Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer

Abstract

Cabozantinib (XL-184) is a potent inhibitor of MET, VEGFR 2/KDR, RET and other receptor tyrosine kinases, such as KIT, AXL and FLT3. Its efficacy against MTC has been demonstrated in a prospective, randomized, placebo-controlled study (EXAM). Cabozantinib comparing to placebo significantly prolonged progression free survival both in hereditary and sporadic MTC, 11.2 vs 4.0 months, respectively. Final analysis showed no global differences in overall survival (OS) between cabozantinib and placebo. However, in a subgroup with RET M918T mutation the difference in OS was significant: 44.3 vs 18.9 months, respectively. Among the most frequent cabozantinib-related adverse events (AEs), observed in >30% of patients were diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes and hypertension. Expert Commentary: Cabozantinib constitutes an effective treatment option with acceptable toxicity in MTC patients showing either germinal or sporadic tumor RET M918T mutation as the drug prolonged OS in these subjects.

Keywords:

• medullary thyroid cancer
• RET M918T mutation
• cabozantinib
• TKI
• VEGFR inhibitor

Key issues

• Cabozantinib is a multikinase inhibitor.

• Cabozantinib demonstrated activity against different receptor tyrosine kinases such as MET, vascular endothelial growth factor receptor (VEGFR) 2/KDR, RET, KIT, AXL and FLT3.

• Cabozantinib compared with placebo significantly prolongs progression-free survival in advanced, progressive medullary thyroid carcinoma, 11.2 versus 4.0 months, respectively.

• Cabozantinib compared with placebo significantly prolongs overall survival in MTC patients with RET M918T mutation, both hereditary and sporadic, 44.3 versus 18.9 months, respectively.

• Cabozantinib shows efficacy in case of medullary thyroid carcinoma bone metastases.

• Diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes and hypertension are the most common cabozantinib-related side effects observed in >30% treated patients.

• Hypertension, hemorrhage, venous and arterial thrombosis, gastrointestinal (GI) perforation, GI fistula, wound complication and osteonecrosis are associated with VEGF pathway inhibition.

• Cabozantinib does not prolong QTc interval.

• Most of the cabozantinib-related side effects are manageable by dose modifications and concomitant medical therapy.

Financial & competing interests disclosure

J Krajewska has participated in a Bayer HealthCare Pharmaceuticals Advisory Board. T Olczyk has nothing to disclose. B Jarzab has participated in AstraZeneca and Sobi Advisory Boards and has received honoraria from Sanofi, Ipsen, Novartis, Amgen, Bayer HealthCare Pharmaceuticals, Roche, Pfizer, Eisai, Oxigene and Exelixis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.