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Apatinib therapy improves progression-free survival in iodine-refractory thyroid cancer

22nd December 2021

Apatinib therapy in patients with radioactive iodine-refractory thyroid cancer is safe and able to improve progression-free survival

The use of apatinib therapy in patients with radio-active iodine-refractory thyroid cancer has been found to be safe and effective, improving progression-free survival. This was the main result from the Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY] trial, undertaken by a team from the Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking, China.

The incidence of thyroid cancer has been increasing globally over the past three decades and affects around 5 to 6% of men and women. Differentiated thyroid cancer (DTC) , which includes papillary and follicular histologies, is the most common type, accounting for over 90% of all thyroid cancers. Although radioactive iodine therapy is effective for a large proportion of patients with DTC, unfortunately around 5 to 15% of patients become refractory to therapy, prompting the need for alternatives.

Apatinib is a small-molecule angiogenesis inhibitor which suppresses vascular endothelial growth factor (VEGF) signalling. The value of apatinib therapy in radioactive iodine-refractory DTC has been examined in two small studies. In the first including 10 patients, the drug was described as a promising therapy, whereas in the second, dosing schedule study, undertaken with 20 patients, the drug produced a similar efficacy with both doses.

Based on these preliminary studies, the Chinese team, decided to undertake a randomised, double-blind, placebo trial of apatinib in patients with progressive, locally advanced or metastatic radioactive iodine-refractory DTC. The REALITY trial was conducted in adults (18 years and over) and the inclusion criteria were those whose target lesion had lost iodine uptake function, where the lesion had progressed within 12 months after radioactive iodine treatment. In addition, iodine refractory patients receiving chemotherapy or radiotherapy, at least one month prior to the first use of study treatment were also included. Participants were randomised 1:1 to apatinib, given at a dose of 500 mg once daily until disease progression or intolerable side-effects developed or matching placebo. Tumour assessment was performed with CT or MRI imaging and the primary endpoint was investigator assessed progression-free survival (PFS), which was defined as the time from randomisation to disease progression or death from any cause. Secondary endpoints included overall survival (OR) and the objective response rate (ORR).

Findings

A total of 92 patients with a mean age of 57.7 years (60.9% female) were randomised to apatinib therapy or placebo.

With a median follow-up time of 18.1 months, the median PFS was 22.2 months in the apatinib group and 4.5 months in the placebo group (hazard ratio, HR = 0.26, 95% CI 0.14 – 0.47). The 12-month PFS rate was 60.3% for apatinib compared to 12.4% in the placebo arm although this decreased to 37.2% and 4.1% (apatinib vs placebo). The ORR was 54.3% for apatinib compared to 2.2% (placebo) and the overall 12-month survival rate was 95.4% vs 79.7% (apatinib vs placebo).

In terms of safety, the most common adverse event (grade 3 or higher) was hypertension (34.8%), hand-foot syndrome (17.4%) and proteinuria (15.2%) and none of these effects were observed in the placebo group.

The authors concluded that apatinib therapy significantly improved PFS and suggested that it should be considered as a new treatment for patients with radioactive iodine-refractory DTC.

Citation

Lin Y et al. Apatinib vs Placebo in Patients With Locally Advanced or Metastatic, Radioactive Iodine–Refractory Differentiated Thyroid Cancer. The REALITY Randomized Clinical Trial JAMA Oncol 2021

Apatinib neoadjuvant chemotherapy effective in advanced gastric cancer

15th July 2021

Positive findings that apatinib neoadjuvant chemotherapy produces an R0 section rate of 75% in advanced gastric cancer required confirmation.

Internationally, data from 2018 reveal how there were just over 1 million cases of gastric cancer, leading to 782,000 deaths. Fortunately, early treatment of gastric cancer either through endoscopic resection or surgery, provides a cure rate of over 90%. In contrast, in patients with locally advanced gastric cancer, prognosis is poor, with a 5-year overall survival rate of 20–30% for surgery-only patients. Among those with advanced gastric cancer, systemic chemotherapy has become the standard treatment, in particular, the combination of S-1, which is an oral fluoropyrimidine derivative and oxaliplatin (SOX) and this regime has been shown to be effective. Another therapeutic approach involves treatments targeting vascular endothelial growth factor (VEGF), which has been shown to have an important role in promoting tumour angiogenesis. Apatinib is a small molecule tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor receptor 2 and which inhibits the action of VEGF. In fact, early data suggest that apatinib can improve overall survival in advanced gastric cancer.

In a review of 14 trials, the use of neoadjuvant chemotherapy, has been shown to improve tumour stage and survival in patients with advanced gastric cancer. However, little is known about the value of Apatinib in combination with neoadjuvant chemotherapy. This led a team from the Department of Gastric Surgery, Fujian Medical University Union Hospital, Fujian Province, China, to examine the effectiveness of this combination in patients with locally advanced gastric cancer. They conducted a multi-centre, open-label phase II, non-randomised controlled trial, in patients with confirmed primary gastric adenocarcinoma, without previous surgery, chemotherapy, radiotherapy or targeted therapy and no evidence of metastases. Patients with MO (i.e., no metastases) and either T2 to T4 (where the tumour has spread through the layers of the muscle into the connective tissue outside the stomach. All enrolled participants received 2 to 5 preoperative and 6 postoperative cycles of apatinib plus SOX every three weeks. Apatinib was given at a dose of 500 mg daily for 21 days and S1 twice daily on days 1 to 14 and intravenous oxaliplatin 130mg/square metre on day 1. Patients achieving a good response underwent surgery whereas those with a poor response received two further courses of adjuvant chemotherapy. The primary endpoint was the RO section rate (i.e., margin-negative resection with no tumour in the primary tumour bed) and which is the goal of surgery. The radiologic response was assessed using contrast-enhanced CT or magnetic resonance imaging.

Findings
A total of 48 patients with a mean age of 63.2 years (77.1% male) were included. All participants received 156 preoperative cycles neoadjuvant chemotherapy. The majority of patients (39.5%) had stage T3 cancer and nearly a third (36.9%) had stage T4 disease. Overall, 40 underwent surgery (38 radical gastrectomy and 2 exploratory laparotomy), with an R0 section rate of 75%. The radiological response rate was 75% and the pathological response rate, 54.2%.

Commenting on these early findings, the authors stated how the data indicated the effectiveness of apatinib and SOX chemotherapy as a neoadjuvant therapy for locally advanced gastric cancer. They concluded that apatinib plus SOX appeared to be an effective and well-tolerated regime and called for more studies to confirm this preliminary conclusion.

Citation
Lin JX et al. Effectiveness and Safety of Apatinib Plus Chemotherapy
as Neoadjuvant Treatment for Locally Advanced Gastric Cancer A Nonrandomised Controlled Trial
. JAMA Oncol 2021