Apatinib, a small molecule angiogenesis inhibitor with a high selectivity for vascular endothelial growth factor receptor-2, prolonged both progression-free and overall survival (OS) compared with placebo in patients with locally advanced or metastatic, radioactive iodine-refractory differentiated thyroid cancer (RAI-DTC) and had a manageable safety profile, a planned interim analysis of a phase III randomized clinical trial found.
In a cohort of 92 patients equally randomized to apatinib or placebo, the median progression-free survival (PFS) was 74% longer at 22.2 months (95% CI, 10.9 months-not reached) in the apatinib arm compared with a median of 4.5 months (95% CI, 1.94-9.17 months) in the placebo arm at a hazard ratio (HR) of 0.26 (95% CI, 0.14-0.47; P<0.001), Yansong Lin, MD, PhD, Chinese Academy of Medical Science and Peking University Medical College, Beijing, China and colleagues report in JAMA Oncology.
“Patients with radioactive iodine-refractory DTC (RAIR-DTC) have a poor prognosis, with a 10-year survival rate of 10% [so there is a] large unmet clinical need [for these patients] and the limited treatment options warrant the exploration of alternative strategies for patients with RAIR-DTC,” Lin and colleagues observed.
“The findings from this trial indicate that apatinib might provide a new treatment option for patients with radioactive iodine-refractory differentiated thyroid cancer,” they concluded.
The Efficacy of Apatinib in Radioactive Iodine-Refractory Differentiated Thyroid Cancer or REALITY study was carried out at 21 sites in China. Approximately one-third of all incident cases of thyroid cancer worldwide occur in China.
Patients had locally advanced or metastatic RAIR-DTC (papillary, follicular, Hurthle cell, and poorly differentiated carcinoma) that had progressed within 12 months after the last treatment.
They were randomized to active therapy received apatinib at a dose of 500 mg a day which could be reduced to a minimum of 250 mg a day if poorly tolerated.
“The primary end point was investigator-assessed PFS,” the authors explained. Secondary endpoints included OS, overall response rate (ORR), disease control rate (DCR), time to objective response and safety.
PFS at both 12 and 24 months were both significantly longer in the apatinib group compared with placebo as was median OS:
- PFS at 12 months: apatinib: 60.3% (95%CI, 40.8-75.2%) versus 12.4% (95% CI, 3.4-27.4%) for placebo.
- PFS at 24 months: apatinib: 37.2% (95% CI15.1-59.7%) versus 4.1% (95% CI, 0.3-17.2%) for placebo.
- Median OS: apatinib not reached (95% CI, 26.25 months to not reached) versus 29.9 months (95% CI, 18.96 to not reached) in the placebo group.
The ORR in patients treated with active therapy was 54.3% (95% CI, 39.0-69.1%) compared to only 2.2% (95% CI, 0.1-11/5%; P<0.001) among placebo controls.
Moreover, the DCR was excellent among patients treated with apatinib at 95.7% (95% CI, 85.2-99.5%) at a median follow-up of 18.1 months (IQR, 12.7-22.2 months) compared with placebo controls among whom the DCR was 58.7% (95% CI, 43.2-73%; P<0.001).
The was an extension phase of the trial during which 35 out of 46 patients originally randomized to placebo received apatinib, to which the ORR was 51.4%, the researchers noted.
As the authors pointed out, the median duration of treatment with apatinib was 7.8 months (range, 1.0-25.9 months) compared to 2.6 months (range 0.2-25.6 months) in placebo patients.
Grade 3 or higher adverse event (AE) rates were fairly universal with apatinib with over 78% in the active treatment group reporting an AE compared to 17.4% of placebo patients.
Slightly over one-third of apatinib patients required a dose reduction due to treatment-related adverse events (AEs), mainly the hand-foot syndrome, proteinuria and hypertension.
Nevertheless, the authors noted that the safety profile of apatinib was “manageable”, and concluded that “apatinib offers a favorable benefit-risk profile in patients with RAID-DTC.”
Commenting on the findings, Electron Kebebew, MD, Stanford University, Stanford, California, pointed out over the past decade, a number of new therapeutic alternatives have been approved by the FDA for progressive, locally advanced and metastatic thyroid cancer refractory to standard therapy including the angiogenesis inhibitors sorafenib and lenvatinib along with driver mutation-targeting agents.
As he suggested, the response rates and toxic effects seen in the REALITY study with apatinib were comparable to those of lenvatinib but higher than those from sorafenib based on the results of the SELECT and DECISION trials.
However, in the lenvatinib trial, OS was longer in patients over the age of 65, which was not the case in the REALITY trial.
[“Thus, t]he study’s findings suggest that apatinib may be an alternative to other currently used angiogenesis inhibitors in patients with advanced and metastatic RAIR-DTC in the Chinese population and could have a role in other populations as well,” Kebebew said.
Nevertheless, Kebebew felt the study raises a number of issues, the first of which involves when exactly treatment for progressive disease should be introduced.
“The second issue is determining which agent should be used… for progressive RAIR-DTC with no actionable mutation or whether it should be used even in patients with an actionable mutation,” he added.
Thirdly, the most appropriate treatment needs to be identified for patients who are likely to respond to apatinib or to other currently approved agents with a lower risk of treatment-related adverse effects.
“It is important to consider these issues when contemplating angiogenesis inhibitor therapy for progressive RAIR-DTC because a complete response is rarely, if ever , achieved, thus necessitating continued therapy with these agents for disease control,” the editorialist wrote, and added, “[A]s our treatment options expand, it will be essential to know the when, what and who aspects of use for the growing list of new angiogenesis inhibitors as treatment alternatives for progressive RAID-DTC.”
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The angiogenesis inhibitor apatinib prolonged progression-free and overall survival compared with placebo in patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer.
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Apatinib may represent a good alternative to other currently approved angiogenesis inhibitors in this patient population.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded by the National Natural Science Foundation of China, among others along with Jiangsu Hengrui Pharmaceuticals.
Neither Lin nor Kebebew had any conflicts of interest to declare.
Cat ID: 120
Topic ID: 78,120,730,110,120,192,925
