Pazopanib's Activity in Thyroid Cancer Not Predicted by Thyroglobulin

Keith Bible, MD, PhD

A phase II Mayo Clinic consortium study confirmed the significant clinical activity seen with pazopanib (Votrient) for patients with radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC); however, the trial was unable to uncover an effective predictive biomarker for the multikinase inhibitor, according to findings presented by Keith Bible, MD, PhD, at the 2015 International Thyroid Congress.

In the final analysis of the phase II study, pazopanib demonstrated a partial response rate of 37% in patients with pretreated RAI-refractory DTC (95% CI, 24.6-50.1), which Bible labeled as a high-level of response. The primary biomarker explored in the study was serum thyroglobulin (Tg), which did not serve as a predictor of outcome.

Pazopanib is an inhibitor of c-KIT, FGFR, PDGFR and VEGFR that is FDA-approved as a treatment for patients with soft tissue sarcoma or renal cell carcinoma. Investigators are attempting to identify markers that can help with early prediction of outcomes, “so as not to have to continue treatment for a longer period of time,” according to Bible, professor of oncology at the Mayo Clinic.

“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,” he said. “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.”

At the meeting, Bible presented data that focused on the primary endpoint of changes in serum Tg post-initiation of pazopanib. Response was analyzed as a secondary endpoint. The study enrolled 60 patients with RAI-refractory DTC from across the United States, Asia, and Australia. A majority of those treated with pazopanib (91.7%) had received prior systemic therapy following RAI.

Following the first cycle of pazopanib, Tg changes did not differ between those who did and did not respond to therapy. Among those with a partial response, the overall Tg nadir level represented a median of decline of 86.8% (interquartile range [IQR], 70.9-90.7). In those with stable disease, the nadir was reduced by 69% from baseline (IQR, 27.7-78.1). A comparison of the two arms was significant (P = .002).

Despite this difference, changes in Tg could not be confirmed as a robust predictor of response to pazopanib, particularly since an initial decline was not evident. In addition to Tg levels, mutations in BRAF, p53, JAK3, and/or HRAS were identified in 11 of 16 patients examined (69%). However, none of these mutations correlated with treatment response.

Overall, adverse events (AEs) in the trial were consistent with expectation, and no deaths were attributed to pazopanib, Bible emphasized. Three of the 60 patients discontinued the study without tumor burden reevaluation.

Consistent with the class, Bible pointed out that hypertension was the most common AE associated with pazopanib for patients with RAI-refractory DTC. Other grade ≥3 AEs included fatigue (n = 8; 13.3%), decreased neutrophil count (n = 8; 13.3%), diarrhea (n = 7; 11.6%), hand-foot syndrome (n = 7; 11.6%), and increased AST/ALT liver enzymes (n = 6; 10%).

Investigators will continue to work toward identifying a marker that can serve as a useful indicator response for VEGFR tyrosine kinase inhibitors. Additionally, studies are continuing to assess pazopanib in patients with thyroid cancer. In addition to DTC, a phase II study sponsored by the NCI is looking at intensity-modulated radiation therapy and paclitaxel with or without pazopanib for patients with anaplastic thyroid cancer. This study hopes to enroll 121 participants (NCT01236547).

Bible KC, Suman VJ, Molina JR, et al. Pazopanib in patients with progressive, radioactive iodine-refractory, metastatic differentiated thyroid cancer lacking thyroglobulin antibodies: Mayo Phase 2 Consortium Study Results. Presented at: International Thyroid Congress; 18-23, 2015; Orlando, FL. Abstract 103.