Abstract
ABSTRACT Background Sensitivity analyses are critical to understanding the strength of conclusions made in the primary analysis. A randomised phase III trial OVA-301 compared the efficacy of trabectedin 1.1 mg/m2 in combination with PLD 30 mg/m2 given every 3 weeks vs. PLD 50 mg/m2 every 4 weeks in patients with relapsed ovarian cancer. Primary endpoint was PFS based on independent radiology review (IRR) per RECIST. Secondary PFS analyses were based on independent oncologist (IO) and investigator's assessments (IA). Methods Patients were assessed symmetrically every 8 weeks in both arms. To avoid bias of the disease assessment time, two conservative sensitivity analyses of PFS were performed. Two different conservative analyses considered the scheduled date of PFS evaluation instead of the actual date of imaging moving the actual date to: #1) the last scheduled date of assessment immediately before the actual evaluation and to #2) the closest scheduled date before or after the actual evaluation. Results The treatment effect based on the actual dates of assessment in favour of the combination arm is maintained across the performed sensitivity analyses. Summary of the two sensitivity PFS analyses compared with the pre-planned PFS analysis. Analysis n Trabectedin + PLD PLD HR CI 95% LR test (p value) PFS by IR * 645 328 317 0.789 0.646-0.963 0.0190 PFS by IR ( #1 ) 645 328 317 0.813 0.666-0.993 0.0245 PFS by IR ( #2 ) 645 328 317 0.822 0.674-1.004 0.0317 PFS by IO * 671 336 335 0.724 0.599-0.876 0.0008 PFS by IO ( #1 ) 671 336 335 0.749 0.620-0.906 0.0010 PFS by IO ( #2 ) 671 336 335 0.757 0.626-0.916 0.0013 PFS by IA * 672 337 335 0.723 0.608-0.859 0.0002 PFS by IA ( #1 ) 672 337 335 0.742 0.624-0.882 0.0001 PFS by IA ( #2 ) 672 337 335 0.747 0.629-0.888 0.0001 CI, confidence interval; HR, hazard ratio; IA, investigator assessment; IO, independent oncology review; IR, independent radiology review; LR, log-rank; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin. * *Main PFS analyses. #1 #1: Conservative PFS sensitivity analysis; imputation to the previous schedule evaluation. #2 #2: Sensitivity analysis with imputation to the closest scheduled evaluation. Conclusions The consistently observed significantly better PFS for the trabectedin combination based on adjusting progression times by moving assessments to scheduled times added methodological strengths and increased reliability and interpretability of the prior findings of this phase III trial. Disclosure A. Tanovic: I am an employee at PharmaMar and stock owner. J. Gomez Garcia: I am an employee at PharmaMar and stock owner. A.M. Poveda: I received funding for research from PharmaMar. All other authors have declared no conflicts of interest.
Published Version
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