No survival benefit with pegylated liposomal doxorubicin and trabectedin followed by platinum at progression for patients with recurrent ovarian cancer
The randomized phase III INOVATYON trial that investigated whether the sequential use of trabectedin/PLD (TP) followed by platinum-based therapy at progression is associated with an improved overall survival compared to carboplatin/PLD (CP). Results of this trial presented at ESMO 2020 demonstrate that this is not the case. Moreover, the progression-free survival (PFS) was better with CP compared to TP. Interestingly, TP did seem to induce a better PFS after the subsequent line of therapy, especially when platinum was administered as a subsequent treatment line. Based on these findings, platinum-based regimens should remain the standard of care for women with recurrent ovarian cancer and disease progression within 6-12 months after their last line of platinum-based therapy.
Introduction
In the CALYPSO trial, pegylated liposomal doxorubicin (PLD) and carboplatin demonstrated an improved progression-free survival (PFS) compared to carboplatin/paclitaxel in patients with recurrent ovarian cancer and a platinum-free interval (TFIp) of 6-12 months. Based on these findings, PLD-carboplatin is generally considered as the preferred treatment option in this setting. However, a subgroup analysis of the OVA-301 trial zooming in on patients with TFIp of 6-12 months seemed to suggest that trabectedin/PLD was superior to PLD alone in terms of overall survival (OS). Interestingly, this benefit seemed to be particularly pronounced in the subgroup of patients who received platinum as first subsequent line of treatment. This observation formed the basis for the randomized phase III INOVATYON trial that investigates whether the sequential use of trabectedin/PLD (TP) followed by platinum-based therapy at progression is associated with an improved OS compared to carboplatin/PLD (CP).
To this end, patients with relapsed ovarian cancer with a TFIp of 6-12 months after the end of first- or second-line platinum therapy were randomly assigned (1:1) to CP (PLD 30 mg/m2 plus carboplatin AUC 5 once every four weeks) or TP (PLD 30 mg/m2 plus trabectedin 1.1 mg/m2 once every three weeks) for up to six cycles or until disease progression. At disease progression, subsequent therapy at the investigator’s discretion was given in the CP arm while patients in the TP arm had to be rechallenged with a platinum-based regimen at progression. In total, 617 patients from 117 European sites were recruited, including 10 Belgian patients.
Results
Overall, patient baseline characteristics were well balanced between both arms. The median age of patients in the trial was 64 years, almost all of them had an ECOG performance status of 0-1 and about 85% had a tumour with a serous histology. Seventy percent of patients received the study drug in second line, while the remaining 30% had received 2 prior lines of therapy. Approximately 10% of patients received a previous anthracycline-based chemotherapy regimen and the median last TFIp was 8.4 months.
In total, 68.1% of patients in the CP arm and 53.4% of patients in the TP arm completed six cycles of treatment. The most common reason for treatment interruption was disease progression (64% vs. 50% respectively). However, slightly higher numbers of unacceptable toxicity (19.3% vs. 15.1%) and patient refusal or withdrawal of consent (12.8% vs. 4.6%) were reported in the TP arm. After a median follow-up of 44 months, the study did not meet its primary endpoint and failed to demonstrate an improved OS for TP over CP. The median OS was very comparable between both study arms at 21.3 months with CP vs. 21.5 months in the TP arm (HR [95%CI]: 1.10 [0.92-1.32]; p=0.284). Nevertheless, a qualitative, but not statistically significant, interaction was observed according to the number of prior lines, with a hazard ratio in favour of TP for patients who received two prior lines of treatment (HR [95%CI]: 0.87 [0.63-1.22]).
The PFS, which was a secondary endpoint in this study, was statistically longer with the CP regimen (9.0 months) compared to TP (7.5 months, HR [95%CI]: 1.26 [1.07-1.49], p=0.005). Since this study was designed to explore the efficacy of a sequential treatment, the use of subsequent therapies was also analysed. PFS after the subsequent line, calculated from the start of subsequent therapy, was in favour of the trabectedin-PLD combination with an improvement from 5.7 months with CP to 7.4 months with TP (HR [95%CI]: 0.84 [0.70-1.02]; p=0.086). Of note, this difference crossed the threshold for statistical significance when platinum was used as a subsequent treatment, according to the study protocol (HR [95%CI]: 0.80 [0.65-0.98]; p=0.028).
With respect to safety, the CP regimen was found to be associated with a more favourable toxicity profile than TP, with lower rates of haematological toxicity (28% vs. 45%), gastrointestinal toxicity (7% vs. 18%), asthenia (0.3% vs. 3%), and hepatic toxicity (1% vs. 18%) of grade 3 or more. Any grade neurotoxicity was observed in 18% of patients in both study arms. Finally, quality of life assessment on global health status, fatigue, nausea/ vomiting/ loss of appetite, attitude to disease/treatment, hormonal/menopausal symptoms, and side effects favours the carboplatin-PLD combination.
Conclusion
Trabectedin/PLD followed by platinum-based therapy at progression did not improve the OS compared to carboplatin/PLD in patients with recurrent ovarian cancer. The PFS was longer with carboplatin/PLD while PFS after the subsequent line of treatment was in favour of trabectedin/PLD, particularly when platinum was administered. A qualitative, although not statistically significant, interaction was observed regarding the number of prior lines. Carboplatin/PLD showed a better safety profile in terms of haematological, gastrointestinal, asthenia and hepatic toxicities and the quality of life assessment was in favour of carboplatin/PLD too. As such, platinum-based regimens should remain the standard of care in patients with recurrent ovarian cancer who experienced disease progression within 6-12 months after their last line of platinum-based therapy. However, given the similar OS outcomes in this trial, trabectedin/PLD could be an option for patients who received multiple prior lines of platinum and who need a longer recovery time from specific platinum-related toxicities.
Reference
Colombo N, Gadducci A, Sehouli J, et al. 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 last platinum line. Presented at ESMO 2020; Abstract LBA30.
