The final analysis of overall survival (OS) data from the phase III AGO-OVAR 12 trial of nintedanib (Ofev) plus carboplatin/paclitaxel versus carboplatin/paclitaxel alone in women with chemotherapy-naïve advanced ovarian cancer did not demonstrate a survival advantage with the addition of nintedanib, according to the findings presented at the European Society of Gynaecological Oncology (ESGO) 2017 Congress.
In addition, long-term progression-free survival (PFS) results did not confirm earlier reported gains with nintedanib.
After a median follow-up of more than 5 years, 44.3% of patients had an OS event. The median OS was similar at 62.0 months with nintedanib plus chemotherapy compared to 62.8 months with chemotherapy alone (hazard ratio [HR], 0.99; 95% CI, 0.85-1.17).
The updated PFS analysis at 60+ months of follow-up showed treatment with nintedanib plus chemotherapy resulted in a median PFS of 17.6 months compared to 16.6 months for chemotherapy (HR, 0.85; 95% CI, 0.75-0.98).
“We observed a median overall survival longer than 5 years in both arms,” commented Isabelle Ray-Coquard, MD, PhD, Centre Léon Bérard in Lyon, France, who presented final OS and updated PFS results from the GCIG-Intergroup AGO-OVAR 12 trial (NCT01015118). This study randomized 911 patients in a 2:1 ratio to chemotherapy plus nintedanib and 455 to sole chemotherapy. All patients received carboplatin at AUC 5 or 6 plus paclitaxel at 175 mg/m2 and patients in the exploratory arm received oral nintedanib at 200 mg twice daily for six 21-day cycles. The patients were chemotherapy-naïve, with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV disease, and had undergone debulking surgery prior to study entry. The patients were stratified by FIGO stage, carboplatin starting dose (AUC 5 mg/mL per minute or 6 mg/mL per minute), and by the presence of macroscopic residual post-operative tumor.
Previously reported findings from this trial demonstrated that the primary endpoint of PFS by RECIST 1.1 criteria was met; median PFS was observed of 17.3 months with the nintedanib plus chemotherapy regimen versus 16.6 months with chemotherapy (HR, 0.84; 95% CI, 0.72-0.98; P
Nintedanib is an oral inhibitor of several receptors, including the VEGF, FGF, and PDGF receptors.
However, the post-hoc analysis reported at this congress showed no statistically significant differences in OS in patients overall or across subgroups stratified by differentiation grade or histological class.
“In fact, none of the subgroups defined by randomization strata showed a statistically significant difference in OS between treatment groups,” Ray-Coquard said. Slight trends that did not reach statistical significance favoring the nintedanib arm were seen in patients from North America (HR, 0.1646), as well as in patients aged between 65 and 74 years and patients older than 75 years, compared to patients younger than 65 years (HR, 0.6813).
Updated PFS results did show improved PFS of 27.7 months in non-high-risk patients (FIGI III and residual tumor ≤ 1 cm) treated with nintedanib versus 21.7 months with chemotherapy (HR, 0.77; 95% CI 0.64-0.93). However, OS was similar between the treatment arms.
“The observed advantage of nintedanib regarding PFS in the non-high-risk subgroup did not translate into a significant OS advantage,” said Ray-Coquard.
Further analysis of OS in the non-high-risk subgroup but in patients having peritoneal disease or ascites showed median OS was 60.8 months versus 50.0 months with nintedanib versus chemotherapy, respectively (HR, 0.73; 95% CI, 0.53-1.00).
Another post hoc analysis was done comparing patients with high-risk disease, defined as FIGO stage III and postoperative macroscopic residual tumor greater than 1 cm or FIGO stage IV. Median PFS was 12.7 months with nintedanib compared to 11.3 months with chemotherapy (HR, 1.03). Among high-risk patients, median OS was 40.4 with nintedanib versus 42.7 months with chemotherapy (HR, 1.14).
Overall, 86.3% versus 92% of patients in the nintedanib and chemotherapy arms completed all 6 cycles of chemotherapy, and 51.7% of patients receiving nintedanib required a dose reduction.
Adverse events led to death in 3.3% versus 3.6% of patients on nintedanib versus chemotherapy.
“Nintedanib does not provide any meaningful benefit when combined with carboplatin plus paclitaxel as frontline therapy of advanced ovarian cancer,” Ray-Coquard summarized.
However, “OS was excellent in the OVAR 12 trial in both treatment arms, and confirms the progress we made over the years,” she added.
Ray-Coquard I, Cibula D, Mirza MR, et al. AGO-OVAR 12: a randomized placebo-controlled GCIC/ENGOT-Intergroup phase III trial with chemotherapy +/- nintedanib for advanced ovarian cancer: overall survival results. Abstract presented at: 2017 ESGO Congress; November 4-7, 2017; Vienna, Austria.