An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer

Abstract

; the Mayo Phase 2 Consortium 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 a = 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.

Case Report: Anlotinib Therapy in a Patient With Recurrent and Metastatic RAIR-DTC Harboring Coexistent TERT Promoter and BRAFV600E Mutations

“…However, the dose of L-T4 could be reduced to 62.5 μg/d since C28, indicating the distribution or utilization of L-T4 might be influenced by anlotinib, it also reminds clinicians to be aware of this problem and implement measures to minimize the occurrence of overdosing and the potential for long-term complications. Interestingly, Bible et al ( 5 ) observed TSH levels increased by >15% between baseline and cycle one/4 weeks reassessment in 64.6% of RAIR-DTC patients treated with pazopanib, indicating that early TSH increment is frequent in response to pazopanib therapy.…”

“…RAIR-DTC is insensitive to conventional chemotherapy. Many targeted drugs [including donafenib ( 4 ), pazopanib ( 5 , 6 ), cabozantinib ( 7 ), vandetanib ( 8 ), axitinib ( 9 ), sunitinib ( 10 ), motesanib ( 11 )] are increasingly being used to treat RAIR-DTC due to many signaling pathways and gene mutations that driving thyroid tumorigenesis have been identified. Although sorafenib and lenvatinib have been approved by the U.S. Food and Drug Administration to be used in RAIR-DTC, not all patients have access to or are able to afford those drugs ( 12 ).…”

Historical aspects and modern concepts in the treatment of patients with differentiated thyroid cancer, refractory to radioactive iodine therapy

“…В то же время вероятность ответа на лечение данным препаратом на основании оценки исследуемых биомаркеров, предшествующей терапии или мутационного статуса опухоли спрогнозировать не удалось. Исследователи подчеркнули, что результаты являются обнадеживающими, однако достоверных доказательств его эквивалентной, превосходящей или недостаточной эффективности по сравнению с другими ТКИ при рефрактерном к РЙТ дифференцированном РЩЖ по-прежнему отсутствуют [38].…”

Advancements in the treatment of differentiated thyroid cancer

“… 96 Other agents under investigation include axitinib, pazopanib, and sunitinib. 97 , 98 Kinase inhibitor therapy is often limited by its side-effect profile, which includes nausea, diarrhea, fatigue, weight loss, hand-foot syndrome, hypertension, and QTc prolongation, so medical comorbidities should be assessed prior to therapy. 12 , 18 , 43 , 99 , 100 Although significant, treatment-emergent hypertension in lenvatinib therapy has been correlated with improved outcomes.…”