An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer
Keith C Bible, Michael E Menefee, Chia-Chi Josh Lin, Michael J Millward, William J Maples, Boon Cher Goh, Nina J Karlin, Madeleine A Kane, Douglas R Adkins, Julian R Molina, Ross C Donehower, Wan-Teck Lim, Patrick J Flynn, Ronald L Richardson, Anne M Traynor, Joseph Rubin, Patricia M LoRusso, Robert C Smallridge, Jill K Burton, Vera J Suman, Aditi Kumar, Jessie S Voss, Kandalaria M Rumilla, Benjamin R Kipp, Ashish V Chintakuntlawar, Pamela Harris, Charles Erlichman, Keith C Bible, Michael E Menefee, Chia-Chi Josh Lin, Michael J Millward, William J Maples, Boon Cher Goh, Nina J Karlin, Madeleine A Kane, Douglas R Adkins, Julian R Molina, Ross C Donehower, Wan-Teck Lim, Patrick J Flynn, Ronald L Richardson, Anne M Traynor, Joseph Rubin, Patricia M LoRusso, Robert C Smallridge, Jill K Burton, Vera J Suman, Aditi Kumar, Jessie S Voss, Kandalaria M Rumilla, Benjamin R Kipp, Ashish V Chintakuntlawar, Pamela Harris, Charles Erlichman
Abstract
Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.
Keywords: differentiated thyroid cancer; kinase inhibitor; pazopanib; radioactive iodine refractory.
Conflict of interest statement
No competing financial interests exist.
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Source: PubMed