Women with chemotherapy-naive advanced ovarian cancer gained significant delays in the progression of their disease when they were treated with nintedanib plus carboplatin/paclitaxel compared with women treated with carboplatin/paclitaxel alone, according to the results of the phase III AGO-OVAR 12 trial. Nintedanib is an oral inhibitor of the VEGF receptors, fibroblast growth factor receptors, and platelet-derived growth factor receptors.
“The efficacy of nintedanib seemed to be particularly notable in patients with low postsurgical disease burden, as defined by FIGO stage IIB–III and 1 cm or smaller residual postoperative tumor,” wrote Andreas du Bois, MD, of Kliniken Essen Mitte, Germany, and colleagues in Lancet Oncology. “Pending the overall survival results, further studies are needed to prospectively assess the clinical value of nintedanib in patients with advanced ovarian cancer and especially in cohorts with lower tumor burden.”
From 2009 to 2011, du Bois and colleagues screened 1,503 patients with advanced ovarian cancer and randomly assigned 1,366 at a 2:1 ratio to 6 cycles of carboplatin and paclitaxel with (n = 911) or without (n = 455) nintedanib. All patients in the study were chemotherapy-naive, had International Federation of Gynecology and Obstetrics (FIGO) stage IIB–IV disease, and had undergone debulking surgery prior to treatment. The patients were stratified by FIGO stage, carboplatin starting dose (AUC 5 mg/mL per min or 6 mg/mL per min), and by complete tumor clearance.
After an average of 22.4 months of follow-up, 53% of patients assigned nintedanib had disease progression or death compared with 58% of patients assigned placebo. Treatment with nintedanib resulted in a median progression-free survival of 17.2 months compared with 16.6 months for placebo (P = .024).
According to the researchers, the most commonly occurring adverse events were gastrointestinal including diarrhea (nintedanib [grade 3, 21%; grade 4, < 1%] vs placebo [grade 3 only, 2%]), and hematological including neutropenia, thrombocytopenia, and anemia.
Looking at data from pre-planned and post-hoc subgroup analyses, the researchers found that “progression-free survival was greater in the nintedanib group than in the placebo group for patients who had been planned to receive a carboplatin dose of AUC 5 mg/mL per min, but not AUC 6 mg/mL per min. Progression-free survival was also improved in the nintedanib group compared with the placebo group for patients with FIGO stage IIB–III disease, but not for those with FIGO stage IV disease.”
Another post-hoc analysis compared patients with high-risk disease and non–high-risk disease. High-risk disease was defined as FIGO stage III and postoperative macroscopic residual tumor greater than 1 cm, or FIGO stage IV. Patients classified as having non–high-risk disease had a median progression-free survival of 27.1 months when treated with nintedanib compared with 20.8 months for patients assigned placebo. Among high-risk patients no significant difference in progression was noted between the treatment groups.
In an editorial that accompanied these results, Sean Kehoe, MD, of the Institute of Cancer and Genomics at the University of Birmingham, United Kingdom, wrote that in the similar ICON7 trial, which looked at bevacizumab added to first-line therapy, patients with high-risk disease had better overall survival, and questioned how the difference in these trial results can be explained.
“Du Bois and colleagues proposed that the high proportion of patients with complete tumor clearance meant that a cohort of patients, categorized in ICON7 as high-risk, were classed as low-risk in this study; hence the improved efficacy in the low-risk patients,” he wrote. “This finding shows, for the first time—some might say at last—the effect of surgical intervention on ovarian cancer chemotherapy trials.”