The INOVATYON study is a randomized phase 3 international (EU) study comparing the combination of trabectedin and pegylated liposomal doxorubicin (PLD) followed by platinum rechallenge upon progression versus the combination of carboplatin and PLD in patients with recurrent ovarian cancer progressing within 6 to 12 months after their last platinum line. Patients from 117 European sites were randomized (1:1) to receive the combination of trabectedin (1.1 mg/m2) and PLD (30 mg/m2) or carboplatin (AUC 5) and PLD (30 mg/m2). Treatment continued for 6 cycles or until disease progression. At progression, all patients in the trabectedin/PLD arm had mandatory platinum rechallenge, whereas rechallenge was administered at investigators’ discretion for those in the carboplatin/PLD arm. The primary objective was overall survival (OS), and secondary objectives included progression-free survival (PFS), second PFS (from subsequent therapy), treatment safety, and quality of life. RECIST tumor evaluation was completed at 12 and 24 weeks. The study was powered to be able to demonstrate superiority of trabectedin/PLD over carboplatin/PLD.
Of 617 enrolled patients, 307 were randomized to the trabectedin/PLD arm and 304 were randomized to the carboplatin/PLD arm. The median treatment-free interval from the last platinum line was 8.4 months, and 30% of patients received 2 previous platinum lines. In the trabectedin/PLD arm, treatment was interrupted before the sixth cycle in 46% of patients (54% due to progression or death, 19% due to toxicity, and 13% due to patient refusal). Treatment was interrupted before the sixth cycle for 28% of patients in the carboplatin/PLD arm (70% due to progression or death, 15% due to toxicity, and 5% due to patient refusal).
At median follow-up (44 months), the median OS was 21.5 months versus 21.3 months for the trabectedin/PLD and carboplatin/PLD arms, respectively (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.92-1.32; P = .284). In the trabectedin/PLD arm there were 236 deaths, and in the carboplatin/PLD arm there were 230 deaths at median follow-up. Median PFS was 7.5 months for the trabectedin/PLD arm versus 9.0 months for the carboplatin/PLD arm (HR, 1.26; 95% CI, 1.07-1.49; P = .005).
For the trabectedin/PLD arm, 73.6% of patients received subsequent therapy versus 74.0% in the carboplatin/PLD arm. However, the type of therapy differed markedly. For the trabectedin/PLD arm, 63.2% of patients received platinum-based subsequent therapy, whereas this was the case for only 17.8% of those in the carboplatin/PLD arm. Median PFS after subsequent therapy was 7.4 months for the trabectedin/PLD arm versus 5.7 months with carboplatin/PLD (HR, 0.84; 95% CI, 0.70-1.02; P = .086). When focusing specifically on data for patients in the trabectedin/PLD arm receiving platinum-based subsequent therapy, median PFS was 7.6 months and 5.7 months for the trabectedin/PLD and carboplatin/PLD arms, respectively (HR, 0.80; 95% CI, 0.65-0.98; P = .028). Subgroup analysis based on BRCA status, extent of disease, histology, and whether patients received subsequent therapy did not identify any patient subgroups more likely to experience a benefit from trabectedin/PLD.
Treatment-emergent adverse events grade ≥3 were more frequent in the trabectedin/PLD arm (69%) than in the carboplatin/PLD arm (36%). The difference was notable for neutropenia (39% for trabectedin/PLD vs 22% for carboplatin/PLD; P <.001), gastrointestinal adverse events (18% for trabectedin/PLD vs 7% for carboplatin/PLD; P <.001), and hepatotoxicity (18% for trabectedin/PLD vs 1% for carboplatin/PLD; P <.001).
Quality of life was diminished in the trabectedin/PLD arm versus the carboplatin/PLD arm in the areas of fatigue, nausea and vomiting, and appetite loss (as assessed using the EORTC-QLQL-C30 instrument), as well as attitude to disease/treatment, hormonal/menopausal symptoms, and other chemotherapy side effects (as assessed using the EORTC-QLQ-OV28 instrument).
The authors concluded that this study did not meet the primary end point of improving OS with trabectedin/PLD as compared with carboplatin/PLD. However, trabectedin/PLD and carboplatin/PLD did result in similar OS, indicating that trabectedin/PLD may be a viable treatment regimen for those who need a longer recovery time from platinum-specific toxicities.
Abstract and Late-Breaker Presentation LBA30. ESMO 2020. September 21, 2020. INOVATYON study: randomized phase III international study comparing trabectedin/PLD followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after the last platinum line.