Pazopanib Activity in RAI-Refractory Differentiated Thyroid Cancer Corroborated in Prospective Study

Pazopanib (Votrient) was confirmed active with manageable toxicities as treatment of patients with progressive radioactive-iodine–refractory (RAIR) differentiated thyroid cancer (DTC), based on results of a prospective study published in the journal Thyroid.¹

Multikinase inhibitors like pazopanib, in addition to FDA-approved agents like sorafenib (Nexavar) and lenvatinib (Lenvima), as well as cabozantinib (Cabometyx), vandetanib (Caprelsa), axitinib (Inlyta), sunitinib (Sutent), and the novel agent motesanib (AMG-706), have shown to be effective for treating progressive RAIR-DTC, and even metastatic disease. The activity observed with these drugs warrants more utilization in this disease, as later-line therapy. A phase 2 study previously revealed high activity levels, including a 49% partial response (PR) rate in patients with RAIR-DTC treated with pazopanib,2 warranting a confirmatory study.^1,2

“The need for additional therapeutics in RAIR-DTC is clear; although approved for use in RAIR-DTC by the United States FDA, neither sorafenib or lenvatinib have curative potential in this disease. Additional therapeutic options are thus inevitably required for patients seeking additional therapy upon progression through, or poorly tolerating, the 2 FDA-approved agents,” wrote the study authors, led by Keith C. Bible, MD, PhD, of the Mayo Clinic.

The overarching goal of the confirmatory prospective study was to validate the efficacy and safety of pazopanib in a more heavily pretreated group of patients with progressive RAIR-DTC.1 Bible et al hypothesized that predictions on therapeutic response to pazopanib could be drawn based on the thyroglobulin (Tg) antibody biomarker, and ultimately, physicians could make better selections on which patients to treat with pazopanib.¹

Sixty-two patients from 12 international sites were evaluated in the study. After eligibility screening and registration, 60 patients were left who received pazopanib and were evaluable for efficacy and safety.

Baseline characteristics show that the study population was 55% male, had a median age of 60 years (range, 51-69) and the majority of patients (61.7%) had an ECOG performance status of 0 while others scored a 1 (31.7%) or 2 (6.7%). In terms of histologic subtype, 60.0% of patients had papillary thyroid cancer, 26.7% had follicular thyroid cancer, and 13.3% had Hürthle cell thyroid cancer. Just over 58% of patients in the study had received prior radiation, and 90.0% had prior radioiodine. The number of prior systemic therapies was mostly 1 (66.7%), but 22.7% of patients had 2 to 4 prior systemic therapies and 6.7% had none. Sorafenib with or without everolimus (Afinitor) was the most common prior systemic therapy. Disease metastasized to the lung in most of the study population (90.0%), followed by the nodes (75.0%), bone (35.0%), liver (13.3%), subcutaneous/soft tissue (10.0%), trachea with or without the larynx (3.3%), abdomen (1.7%), and brain (1.7%).

According to the most recent data from the study, 22 patients (36.7%; 95% CI, 24.6%-50.1%) have had PRs. Notably, the PR confidence interval in the confirmatory study overlaps with that of the phase 2 study PR rate of 49%. The median duration of response, in regard to attained RECIST PRs, was 10.3 months. Bible et al also estimated the median PFS to be 11.4 months and the median OS to be 2.6 years. Two patients were still on treatment at the time of data cutoff.

Forty-four patients in the study had Tg level available and of those, 18 had a PR to pazopanib, including 22.2% of patients whose Tg levels dropped more than 50% after cycle one and 45.7% of those who had a Tg level decreased less than 50% after the first cycle of treatment. This result was not statistically significant, and therefore Bible et al concluded that Tg could not predict response to pazopanib, but Tg nadir was greater in patients who achieved a PR versus those who did not (P = .002).

Pazopanib was administered orally in fasting patients at a dose level of 800 mg, which continued until disease progression, dose reduction, or intolerability of the drug. During treatment with pazopanib, dose reductions were required in 55.5% of patients; the median dosage received by the cohort was 600 mg/day. The most common grade 3 to 5 toxicities reported in the study were hypertension (21.7%), fatigue (8.3%), and neutropenia (8.3%).

The majority of patients (72.0%) who discontinued treatment did so due to disease progression, but 10.3% discontinued pazopanib due to adverse events (AEs). The AEs leading to treatment discontinuation included grade 4 thrombosis, grade 3 oral mucositis, grade 3 alanine aminotransferase increase, grade 3 hand and foot syndrome, and grade 4 hypertension. There were also 2 deaths in the study.

Overall, the prospective study was valuable for confirming the activity of pazopanib, even though Tg was not recognized as a predictive biomarker. In the published finding, Bible et al wrote “…no predictive biomarkers were found to facilitate the robust early identification of patients likely to respond to pazopanib therapy in RAIR DTC. The present trial importantly nevertheless provides substantiating and confirmatory evidence in support of the therapeutic efficacy and tolerability of pazopanib in treating RECIST progressive and metastatic RAIR-DTC.”

_References:

_{Bible KC, Menefee ME, Lin CC, et al; Mayo Phase 2 Consortium. An international phase 2 study of pazopanib in progressive and metastatic thyroglobulin antibody negative radioactive iodine refractory differentiated thyroid cancer. Thyroid. Published online July 29, 2020. doi:10.1089/thy.2019.0269}

_{Bible KC, Suman VJ, Molina JR, et al; Endocrine Malignancies Disease Oriented Group; Mayo Clinic Cancer Center; Mayo Phase 2 Consortium. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11(10):962-972. doi:10.1016/S1470-2045(10)70203-5}