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7th July 2022
Apatinib addition to pegylated liposomal doxorubicin (PLD) led to a significant improvement in progression-free survival compared to patients given PLD alone in platinum-resistant ovarian cancer, according to the results of a randomised trial by Chinese researchers.
Across the world in 2020, there were an estimated 313,959 incident cases of ovarian cancer (1.6% of all cancers) and which resulted in 207,252 deaths. The symptoms of epithelial ovarian cancer are generally non-specific, and include for instance, abdominal bloating, fatigue, headaches and this probably explains how around 75% of patients present with advanced (stage III or IV) disease. Although adjuvant chemotherapy with carboplatin/paclitaxel has become standard, round 70 % of ovarian cancer patients still relapse after primary cyto-reductive surgery and first-line chemotherapy. In such cases, an emerging therapeutic option is mono-therapy with pegylated liposomal doxorubicin (PLD), docetaxel, paclitaxel, or topotecan. However, addition of monoclonal antibodies to mono-therapy is being seen as another treatment strategy. For example, the monoclonal antibody bevacizumab, which targets all isoforms of vascular endothelial growth factor (VEGF)–A is an effective option as demonstrated in the AURELIA trial, where adding bevacizumab to chemotherapy produced a statistically significant improvement in progression-free survival and overall response rate. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2 and apatinib addition to oral etoposide showed promising efficacy and manageable toxicities in patients with platinum-resistant ovarian cancer. Nevertheless, a limitation with the study was that apatinib was added to etoposide hence the authors were unable to measure the comparative effectiveness of either agent alone.
For the present study, the Chinese researchers examined the efficacy and safety of apatinib addition to PLD compared to PLD alone in platinum resistant ovarian cancer. They performed an open label, randomised trial in adult women with ovarian cancer and who had experienced disease progression during or within 6 months of discontinuing any prior platinum-based chemotherapy. Individuals were randomised 1:1 to receive either PLD alone (40 mg/m2) intravenously every 4 weeks or apatinib addition to PLD (250 mg, orally once daily). The primary outcome of interest was progression-free survival (PFS) and which was defined as the time from randomisation to the first documented tumour progression or death.
Apatinib addition to PLD
A total of 152 patients were randomised to either apatinib and PLD (78) or PLD alone. The median age of those using the combination was 54 years.
Overall, 47.4% of patients assigned to the combination and 67.6% of those using PLD alone experienced a progression event or death. The median PFS was 5.8 months for the combination and 3.3 months in the PLD arm (hazard ratio, HR = 0.44, 95% CI 0.28 – 0.71, p < 0.01).
A post hoc analysis of updated overall median survival was found to be 23 months for the combination but only 14.4 months for PLD alone.
The most frequent grade 3 or higher treatment-emergent adverse events were a decreased neutrophil counts (14.9%) in the combination group compared with 8.3% in the PLD group.
The authors concluded that apatinib addition to PLD showed promising efficacy and could represent a new alternative treatment for women with platinum-resistant ovarian cancer.
Wang T et al. Effect of Apatinib Plus Pegylated Liposomal Doxorubicin vs Pegylated Liposomal Doxorubicin Alone on Platinum-Resistant Recurrent Ovarian Cancer: The APPROVE Randomized Clinical Trial JAMA Oncol 2022
7th June 2022
Apatinib therapy seems to be an effective treatment option for patients with advanced thymic epithelial tumours who failed to achieve a satisfactory response after platinum-based chemotherapy. This was the conclusion of a small, Phase II trial by Chinese researchers.
Thymomas (T) and thymic carcinomas (TC) are tumours of the thymus gland and referred to as thymic epithelial tumours (TETs). These cancers are rare with an incidence of 1.7 per million per year in Europe. The mainstay of treatment for TETs is surgery and one retrospective analysis of outcomes after surgical resection found that the 5-year disease-free survival rate and overall survival rate was 59.7% and 66.2%, respectively. Despite the success of surgery, however, approximately 10-15% of resected tumours reoccur and, in cases of metastatic disease, one analysis has found that patients may benefit from a pemetrexed (platinum)-based chemotherapy regimen. Nevertheless, when chemotherapy fails, treatment options are limited. Some evidence suggests that in high risk TETs, there is increased expression of several vascular endothelial growth factors, which possess an angiogenic properties and have stimulant role in TETs. This finding indicates the potential value of angiogenesis inhibitors such as apatinib therapy as a treatment option in those failing to respond to chemotherapy. In fact, a study of a single patient with advanced thymic carcinoma found that apatinib therapy led to a progression-free survival of 6.3 months. Moreover, a second single patient study with advanced thymic squamous cell carcinoma also showed that apatinib therapy produced a 5-month overall response and a 10-month progression-free survival.
In light of these preliminary and potentially beneficial effects, the researchers decided to further investigate the value of this treatment in patients with TETs who had failed to respond to platinum-based chemotherapy. They performed an open-label, single-arm Phase II trial in adult patients with confirmed either T or TC and who had progressed after the failure of at least one line of systemic chemotherapy and had a life-expectancy of at least 3 months. Patients received apatinib therapy at a dose of 500mg once daily and a period of 28 days was considered as a treatment cycle. The primary endpoint was the confirmed objective response rate (OOR) and which they defined as the proportion of patients with the best response of complete response (CR) and partial response (PR). Secondary end points included progression-free survival (PFS) and overall survival (OS).
Apatinib and overall response
A total of 29 patients with a median age of 53 (68% male) were included although 4 patients were subsequently excluded. The remaining 25 patients received at least 1 apatinib cycle.
Overall, 1 patient achieved a complete response and 9 had a partial response, with an OOR of 40% (95% CI 21 – 61%). The median PFS was 9 months (95% CI 5.4 – 12.6) and the median OS was 24 months (95% CI 8.2 – 39.8).
The authors concluded that while this was the first prospective trial of apatinib therapy in patients with advanced TETs, the drug showed encouraging anti-tumour therapy and could serve as an alternative option for those with advanced disease.
Song Z et al. Apatinib in patients with recurrent or metastatic thymic epithelial tumor: a single-arm, multicenter, open-label, phase II trial BMC Med 2022
22nd December 2021
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).
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.
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
15th July 2021
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.
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.
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