PM01183 . We Analyzed the Effect of Lurbinectedin on Several Human Cancer Cell Lines Including Lung (A549), Ewing Sarcoma (A673), Colon (HCT-116, HT-29), Breast (MCF7, MDA-MB-231), Cervix (HeLa), and Pancreas (PSN-1) ...

October 2016 // Molecular Cancer Therapeutics /// 2016 American Association for Cancer Research.


*.- PM01183 ( Lurbinectedin ) Targets DNA to Arrest Cancer Cell Growth .

*.- Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells .

Gema Santamaría Nu~nez, Carlos Mario Genes Robles, Christophe Giraudon, Juan Fernando Martínez-Leal, Emmanuel Compe, Fr ed eric Coin, Pablo Aviles,
Carlos María Galmarini1, and Jean-Marc Egly .

ABSTRACT :

We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts.

This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis.

The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair.

Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism.

...

Mol Cancer Ther; 15(10); 1–14. 2016 AACR.

PharmaMar está Presente en el 16º Congreso de la Sociedad Internacional de Cáncer Ginecológico " Con Nueva Evidencia Clínica con Yondelis® " .

PharmaMar is present at the 16th International Gynecologic Cancer Society Meeting with new evidence on Yondelis® .



Madrid, 31 de octubre de 2016.- 

PharmaMar (MSE:PHM) presenta los datos obtenidos en varios estudios clínicos llevados a cabo con su compuesto antitumoral
de origen marino Yondelis®, durante el 16º congreso bienal de la Sociedad Internacional de Cáncer Ginecológico (IGCS, por sus siglas en inglés), que se celebra del 29 al 31 de octubre en Lisboa (Portugal).

A través de varias presentaciones, PharmaMar pone de relieve el papel de Trabectedina en el manejo de los pacientes con cáncer de ovario platino-sensible.

Entre otros, se presenta el análisis de supervivencia global de los tratamientos con platino frente a tratamientos sin platino tras recibir trabectedina en combinación con doxorubicina liposomal pegilada (DLP) o DLP como agente único, en pacientes con cáncer de ovario recurrente; así como un ensayo clínico de fase II que sugiere que trabectedina en combinación con bevacizumab podría ser un régimen prometedor en pacientes parcialmente sensibles a platino con cáncer de ovario ecurrente.

Además de la exposición de los resultados clínicos, la Compañía presenta un estudio de costes y supervivencia de trabectedina en combinación con DLP en segunda línea seguido de quimioterapia basada en platino, frente al esquema de mantenimiento de bevacizumab en primera línea en pacientes con alto riesgo de cáncer de ovario. Como principal conclusión se extrae que la supervivencia alcanzada con ambos es equivalente, siendo el coste del manejo con el régimen de trabectedina inferior.

Por último, PharmaMar ha organizado el simposio satélite titulado `Managing relapsed ovarian cancer in a rapidly evolving landscape´ en el que se darán cita expertos internacionales que analizarán, entre otros temas, en qué momento es conveniente tratar con platino y cuándo no; el papel de trabectedina + DLP cuando no es conveniente tratar con un nuevo platino; y tratamientos del cáncer de ovario teniendo en cuenta el consenso de Tokio 2015 de la Gynecologic Cancer Intergroup y la práctica clínica diaria.

Principales estudios presentados en IGCS 2016:

Yondelis® (trabectedina):

*.- OS analysis by treatments received after trabectedin/PLD or PLD alone in patients with recurrent ovarian cancer: Platinum vs. non- platinum (OVA-301) e-poster. Autor principal: Andrés Poveda, MD, et al. Instituto Valenciano de Oncología, Valencia, España.

*.-  Randomized, non-comparative, phase II trial of bevacizumab and trabectedin with or without carboplatin in platinum partially- sensitive recurring ovarian cancer women (IRFMN-OVA-6152 study).
Sesión oral e-poster. Autor principal: Prof. Nicoletta Colombo, PhD, et al. Instituto Europeo de Oncología, Milan, Italia.

*.-  Audit of trabectedin use in high grade serous carcinoma e-poster. Autor principal: S. Thair, MD, et al. Broomfield Hospital, Oncology, Chelmsford, Reino Unido.

*.-  Trabectedin in heavily pretreated recurrent ovarian cancer patients: 
A case-control study e-poster. 
Autor principal: Prof. P. Benedetti Panici, et al, Policlinico Umberto I - Sapienza University of Rome, Italia.

*.-  Trabectedin plus pegylated liposomal doxirubicin –at first relapse- followed by platinum based chemotherapy versus bevacizumab- based maintenance schema in first line, high-risk ovarian cancer patients: a cost-comparison study
e-poster.

 Coautores: J.M. Fernández Santos, PharmaMar, Colmenar Viejo,
Madrid; J.M. del Campo, clínica Diagonal, Barcelona, España .

Yondelis en Pacientes con Cáncer de Ovario Recurrente Fuertemente Pretratados . Un estudio caso-control realizado en China .

International Gynecologic Cancer Society Meeting ( IGCS ) Portugal del 26 al 31 Octubre 2016 .

Abstract:

TRABECTEDIN IN HEAVILY PRETREATED RECURRENT OVARIAN CANCER PATIENTS: A CASE-CONTROL STUDY .

Background and Aims: Trabectedin has been approved for recurrent ovarian cancer (ROC) treatment in combination with pegylated liposomal doxorubicin. Trabectedin was also effective and tolerable as single agent in pretreated ROC patients. The aim of our study was to analyze the safety and efficacy of single agent Trabectedin in heavily pretreated ROC patients. Methods: Patients with ROC treated with single agent Trabectedin 0,6 mg/m2 every 10 days (10dTr) at our Institution were included. Response and toxicity to treatment were evaluated according to RECIST and CTCAE criteria, respectively. We matched results with an historical group of ROC patients submitted to weekly Paclitaxel 80 mg/m2 (wP). Overall survival (OS) was analyzed. Results: From 2010 to 2015 we treated 34 ROC patients with 10dTr. Patients characteristics are presented in table 1. Comparison with 34 patients treated with wP showed no difference in clinical response (Table 2). No different hematological and non-hematological toxicities were found except for grade 3/4 thrombocitopenia and reversible AST/ALT elevation (12% versus 6% and 24% versus 3% of patients in 10dTr and wP group respectively). There were no treatment-related deaths nor cases of liver failure. Median OS of patients who received 10dTr was 11 months, compared with 5 months of wP (p=0.07). Conclusions: 10dTr seems to be a valid option in heavily pretreated ROC patients, with acceptable toxicity profile. Prospective studies investigating efficacy and quality of life are needed.

Yondelis . In high-risk patients, a TPLD-P treatment choice is as effective, whilst less costly, compared to a CBEV schema.

International Gynecologic Cancer Society Meeting ( IGCS ) Portugal del 26 al 31 Octubre 2016 .

Demostrado :  Para las mujeres en alto riesgo de recaída, una estrategia de tratamiento hecha de terapia de iniciación estándar seguido de la trabectedina más doxorrubicina liposomal pegilada y posterior quimioterapia basada en platino (TPLD-P) a la recurrencia, es decir, al menos, tan eficaz y menos costoso, en comparación con el mantenimiento basado en la quimioterapia de bevacizumab (CBEV). Abstract:

Trabectedin plus pegylated liposomal doxorubicin –at first relapse- followed by platinum based chemotherapy versus bevacizumab-based maintenance schema in first line, high-risk ovarian cancer patients .

Background and Aims: We aim to demonstrate that, for those women in high risk of relapse, a treatment strategy made of standard initiation therapy followed by trabectedin plus pegylated liposomal doxorubicin and subsequent platinum-based chemotherapy (TPLD-P) at recurrence, is, at least, as effective, and less costly, compared to chemotherapy-bevacizumab based maintenance (CBEV). Methods: Endpoints were collected from OVA-301 and ICON7 trials. Costs were considered from the Spanish and British National Healthcare System (NHS) perspective; EMA approved drug dosages used as base case. The Restricted Mean Survival Time (RMST) at 5 years was taken as measure of efficacy. Hypothesis testing is performed using ANOVA (α=0.05), and Probabilistic Sensitivity Analysis (PSA) followed. Results: RMST was 38.4 (95% CI: 37.1 – 40.0) and 39.3 (95%CI: 37.0 – 41.7) months, for the TPLD-P and the CBEV arm, respectively (p=0.336). TPLD-P treatment average costs 28,792 € (£32,319.81), CBEV reached 37,411€ (£45,375.59); according to the approved label dosage. Average costs per survived month were 1,002.64 € (95% CI: 963.07 – 1,037.43) versus 1,425.95 € (95% CI: 1,343.88 – 1,514.59) in Spain, and £841.42 (95% CI: 808.22- 870.62) versus £1,154.60 (95% CI: 1,088.14 – 1,226.37) for the UK. Finally, the ratio of required number of treatments that are needed to achieve the same clinical effect accruing same costs was found; yielding 1.42 (95% CI: 1.30 – 1.57) for Spain and 1.37 (95% CI: 1.25 – 1.52) for the UK. The subsequent PSA analysis enforced the above conclusions. Conclusions: In high-risk patients, a TPLD-P treatment choice is as effective, whilst less costly, compared to a CBEV schema.