status ◽

Medullary Thyroid ◽

Ret Mutation

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Vandetanib (ZD6474) in the Treatment of Medullary Thyroid Cancer

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s6197 ◽

2011 ◽

Vol 5 ◽

pp. CMO.S6197 ◽

Cited By ~ 10

Author(s):

Hari Deshpande ◽

Sanziana Roman ◽

Jaykumar Thumar ◽

Julie Ann Sosa

Keyword(s):

Thyroid Cancer ◽

Growth Factor ◽

Phase Ii ◽

Medullary Thyroid Cancer ◽

Kinase Inhibitor ◽

Locally Advanced ◽

Growth Factor Receptor ◽

Good Choice ◽

Phase Ii Trials ◽

Medullary Thyroid

Vandetanib (ZD6474) is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factor receptors, including RET (Rearrange during transfection), vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). The activity against RET and VEGF made it a good choice in the treatment of medullary thyroid cancer (MTC). As there is considerable cross talk between growth factor pathways, dual inhibition with such agents has become an attractive strategy, in the treatment of many malignancies with encouraging Phase II clinical trial data to date. Vandetanib was tested in two Phase II trials in the treatment of patients with medullary thyroid cancer at doses of 100 mg and 300 mg daily respectively. The encouraging results of these 2 trials led to a randomized phase II trial comparing this medication to placebo using a crossover design. More than 300 patients were included in this study, which ultimately showed a significant improvement in progression-free survival in patients taking vandetanib. Based on these results, the Oncology Drug Advisory Committee (ODAC) of the Food and Drug Administration (FDA) recommended that vandetanib be approved for the treatment of patients with unresectable locally advanced or metastatic medullary thyroid cancer.

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Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.0126 ◽

2018 ◽

Vol 36 (10) ◽

pp. 968-974 ◽

Cited By ~ 36

Author(s):

Xavier Pivot ◽

Igor Bondarenko ◽

Zbigniew Nowecki ◽

Mikhail Dvorkin ◽

Ekaterina Trishkina ◽

...

Keyword(s):

Breast Cancer ◽

Epidermal Growth Factor Receptor ◽

Adverse Event ◽

Growth Factor ◽

Response Rate ◽

Pathologic Complete Response ◽

Growth Factor Receptor ◽

Complete Response ◽

Phase Iii ◽

Epidermal Growth

Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2–positive early breast cancer in the neoadjuvant setting ( ClinicalTrials.gov identifier: NCT02149524). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.

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