Pazopanib Treatment Outcome Not Predicted by Thyroglobulin Status

Keith Bible

Keith Bible, MD, PhD

At the 2015 International Thyroid Congress, Keith Bible, MD, PhD, Mayo Clinic professor of oncology described the current status of using VEGFR tyrosine kinase inhibitors to treat thyroid cancer:

Most tyrosine kinase inhibitors are promiscuous, having a footprint across the kinome that is very messy and seems to have activity for thyroid cancer, but I think we are still struggling to know how that footprint varies. It is striking to me that we can often go from one kinase inhibitor to the next and get sequential responses, when in theory they are all at least primarily targeting VEGFR. So I think we have a lot to learn about off-target effects and what is really most important in these agents and what is most beneficial in these patients.

Investigators are attempting to identify markers that can help with early prediction of outcomes within short time frames of treatment initiation, “so as not to have to continue treatment for a longer period of time,” according to Bible. On behalf of the Mayo Phase II Consortium, Bible presented data that focused on the primary endpoint of changes in serum thyroglobulin (Tg) post-initiation of pazopanib treatment to determine whether or not Tg changes may be used as an early (≤4 weeks) predictor of treatment-mediated success for patients with progressive, metastatic radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Analysis of Response Evaluation Criteria In Solid Tumors (RECIST) response was analyzed as a secondary endpoint.

Sixty patients with RAIR-DTC under the Mayo Clinic Phase II Consortium from across the USA, Asia, and Australia were treated with pazopanib between May 2009 and December 31, 2011. Three of these patients went off of the study without tumor burden re-evaluation. Bible pointed out that hypertension grade 3 and above was the most common adverse event (AE) of pazopanib treatment for patients with RAIR-DTC, with 53% of these patients requiring additional therapy. Other side effects listed in order from most common to least frequent included: fatigue (n=8), decreased neutrophil count (n=8), diarrhea (n=7), hand-foot syndrome (n=7), and increased AST/ALT liver enzymes (n=6). Overall, the AEs were consistent with expectation. Bible emphasized, most favorably no deaths were attributed to pazopanib therapy.

In the final analysis, changes in Tg did not serve as a predictor of outcome, but rather there was only a coincidental decrease that correlated with general treatment, but not favorable outcome. Twenty two (37%; 95% CI: 24.6-50.1%) patients had partial RECIST responses. This outcome result was considered by Bible to be “a high level.” Of the sixty patients that were treated and evaluated, over 90% had previously received systemic pazopanib therapy in addition to radioiodine. Prior pazopanib treatment did not correlate with treatment success either. Mutations inBRAF,p53,JAK3, and/orHRASwere identified in 11 of 16 patients examined. However, none of these mutations would correlate with treatment response.

Bible stated that we have not been able to confirm that induced changes in thyroglobulin can be a robust predictor of response to pazopanib therapy. Moreover, neither mutational analysis nor prior treatment served as a predictor of future success either. Nonetheless, pazopanib was confirmed to have significant clinical activity in progressive, RAI-refractory DTC. Accordingly, investigators continue to work toward identifying, on an empirical level, which markers can serve as a useful indicator of whether or not a given VEGFR tyrosine kinase inhibitor working in a particular individual is likely to provide effective therapeutic benefit.

Bible KC. Pazopanib in patients with progressive, radioactive iodine-refractory, metastatic differentiated thyroid cancer lacking thyroglobulin antibodies: Mayo Phase 2 Consortium Study Results. Presented at the 2015 International Thyroid Congress: October 21, 2015. Abstract #103.