A New Clinical Entity for Ovarian Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman received honoraria from Johnson & Johnson (study sponsor) for consultant work on a scientific advisory board.
Synopsis: Trabectedin, administered in combination with pegylated liposomal doxorubicin, led to improved progression-free (PFS) and overall survival (OS) in women with partially chemosensitive recurrent ovarian cancer, with a manageable safety profile.
Source: Poveda A, et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: Outcomes in the partially platinum-sensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 2011;22:39-48.
Ova-301 was a large (n = 672), open-label phase III trial comparing pegylated liposomal doxorubicin (PLD) to combination PLD and trabectedin (PT) in women with recurrent ovarian cancer. The trial's overall population was previously reported and demonstrated a significant impact on PFS, without a significant improvement in OS. Stratification analysis revealed the impact of benefit was not present in platinum-resistant (treatment-free interval [TFI], < 6 months) patients. Since there is bias to reinstitution of platinum-based therapies in platinum-sensitive patients, the authors conducted the current study to look at the performance of PT in patients with intermediate chemosensitivity (TFI, 6-12 month). The study population was approximately one-third of the overall population and had similar entry characteristics. As anticipated from the previous analysis, PFS was significantly improved (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45-0.92; P = 0.0152), resulting in a median improvement of 2 months (7.4 months vs 5.5 months). However, OS also was improved (HR, 0.59; 95% CI, 0.43-0.82; P = 0.0015), resulting in a median improvement of nearly 6 months (23.0 months vs 17.1 months). The safety profile for this cohort was similar to that observed in the overall trial, with the combination arm demonstrating more transient neutropenia and liver function test abnormalities, but with reduced hand-foot syndrome and stomatitis. Interestingly, the authors opined that the significantly longer delay to reinstitution of platinum-based subsequent therapy may have contributed to this effect on OS. An ancillary updated OS analysis from the original trial also was presented with approximately one-third more events, demonstrating a persistent, but nonsignificant, improvement in OS. The authors acknowledge this hypothesis-generating analysis demonstrates superior performance to the new non-platinum doublet in partially platinum-sensitive recurrent ovarian cancer.
Commentary
Trabectedin is a marine-derived (Ecteinascidia turbiata) anti-neoplastic agent that exerts its effect by covalently binding to DNA, and therefore disrupting transcription. This leads to cell cycle arrest and apoptosis. It was studied in ovarian cancer as a single agent with modest activity, but was noted to have synergy in vitro with PLD. This led to the phase III study in recurrent ovarian cancer detailed above. The data were strong enough to lead the combination to registration in the European Union, but because of lack of OS and inconsistency in assessment of the primary endpoint and toxicity concerns, the combination was not approved in the United States. As the survival data mature, this may be reconsidered. However, the dataset of this well-conducted trial continue to be mined for important therapeutic opportunities. The current report is one example. This is particularly provocative because, while the treatment standards for platinum-resistant and platinum-sensitive patients are well outlined, the cohort with TFIs between 6 and 12 months from primary completion are more controversial. Surveys of oncologists around the United States will split on reintroducing a platinum compound with a non-platinum compound. Usually toxicity, schedule, and tolerance drive the choice. Here we have a new therapeutic combination, which uses a commonly used drug in this setting, PLD, and demonstrates a large benefit, not only in PFS but also in OS. Another recent report has demonstrated that the addition of carboplatin to PLD also is active in this same cohort. This has served as the primary foundation of a new phase III trial comparing PT vs PLD and carboplatin in women defined with intermediate chemosensitive recurrent disease.
Additional Reading
- Pujade-Lauraine E, et al. A randomized phase III study of carboplatin (C) & pegylated liposomal doxorubicin (PLD) (C-D) vs carboplatin (C) & paclitaxel (P) (C-P) in relapsed platinum-sensitive ovarian cancer (OC). J Clin Oncol 2009;27:5509.
- Monk BJ, et al. Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 2010;28:3107-3114.
- Sessa C, et al. Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails. J Clin Oncol 2005;23:1867-1874.
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