Currently, targeted therapies for platinum-resistant/platinum-refractory recurrent ovarian cancer mainly include anti-angiogenic agents (VEGFR inhibitors), poly (ADP-ribose) polymerase (PARP) inhibitors, and immunotherapy. PARP inhibitors are recommended only for platinum-resistant/platinum-refractory patients with BRCA mutations, which constitute approximately 15% of patients. The majority of patients in platinum-resistant settings do not benefit from PARP inhibitors. Immunotherapy for ovarian cancer has not made significant breakthroughs. Limited by the efficacy of single-agent anti-angiogenic therapy and chemotherapy in platinum-resistant/platinum-refractory patients, there has been no substantial progress in recent years.
This clinical trial was the first to investigate the safety and effectiveness of chiauranib, a novel multi-targeted kinase inhibitor, in patients with recurrent ovarian cancer. Traditional anti-angiogenic drugs target the VEGF pathway only. Chiauranib inhibits Aurora B and CSF-1R, achieving inhibition of the cell cycle process and improvement of the body’s anti-tumor immune function as long as targeting the VEGF pathway for tumor extinction. When chiauranib is used in combination with chemotherapy, it can play a synergistic lethal role.
In the monotherapy stage, most patients had platinum-resistant ovarian cancer. Among 23 patients, only two (8.7%) showed partial responses. The median PFS of 3·7 months was equivalent to the efficacy of standard chemotherapy, which has an ORR of 5 ~ 17% and a median PFS of around three months. Other anti-angiogenic medicines, such as pazopanib, sorafenib and bevacizumab, were previously found to have an ORR of 3 ~ 15·9% and a median PFS of 2·1 ~ 4·4 months [2,3,4]. Concerning chemotherapy combination, the combined treatment increased ORR to 40·9% in the CE group and 52·4% in the CP group, which was significantly higher than that after treatment with chiauranib alone and roughly double the value after treatment with etoposide or paclitaxel alone (ORR of etoposide was 27% and ORR of paclitaxel was 21%). The median PFS was 5·4 months in the CE group and 5·6 months in the CP group, which was similar to that in the recommended guidelines for pazopanib, sorafenib, and bevacizumab combined with chemotherapy.
As the number of previous lines of treatment increased, the clinical benefits patients received and their tolerance to the treatment decreased. One-third of the patients in our study received three or more lines of chemotherapy, which was higher than that in previous studies in which bevacizumab, pazopanib, and sorafenib were administered [7,8,9]. This study showed that combining chemotherapy with chiauranib might continuously benefit patients who have very limited treatment options. Among these patients, 2 of 46 (4.3%) were platinum-refractory and clear cell. As is well known, these two pathological conditions often represent poor prognosis.
In the monotherapy stage, the regular administration of chiauranib was manageable in ovarian cancer patients. It had a safety profile similar to that of other TKIs. The most common TRAEs were gastrointestinal reactions (diarrhea, loss of appetite, abdominal pain), fatigue, proteinuria, and hypertension. Among 25 patients, 13 (52%) had grade 3 TRAEs; diarrhea (n = 5 [20·0%]) and hypertension (n = 4 [16·0%)]) were the most common TRAEs. Most patients discontinued because of disease progression and only 3 (12%) patients discontinued because of AEs.
The TRAEs were more common in patients treated with chiauranib combined with chemotherapy than in those who were administered either of the monotherapeutic agents. However, these events did not affect the treatment plan of the patients. Hematologic AEs were the most common, and non-hematologic AEs primarily consisted of gastrointestinal reactions and VEGFR target-related AEs. Hematologic AEs, such as neutropenia and leucopenia, were more common in the CP group than in the CE group and in studies with similar study populations where patients were administered anti-angiogenic medicines along with chemotherapy, such as AURELIA [7], MITO11 [8], TRIAS [9] and AEROC [10]. We suggest that the dissimilarities observed may be due to the characteristics of combination chemotherapeutic drugs. Hypertension is a recognized adverse effect linked to the VEGFR pathway, and it was the most frequently reported grade 3 or 4 AEs in patients receiving chiauranib monotherapy, with three patients (12.5%) in the CE group and six patients (27.3%) in the CP group. The incidence of hypertension in both groups was higher than that in other similar studies cited above. Other target-related AEs included fatigue, proteinuria, and hand-foot syndrome, among others; these events occurred at a lower rate than that in other similar studies. The AEs caused by the combined chemotherapy regimens in this study were similar to those caused by chiauranib, etoposide, or paclitaxel monotherapy [11]. No new safety signals were recorded, and the treatment was well tolerated by most patients.
The toxicity caused by VEGFR TKIs has been reported as predictive factor for treatment efficacy [12, 13]. By conducting a post hoc exploratory analysis of toxicity and efficacy, we found that patients with hypertension had a higher objective response rate (45% vs. 23·1%) and a longer duration of overall response (4·5 months vs. 3·7 months) than patients without these conditions. We also found that patients with diarrhea had a higher ORR (42·3% vs. 20%) and longer PFS (6·5 months vs. 3·6 months) than patients without these conditions. Our results were similar to those of other studies, where the authors found that treatment-induced toxicities can be independent predictive biomarkers for the efficacy of VEGFR TKIs in other tumors [12, 13].
Although our study had a limited sample size, the efficacy within this population is currently being investigated in ongoing phase III trials. In addition to inhibiting the formation of tumor neovascularization through VEGFR, it also exhibits high selectivity in inhibiting Aurora B, uniquely affecting the tumor cell cycle progression and cellular proliferation. Meanwhile, reduction Aurora B phosphorylation is effective in reversing paclitaxel resistance in cancer cells [14]. The inhibition of mitosis and angiogenesis is likely to contribute to the antitumor activity at well-tolerated doses in a variety of preclinical tumor models [15]. In addition, chiauranib can also inhibit the activity of CSF-1R, reducing the tumor infiltration and expansion of immunosuppressive cells. This improves the body’s anti-tumor immune function. Through these actions, we believe that it can exert a comprehensive anti-tumor effect in stage III ovarian cancer patients resistant to conventional treatments in the future.
In summary, this was the first study to evaluate chiauranib, a novel multi-targeted kinase inhibitor in patients with platinum resistant ovarian cancer. The administrations of chiauranib along with etoposide or weekly-paclitaxel significantly enhance the treatment efficacy with manageable AEs. This warrants further clinical studies on this novel treatment. A phase III study evaluating the efficacy and safety of chiauranib in combination with weekly paclitaxel versus placebo with weekly paclitaxel in platinum resistant ovarian cancer (including platinum-refractory and clear cell carcinoma) is warranted. The outcomes of this ongoing phase III clinical trial (NCT04921527) and translational research are eagerly awaited.
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