50th Annual Meeting of the American Society of Clinical Oncology (ASCO):

Pazopanib Active in Progressive Metastatic Medullary Thyroid Cancer

The small-molecule kinase inhibitor pazopanib appears to be clinically active in patients with progressive metastatic medullary thyroid cancer (MTC), according to results of a multicenter, international phase 2 study presented by Keith C. Bible, MD, PhD, on June 2, 2014, at the Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois.

Pazopanib MOA
Pazopanib inhibits multiple kinases including vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-alpha and -beta, and c-Kit. Pazopanib is currently approved in the US for the treatment of patients with advanced renal cell carcinoma and for patients with advanced soft tissue sarcoma previously treated with chemotherapy.

In a previous study, pazopanib demonstrated activity in advanced differentiated thyroid cancer (DTC), yielding a response rate of 49%, whereas no responses were observed in patients with advanced anaplastic thyroid cancer. In preclinical studies, the antitumor activity of pazopanib in MTC was similar to that observed in DTC, suggesting the agent may have clinical activity in advanced MTC.

Study Summary
Dr. Bible, of the Mayo Clinic, Rochester, Minnesota, and colleagues undertook a phase 2 trial evaluating the antitumor activity and safety of oral pazopanib administered at 800 mg once daily until disease progression or intolerable toxicity in patients with metastatic progressive MTC. A total of 35 patients enrolled between September 2008 and December 2011.

The median age of enrolled patients was 60 years; 80% were male and 80% were Caucasian. The most common disease sites were the lymph nodes (80%), liver (57%), bone (51%), and lung (46%). Approximately 43% of patients had received either 1 or 2 prior systemic therapies, most commonly vandetanib (17%), octreotide (11%), and cabozantinib (9%). The remaining 57% of patients had received no prior systemic therapies.

After a median treatment duration of 8 cycles, partial responses were observed in 5 of 35 patients, for a response rate of 14%. More than 70% of patients remained on the study for longer than 6 months and 8 patients (23%) were still receiving pazopanib at the time of the analysis. Median progression-free survival and overall survival were 9.4 months and 19.9 months, respectively.

Adverse Events
Grade 3 adverse events reported in more than 1 patient included fatigue (14.3%), diarrhea (8.6%), hand and foot syndrome/reaction (5.7%), and dyspnea (5.7%). Grade 4 adverse events, reported in 1 patient each, included colonic perforation, skin ulceration, and elevated lipase. Adverse events led to treatment discontinuation in 3 patients (8.6%), including 1 patient (2.9%) who died from a potentially treatment-related colonic perforation.

Conclusions
Overall, pazopanib showed “encouraging preclinical and clinical activity,” the investigators concluded, suggesting that pazopanib may represent an alternative option for patients with MTC that is refractory to vandetanib and cabozantinib.

This study also provides a new perspective on therapeutic targets for MTC. Dr. Bible explained to endocrineweb.com that RET kinase has conventionally been considered the most promising therapeutic target in MTC; both FDA-approved agents for MTC—vandetanib and cabozantinib—are RET inhibitors. The observation that pazopanib, a poor inhibitor of RET, is active in MTC suggests that there may be therapeutic targets other than RET to consider in this type of thyroid cancer.

Next Summary:
Younger Age Associated with Higher Risk of Recurrence in Nonmetastatic Papillary Thyroid Cancer
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