1. Experience with trabectedin + pegylated liposomal doxorubicin for recurrent platinum-sensitive ovarian cancer unsuited to platinum rechallenge.

Expert Rev Anticancer Ther. 2016 Nov;16(sup1):11-19.

Colombo N, Hardy-Bessard AC, Ferrandina G, Marth C, Romero I.

INTRODUCTION:As most patients with ovarian cancer experience multiple remissions and relapses, oncologists must prepare ahead for long-term treatment. While platinum-based regimens are standard of care for platinum-sensitive recurrence, there are circumstances in which platinum rechallenge is not the best approach. These situations include patients with limited sensitivity to platinum; patients with residual toxicity from previous platinum therapy; and patients at risk of developing hypersensitivity reactions. An alternative regimen for these patients is the non-platinum combination of trabectedin + pegylated liposomal doxorubicin (PLD). Areas covered: In this review, case studies are presented to illustrate how careful strategic planning, in terms of therapeutic choices and optimal sequencing, can achieve good outcomes in difficult-to-treat patients. Expert commentary: Advantages with use of trabectedin + PLD in selected patients with platinum-sensitive recurrent ovarian cancer include additional time to recover from platinum-related toxicities, avoidance of hypersensitivity reactions, and the 'sequence effect' by which trabectedin may enhance response to next platinum and prolong survival.

2. Factors to consider and questions to ask in the management of recurrent ovarian cancer: a focus on the role of trabectedin + pegylated liposomal doxorubicin.

Expert Rev Anticancer Ther. 2016 Nov;16(sup1):3-10.

González-Martín A, du Bois A.

INTRODUCTION:Given the heterogeneity of both disease and clinical situation, recurrent ovarian cancer continues to be a considerable therapeutic challenge. While newer treatment options have led to improved clinical outcomes, treatment selection has become more complex. An increasing number of clinical questions must be addressed before the optimal strategy and sequence can be decided for an individual patient. Areas covered: In this review, evidence is examined to guide decision-making for the main treatment options of surgery, chemotherapy and targeted therapy. Expert commentary: For each option, the same set of patient- and tumor-related factors can be used to identify appropriate candidates. Over the next few years, results of ongoing randomized studies are expected to shed light on several unresolved issues in the treatment of recurrent ovarian cancer.

3. Trabectedin plus pegylated liposomal doxorubicin: retrospective analysis in heavily pretreated platinum-sensitive ovarian cancer.

Tumori. 2015 Sep-Oct;101(5):506-10. doi: 10.5301/tj.5000371. Epub 2015 Jun 18.

Nicoletto MO, Baldoni A, Casarin A, Randon G, Nardin M, Baretta Z, Lardelli P, Nieto A, Alfaro V, Rigamonti C, Conte PF.

PURPOSE:This retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy.

METHODS:Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).

RESULTS:Three complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.4-50.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment-related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%).

CONCLUSIONS:The overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease.

4. Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study.

Ann Oncol. 2015 May;26(5):914-20. doi: 10.1093/annonc/mdv071. Epub 2015 Feb 26.

Monk BJ, Ghatage P, Parekh T, Henitz E, Knoblauch R, Matos-Pita AS, Nieto A, Park YC, Cheng PS, Li W, Favis R, Ricci D, Poveda A.

BACKGROUND:We investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer.

PATIENTS AND METHODS:A candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone.

RESULTS:Overall, 41 (16%) of the 264 women had BRCA1(mut) (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG(mut) (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1(mut) patients (20/41; 49%) versus BRCA1(wt) patients (62/223; 28%). Within the BRCA1(mut) group, trabectedin + PLD-treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1(wt) patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG(mut) between the two treatment arms. However, trabectedin + PLD-treated patients with XPG(mut) had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG(wt).

CONCLUSIONS:In this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1(mut) had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.

5. Optimizing the treatment of the partially platinum-sensitive relapsed ovarian cancer patient.

EJC Suppl. 2014 Dec;12(2):7-12. doi: 10.1016/S1359-6349(15)70004-2. Epub 2015 Jan 13.

Colombo N

The choice of second-line chemotherapy in patients with recurrent ovarian cancer (ROC) is complex, with several factors to be considered, the most important of which is the length of the platinum-free treatment interval (PFI). Recently ROC patients have been further stratified into platinum sensitive (PS), partially platinum sensitive (PPS) and platinum resistant (PR) subgroups depending on the length of the PFI. Response to second-line therapy, progression-free survival (PFS) and overall survival (OS) are linked to the PFI, all of them improving as the PFI increases. Consequently, there is increasing interest in PFI extension strategies with platinum-free therapeutic options. Such strategies are currently being studied in patients with partially platinum-sensitive disease (PFI 6-12 months), as the treatment of these patients remains clinically challenging. A non-platinum option, trabectedin + pegylated liposomal doxorubicin (PLD) combination, has been evaluated in ROC patients in the pivotal phase III OVA-301 study. The OVA-301 study differed from previous trials in the same setting as it included only patients who were not expected to benefit from or who were ineligible for or who were unwilling to receive re-treatment with platinum-based chemotherapy, including those with PPS and PR disease. Subset analysis of patients with PPS disease in OVA-301 showed that the trabectedin + PLD combination significantly improved PFS compared with PLD alone; median PFS 7.4 versus 5.5 months, p=0.0152. Final survival data from the same subset of patients, showed that trabectedin + PLD also achieved a significant 36% decrease in the risk of death compared with PLD alone (HR=0.64; 95% CI, 0.47-0.88; p=0.0027). Median overall survival (OS) was 22.4 months in the trabectedin + PLD arm versus 16.4 months in the PLD arm. This represents a statistically significant 6-month improvement in median OS in patients treated with trabectedin + PLD compared to those treated with PLD alone.

6. Limitations to the use of carboplatin-based therapy in advanced ovarian cancer.

EJC Suppl. 2014 Dec;12(2):13-6. doi: 10.1016/S1359-6349(15)70005-4. Epub 2015 Jan 13.

Fotopoulou C.

Most patients with recurrent ovarian cancer (ROC) undergo a series of remissions and recurrences, therefore the additive or cumulative toxicity of chemotherapy must be factored into their treatment plan. There are challenges in defining tailored therapeutic approaches, including optimal timing and drug sequencing management strategies to treat patients with ROC. This is particularly relevant as new cytotoxic drugs and biological agents become available. Many of these drugs are associated with increased toxicity and with no observable survival advantage. Therefore current treatment options for the heavily-pretreated relapsing OC patient population are frequently guided by safety considerations and convenience. Rechallenge with platinum-based combination regimes is commonly limited by the risk of cumulative long-term toxicities. Not all patients can continue with platinum at second-line or, indeed, further relapses due to loss of activity or toxicity-related issues including hypersensitivity, neurotoxicity, alopecia and ototoxicity. In particular, hypersensitivity reactions are a concern and have been reported in approximately 15-20% of women receiving the drug. Trabectedin + PLD is a non-platinum combination that is well tolerated, with a manageable safety profile, which is independent of age.

7. Emerging treatment strategies in recurrent platinum-sensitive ovarian cancer: focus on trabectedin.

Cancer Treat Rev. 2014 Apr;40(3):366-75. doi: 10.1016/j.ctrv.2013.08.001. Epub 2013 Aug 8.

Poveda A, Ray-Coquard I, Romero I, Lopez-Guerrero JA, Colombo N

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. In spite of high response rates to the standard front-line treatment for advanced disease with cytoreductive surgical debulking, followed by platinum/taxane-based chemotherapy, most patients eventually relapse developing drug-resistant disease. Owing to the molecular heterogeneity, genetic instability and mutagenicity of OC, increases in survival might be achieved by translating recent insights at the morpho-molecular levels to individual therapeutic strategies. Several emerging treatments have been shown to be active in platinum-sensitive (PS) recurrent OC (ROC), but an optimal strategy still has not been established. Based on the recent results, it is likely that the introduction of novel non-platinum based chemotherapies and molecular targeted therapies will have a major impact on the management of ROC. Some current strategies are focused on the extension of platinum-free interval (PFI) in patients with PS, particularly in those with partially PS disease. Apparently, the PFI extension by an effective non-platinum intervention, such as trabectedin plus pegylated liposomal doxorubicin (PLD), may reduce cumulative platinum-induced toxicities leading to longer survival after the reintroduction of subsequent platinum. The introduction of novel therapies, such as the antiangiogenic monoclonal antibody bevacizumab, opens a new field of targeted therapies in this indication. In this review, we aim to outline the therapeutic potential of new emerging approaches, particularly the role of non-platinum therapy with trabectedin in combination with PLD in patients with PS ROC.

8. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: Overall survival analysis.

Eur J Cancer. 2012 Oct;48(15):2361-8. doi: 10.1016/j.ejca.2012.04.001. Epub 2012 Apr 26.

Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, Pujade-Lauraine E, Park YC, Parekh TV, Poveda AM.

AIM:Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol 2010;28:3107-14).

METHODS:Women, stratified by performance status (0-1 versus 2) and platinum sensitivity (platinum-free interval [PFI]<6 versus ≥ 6 months), were randomly assigned to receive PLD 30 mg/m(2) IV followed by a 3-h infusion of trabectedin 1.1mg/m(2) every 3 weeks or PLD 50mg/m(2) every 4 weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred.

RESULTS:After a median follow-up of 47.4 months, there were 522 deaths among 672 subjects. The median OS for trabectedin+PLD and PLD arms was 22.2 and 18.9 months, respectively (hazard ratio [HR]=0.86; 95% confidence interval [CI]: 0.72-1.02; p=0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD=13.3 months, trabectedin+PLD=10.6 months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin+PLD arm (HR=0.82; 95%CI: 0.69-0.98; p=0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6-12 months had the largest difference in OS (HR=0.64; 95%CI: 0.47-0.86; p=0.0027).

CONCLUSIONS:The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS.

9. Patient-reported outcomes in relapsed ovarian cancer: results from a randomized Phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD alone.

Gynecol Oncol. 2012 Oct;127(1):161-7. doi: 10.1016/j.ygyno.2012.06.034. Epub 2012 Jul 2.

Krasner CN, Poveda A, Herzog TJ, Vermorken JB, Kaye SB, Nieto A, Claret PL, Park YC, Parekh T, Monk BJ.

OBJECTIVE:Trabectedin in combination with PLD improves progression-free survival (PFS) and overall response rate (ORR) in comparison to PLD alone in patients with relapsed ovarian cancer (J Clin Oncol; 2010 28:3107-14). Here we report the impact of the treatment combination on patient-reported functional status and symptoms.

METHODS:Patient-reported outcome (PRO) questionnaires, EORTC-QLQ C30, OV28, and EQ-5D were completed by patients at screening and on Day 1 of every other treatment cycle starting with Cycle 1, and at the end-of-treatment visit.

RESULTS:Of the 672 patients randomized in this study, 663 treated patients completed at least one of the baseline questionnaires. Median cycles of treatment was 6 (131 days) for the combination arm and 5 (143 days) for the monotherapy arm. Longitudinal data analyses showed no significant differences between the treatment arms for any of the pre-specified scales. Similar analyses of other scales, including Health Index scores and Health State on the Visual Analog Scale, support these findings. Start of subsequent therapy was significantly delayed in the combination arm compared with the monotherapy arm (p=0.0032).

CONCLUSIONS:The addition of trabectedin to PLD led to little or no decrement in patient-reported functional status and symptoms in patients with relapsed ovarian cancer, as compared to treatment with PLD alone. The combination led to manageable and non-cumulative overall toxicity with a fewer PLD-associated adverse events, and a significant improvement in PFS and ORR compared to single agent.

10. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval.

Ann Oncol. 2011 Jan;22(1):49-58. doi: 10.1093/annonc/mdq353. Epub 2010 Jul 19.

Kaye SB, Colombo N, Monk BJ, Tjulandin S, Kong B, Roy M, Chan S, Filipczyk-Cisarz E, Hagberg H, Vergote I, Lebedinsky C, Parekh T, Santabárbara P, Park YC, Nieto A, Poveda A.

BACKGROUND:OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6-12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy.

PATIENTS AND METHODS:a detailed analysis of subsequent therapies and survival outcomes in the overall population and in the subsets according to platinum sensitivity was therefore conducted.

RESULTS:similar proportions of patients received subsequent therapy in each arm (76% versus 77%), including further platinum-based regimens (49% versus 55%). Patients in the trabectedin/PLD arm received subsequent chemotherapy at a later time (median delay 2.5 months versus PLD arm). Overall survival from subsequent platinum was significantly prolonged in the partially platinum-sensitive disease subset (hazard ratio = 0.63; P = 0.0357).

CONCLUSION:the superiority of trabectedin/PLD over single-agent PLD in OVA-301 cannot be explained by differences in the extent or nature of subsequent therapies administered to these patients. On the other hand, these exploratory analyses support the hypothesis that the enhanced survival benefits in the partially platinum-sensitive subset might be due to an extended PFI leading to longer survival with subsequent platinum.

11. Changing the Paradigm in the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer. rom Platinum Doublets to Nonplatinum Doublets and Adding Antiangiogenesis Compounds.

Int J Gynecol Cancer. 2009 Dec;19 Suppl 2:S63-7. doi: 10.1111/IGC.0b013e3181c104fa

Monk BJ1, Coleman RL.

OBJECTIVES:The optimal treatment for women with recurrent epithelial ovarian cancer is evolving. The objective of this review is to outline the transition away from platinum doublets toward nonplatinum combinations and review emerging data on antiangiogenesis therapy in this setting.

MATERIALS AND METHODS:Recently published and presented data as well as ongoing clinical trials are discussed.

RESULTS:Current clinical practice largely harmonizes with a paradigm that outlines a treatment algorithm for recurrent ovarian cancer based on the duration of platinum-free exposure. In this model, patients whose penultimate platinum compound exposure (platinum-free interval [PFI]) is longer than 6 months are generally offered a platinum agent or a platinum-containing doublet; those with a shorter interval are usually treated with a single nonplatinum agent. This is based on the simple contention that better clinical outcomes will be realized with platinum in those deemed platinum sensitive (PFI >6 months). However, it is becoming clear from various phase II and phase III clinical studies that the performance of many nonplatinum chemotherapeutic agents is also influenced by this parameter (PFI). Indeed, although definitive comparisons of nonplatinum drugs to novel cytotoxic agents are lacking, the clinical activity of these compounds might approach or exceed that of platinum agents. Although recognized by clinicians, the dichotomy that determines therapy based on PFI has not been formally accepted by the US Food and Drug Administration in all cases of drug labeling. For instance, whereas the combination of gemcitabine and carboplatin is now approved for patients with platinum-sensitive recurrent ovarian cancer, traditionally used platinum-resistant (PFI <6 months) agents such as topotecan and pegylated liposomal doxorubicin are also approved by the US Food and Drug Administration as single agents in platinum-sensitive patients. Furthermore, the nonplatinum doublet pegylated liposomal doxorubicin and trabectedin has recently documented comparable activity to platinum combinations among patients with a PFI of longer than 6 months. To that end, the most prolific developmental therapeutics arena in ovarian cancer is biologically targeted therapy, particularly angiogenesis inhibitors. Although it is unknown if the clinical activity from these new agents will respect the chemotherapy-sensitive dichotomy, it is clear that they have the potential to augment efficacy, possibly in both traditionally chemosensitive and chemoresistant phenotypes.

CONCLUSION:The term platinum sensitive should probably be replaced by chemotherapy sensitive, particularly as new nonplatinum agents and combinations are identified as active in this setting. Nonplatinum doublets are effective in treating platinum-sensitive recurrent disease, and adding antiangiogenesis agents to these combinations is a research priority.