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Authors: Poveda, A.; Vergote, I.; Tjulandin, S.; Kong, B.; Roy, M.; Chan, S.; Filipczyk-Cisarz, E.; Hagberg, H.; Kaye, S. B.; Colombo, N.; Lebedinsky, C.; Parekh, T.; Gmez, J.; Park, Y. C.; Alfaro, V.; Monk, B. J.

Source: Annals of Oncology, Volume 22, Number 1, 2011 , pp. 39-48(10)

Publisher: Oxford University Press

Abstract:

Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD) over PLD alone in relapsed ovarian cancer. The optimal management of patients with partially platinum-sensitive relapse [612 months platinum-free interval (PFI)] is unclear.

Patients and methods: Within OVA-301, we therefore now report on the outcomes for the 214 cases in this subgroup.

Results: Trabectedin/PLD resulted in a 35% risk reduction of disease progression (DP) or death [hazard ratio (HR) 0.65, 95% confidence interval (CI), 0.450.92; P 0.0152; median progression-free survival (PFS) 7.4 versus 5.5 months], and a significant 41% decrease in the risk of death (HR 0.59; 95% CI, 0.430.82; P 0.0015; median survival 23.0 versus 17.1 months). The safety of trabectedin/PLD in this subset mimicked that of the overall population. Similar proportions of patients received subsequent therapy in each arm (76% versus 77%), although patients in the trabectedin/PLD arm had a slightly lower proportion of further platinum (49% versus 55%). Importantly, patients in the trabectedin/PLD arm survived significantly longer after subsequent platinum (HR 0.63; P 0.0357; median 13.3 versus 9.8 months).

Conclusion: This hypothesis-generating analysis demonstrates that superior benefits with trabectedin/PLD in terms of PFS and survival in the overall population appear particularly enhanced in patients with partially sensitive disease (PFI 612 months).

Publication date: 2011-01-01

Sobre la base de estos Resultados, Yondelis ha sido Aprobado en Rusia , Canadá y otros 41 Paises del Mundo para el uso en Cáncer de Ovario Recurrente Platino Sensibles .

Unos Datos que la FDA no quiso entrar a valorar en 2009 ... La FDA pidio el 15 de Julio del 2009 Resultados Finales del OVA 301 , el VicePresidente de J&J dijo en esa Fecha que dichos Resultados estarian listos en un plazo de entre 18 y 24 meses ... si echamos cuentas el plazo dado por el Vicepresidente de J&J se situa entre el 15 de Enero 2011 y el 15 de Julio 2011 .

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Resumen de lo publicado hoy en el Medscape Medical News Oncology ( Posteado por FCSXXX en Zeltianos ) :

Siguen saliendo nuevos datos sobre el Famoso OVA-301, y según van investigando los Oncólogos, mejores datos van sacando. En este caso, se aportan dos nuevos datos, que avalan mejores resultados para la combinación Yondelis+PLD contra el PLD solo:

1*.- Hay un Subconjunto de Pacientes " Parcialmente " Sensibles a Platino ( lo de parcialmente es la novedad ) donde se Aumenta la PFI y la OS ( Progression Free Survival y Overall Survival ).

2*.- Y lo más importante, se han dado cuenta que la Selección de Pacientes en las dos ramas no está equilibrada, si se tiene en cuenta el tiempo que llevaban las Pacientes sin Recaer, y que favorecia mejores datos para PLD sola en este estudio. Realizando las correcciónes matématicas, el riesgo de muerte para la combinación Yondelis+PLD se reduce un 24 % en todo el Estudio, incluidas las Pacientes Refractarias ( aquellas que no responden a Platinos ).

3*.- Lo mejor de todo, las Conclusiones de los Oncologos al final del artículo:

Así, ellos explican, el uso del Agente en Epocas mas tempranas en el Cáncer Ovárico podría proporcionar los mejores efectos. Los datos de modelos Preclínicos han mostrado esto la combinación Trabectedin y Cisplatin " Produjo curas del Cáncer Ovárico Xenografts no curable con cualquier otro régimen. "

4*.- ... y lo que bien podría ser un Nuevo Uso Terapeutico :

- Una gran cantidad de datos indica que la Inflamación es importante para el crecimiento del Cáncer de Ovario y la Progresión y podemos especular que la capacidad del Yondelis para Modular los Factores Inflamatorios y Angiogénicos pueden desempeñar un papel Terapéutico", escribe el Dr. Sessa, del Hospital San Giovanni, Bellinzona, Suiza, y el Dr. D'Incalci, Istituto di Ricerche de Farmacologiche "Mario Negri" de Milán, Italia.

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El Articulo :

Trabectedin Boosts Survival in Relapsed Ovarian Cancer .
Roxanne Nelson.

December 30, 2010

— Trabectedin (Yondelis; Ortho Biotech) combined with pegylated liposomal doxorubicin (PLD) may be an effective option for patients with partially platinum-sensitive, relapsed ovarian cancer.
Trabectedin is already approved for use in platinum-sensitive relapsed ovarian cancer in many regions of the world, but not in the United States. These latest results suggest it may also work in patients who are partially platinum sensitive (with a 6 - 12-month platinum-free interval [PFI]).
The finding comes from a new analysis reported by Andres Poveda, MD, from the Instituto Valenciano de Oncologia, Valencia, Spain, and colleagues in the Annals of Oncology.
The combination of trabectedin and PLD resulted in a 35% reduced risk for disease progression or death among patients with partially platinum-sensitive relapsed disease (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.45 - 0.92; P = .0152), they report.
The median progression-free survival was 7.4 months among patients who received trabectedin/PLD compared with 5.5 months in the PLD-alone group.
A secondary, supportive analysis of progression-free survival conducted by an independent oncology review showed an HR of 0.54 (95% CI, 0.39 - 0.76), which translates to a statistically significant 46% risk reduction for disease progression or death (P = .0002).
The current study is a subset analysis of the OVA-301 study, a large, randomized trial that showed superiority of trabectedin plus PLD over PLD alone among patients with relapsed ovarian cancer who were platinum sensitive.
As previously reported by Medscape Medical News, the OVA-301 study was conducted in 672 women with recurrent ovarian cancer who had failed first-line platinum-based chemotherapy, who were randomly assigned to receive either trabectedin combined with PLD or PLD alone.
The results showed that in a subgroup of women with platinum-sensitive disease, there was a statistically significant improvement in progression-free survival — to 9.2 months for PLD plus trabectedin compared with 7.5 months for PLD alone (P = .017) — and in the overall response rate.
However, there was no improvement in progression-free survival or overall response rate in platinum-resistant patients.
On the basis of these results, trabectedin has been approved in Europe, Canada, and other regions of the world for use in platinum-sensitive recurrent ovarian cancer. However, a US Food and Drug Administration advisory committee rejected its approval in July 2009, and trabectedin remains unavailable in the United States.
Efficacy in Partially Platinum Sensitive
Although the OVA-301 study showed the superiority of trabectedin plus PLD over PLD alone in patients with platinum-sensitive disease, the optimal management of patients with partially platinum-sensitive relapse remains unclear, Dr. Poveda and colleagues comment.
Approximately one third of the patients who participated in the OVA-301 study (n = 214; 32%) had a PFI from 6 to 12 months. The effectiveness of platinum retreatment in relapsed ovarian cancer is highly correlated with the PFI, the authors explain, and point out that both preclinical and clinical data suggest that in relapses of ovarian cancer, "the artificial expansion of PFI with an intervening nonplatinum therapy may be beneficial possibly by reversing platinum resistance, which may be of particular interest to patients with partially platinum-sensitive disease."
In the current report, the authors focused on the outcomes of the subset of partially platinum-sensitive patients and on updated overall survival data (cut-off date, May 2009).
As of the updated cut-off date, 419 of the 672 patients had died (n = 215, PLD; n = 204, trabectedin/PLD). The updated survival data also show that for the entire study population, the trabectedin/PLD combination resulted in a 15% decrease in mortality risk compared with PLD alone (HR, 0.85; 95% CI, 0.70 - 1.03; P = .092).
The median overall survival was 22.4 months (95% CI, 19.4 - 25.1) in the trabectedin/PLD group compared with 19.5 months (95% CI, 17.4 - 22.1) in the PLD group.
Among the subset of partially platinum-sensitive subset of patients, combination trabectedin/PLD resulted in a significant 41% decrease in the risk for death vs PLD alone (HR, 0.59; 95% CI, 0.43 - 0.82; P = .0015). The median overall survival for this group was 23.0 months in the trabectedin/PLD group vs 17.1 months in the PLD group.
For the entire study population, a multivariate analysis showed a significantly longer survival with trabectedin/PLD after covariate adjustment for prognostic factors, with an 18% risk reduction for death (HR, 0.82; 95% CI, 0.67 - 0.99; P = .041).
The authors point out that one of the most relevant prognostic factors was PFI (P < .0001). However, because PFI was significantly unbalanced and favored the PLD group (mean PFI, 13.3 months in the PLD group vs 10.6 months in the trabectedin/PLD group; P = .009), they used a Cox proportional hazards model to compare overall survival in the 2 cohorts and adjusted it by PFI. This analysis subsequently showed a statistically significant 24% risk reduction for death (HR, 0.76; 95% CI, 0.62 - 0.92; P = .0046) for patients receiving combination therapy.
The final overall survival analysis will be conducted when the required 520 events are reached, write the authors. Until then, the current data "suggest that trabectedin in combination with PLD may prolong survival over PLD alone in the overall population of patients with relapsed ovarian cancer."
Time to Subsequent Therapy
The findings were associated with a significant delay in subsequent platinum-based therapy. In the overall OVA-301 study population, similar proportions of patients received subsequent therapy in each treatment group (77% vs 76%).
The authors also noted that the proportion of patients receiving further platinum-based regimens in the trabectedin/PLD group was slightly lower than in the PLD-alone group, at 49% vs 55% (56% vs 57%; P = .8900 in the PFI 6-12 subset).
However, for the partially platinum-sensitive subset of patients, time from randomization to subsequent platinum was significantly longer for patients receiving combination trabectedin/PLD (HR, 0.64; P = .0167; median, 9.8 vs 7.9 months).
In addition, they also experienced significantly longer survival period, counted from the initiation of subsequent platinum-based therapy (HR, 0.63; 95% CI, 0.41 - 0.97; P = .0357; median, 13.3 months for the trabectedin/PLD group vs 9.8 months in the PLD-alone group).
Can More Be Expected From Trabectedin?
In an accompanying editorial, Cristiana Sessa, MD, and Maurizio D'Incalci, MD, speculate whether "more" can be expected from trabectedin in ovarian cancer, aside from being part of an effective second-line therapy.
"A large body of data indicates that inflammation is relevant for ovarian cancer growth and progression and we can speculate that the trabectedin's ability to modulate inflammatory and angiogenic factors may play a therapeutic role," write Dr. Sessa, from San Giovanni Hospital, Bellinzona, Switzerland, and Dr. D'Incalci, from Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy.

Produced cures of ovarian cancer xenografts not curable with any other regimens.
Thus, they explain, earlier use of the agent in ovarian cancer could provide the best effects. Data from preclinical models have shown that combination trabectedin and cisplatin "produced cures of ovarian cancer xenografts not curable with any other regimens."
Efforts should be made to assess whether combining trabectedin with platinum agents is clinically feasible, the authors write. "In addition, the observed inhibitory effect on proangiogenic factors [invites us] to speculate that T could be successfully combined with antiangiogenic therapies, a hypothesis that should be urgently tested at preclinical and clinical levels."
The study was supported by Johnson & Johnson Pharmaceutical Research & Development, LLC, and PharmaMar. Several of the authors have declared financial relationships with Johnson & Johnson or PharmaMar. The editorialists made no disclosures but note that some preclinical experiments were partially supported by PharmaMar.
Ann Oncol. 2011;22:39-48.

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