El Listón sobre la última Aprobacion de la FDA para el Tratamiento de Sarcomas lo puso el Farmaco Pazopanib ( Novartis ) que consiguió la aprobación para su uso en sarcoma sobre la base de un ensayo en el que sólo mostro una mejora en PFS (pero ningún beneficio OS) los expertos del ODAC lo consideraron como beneficioso para controlar la enfermedad .
* Eribulin mejora la supervivencia ( OS ) en pacientes con liposarcoma en 2 Meses en comparacion con el Tratamiento Standar Dacarbazine .
* Sin embargo, no hubo diferencia en la supervivencia libre de progresión (PFS ) entre los dos grupos.
* El beneficio de supervivencia eribulina se observó en los pacientes que se encontraban en su tercera línea de tratamiento del sarcoma.
* Sin embargo, "el aumento de la supervivencia observada con eribulin debe sopesarse frente a la carga de efectos secundarios que los pacientes experimentaron", comentó Gary K. Schwartz, MD, jefe de la División de Hematología y Oncología en la Universidad de Columbia Medical Center, en la Ciudad de Nueva York, que es un portavoz de ASCO.
* Eribulin es más tóxico que el dacarbazina, Señala el doctor Judson . Eventos adversos emergentes del tratamiento (TEAEs) fueron más frecuentes en los pacientes tratados con eribulina que en los tratados con dacarbazina. TEAEs incluido neutropenia (44% vs 24%), pirexia (28% vs 14%), neuropatía sensorial periférica (20% vs 4%), y la alopecia (35% vs 3%). También fueron más frecuentes TEAEs de grado 3 (63% vs 53%) y de grado 4 (26% vs 20%), así como TEAEs mortales (4% vs 1%), señalaron los investigadores.
* Dr. Judson comentado que eribulina no era más activo que la dacarbazina en las medidas convencionales de eficacia, como el porcentaje de respuestas o estabilización de la enfermedad, y que no tiene ningún efecto aparente sobre el control de enfermedades .
* Además Eribulin es mucho más caro. Eribulin cuesta $ 5511 por ciclo de tratamiento, mientras que el comparador y la terapia estándar, dacarbazina, cuesta $ 78 por ciclo. Así que hay un signo de interrogación sobre su rentabilidad, dijo.
* "¿Es asequible para un aumento de 2 meses en la supervivencia sin reducción de la carga tumoral, a pesar de una toxicidad significativa?" preguntó.
* "Sin reducción del tumor o de mejor calidad de vida, Eribulin tan sólo consigue un pequeño aumento en la supervivencia ¿ significativa ?" .
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* Yondelis es el primer estudio de fase 3 de este fármaco en sarcoma, aunque el fármaco ya se sabe que es activo en el sarcoma ya que fue aprobado en Europa en 2007 y desde entonces se esta usando en los Hospitales de 78 paises .
* El estudio de fase 3, presentado por George D. Demetri, MD, director del Centro para el sarcoma y de hueso Oncología del Instituto de Cáncer Dana-Farber, en Boston, se llevó a cabo en 518 pacientes y demostró que la trabectedina había "eficacia mejorada" en comparación con dacarbazina.
* Hubo una diferencia estadísticamente significativa de la PFS (4,2 meses con trabectedina vs 1,5 meses con dacarbazina; HR = 0,55; p 0.0001 .
* Además, los resultados para el momento de postprotocol terapia muestran una diferencia significativa (6,9 meses con trabectedina vs 3,7 meses con dacarbazina; HR = 0,47; p 0,0001).
"La trabectedina ofrece una opción de tratamiento significativa para los pacientes con liposarcoma avanzado o leiomiosarcoma", concluyeron los investigadores.
* Sin embargo, este estudio no encontró mejoría en la OS (12,4 meses con trabectedina vs 12,9 meses con dacarbazina). En su análisis, el doctor Judson señaló que la mediana de OS en el grupo de dacarbazina superado los 3 meses lo que se esperaba, por lo que la falta de una diferencia es "tal vez no sea tan sorprendente." También comentó que la quimioterapia posttrial fue probablemente un factor de confusión.
* Dr. Judson felicitó a los investigadores para la realización de un estudio de fase 3 con trabectedina, y señaló que este estudio muestra el mismo beneficio que se ha visto en "cada otro ensayo con trabectedina": alrededor del 20% al 30% de los pacientes muestran un beneficio clínico prolongado .
* Desafortunadamente, no existe todavía ninguna forma de identificar qué pacientes tendrán el beneficio prolongado. "Se necesita más investigación para encontrar un biomarcador que podría identificar a estos pacientes", añadió.
* La trabectedina era "un tanto más tóxicos" que dacarbazina, el doctor Judson señaló, con pacientes que informaron más náuseas, vómitos, fatiga y diarrea.
* Debido a la trabectedina no está disponible en los Estados Unidos, no hay precio de Estados Unidos a considerar.
* Pero el doctor Judson señaló que la trabectedina se considera que es rentable en el Reino Unido; fue aprobado para el reembolso por el Instituto Nacional de Excelencia Clínica en 2010.
* Dr. Judson también comentó que un beneficio operativo es difícil demostrar de un ensayo clínico en el sarcoma, debido a que un número de fármacos se puede utilizar el protocolo puesto que pueden afectar a la supervivencia en ambos grupos del estudio. Pero en general, los medicamentos están haciendo una diferencia en la supervivencia, dijo: para los pacientes con sarcoma metastásico que no reciben tratamiento, la mediana de OS es de alrededor de 12 meses, mientras que la mediana de OS es ahora aproximadamente 20 meses para los pacientes que han recibido varios tratamientos farmacológicos .
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For the first time, a drug has been shown to improve survival in patients with liposarcoma (LPS) or leiomyosarcoma (LMS), collectively referred to as L-sarcomas.
The new result was achieved with eribulin (Halaven, Eisai Inc), which is currently approved for the treatment of advanced breast cancer. The new data are being submitted for approval of the L-sarcomas as another indication for the drug.
In a trial conducted in 452 patients, eribulin improved overall survival (OS) by 2 months compared with standard therapy, dacarbazine (DTIC-Dome, Bayer HealthCare Pharmaceuticals) (13.5 months with eribulin vs 11.5 months with dacarbazine; hazard ratio [HR], 0.768; P = .0169). However, there was no difference in progression-free survival (PFS) between the two groups.
The results were presented at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting at a session on soft-tissue sarcomas. At that session, another large phase 3 trial was presented showing that trabectedin (Yondelis, PharmaMar) improved PFS in patients with L-sarcomas, but not OS. These data on trabectedin are also to be filed for approval in the United States (the drug is currently approved for the treatment of sarcoma in Europe, Canada, and other countries).
Both trials were hailed as positive, and both will be used in approval submissions, and yet they have exactly opposite results ― eribulin improved OS but not PFS, whereas trabectedin improved PFS but not OS.
But which is clinically more meaningful? This remains an important question, said the discussant for the presentations, Ian Robert Judson, MD, from the sarcoma unit at the Royal Marsden Cancer Hospital, London, United Kingdom.
Eribulin Survival Benefit
The eribulin survival benefit was seen in patients who were on their third line of sarcoma therapy. "Patients whose disease progresses despite two or more lines of treatment have a very poor prognosis," commented lead author of the eribulin study, Patrick Schöffski, MD, MPH, head of the Department of General Medical Oncology, University Hospitals Leuven, in Belgium. "For a disease where such few treatment options exist, a 2-month improvement [as seen with eribulin] in survival is significant," he added.
However, "the survival gain seen with eribulin must be weighed against the burden of side effects patients experienced," commented Gary K. Schwartz, MD, chief of the Division of Hematology and Oncology at Columbia University Medical Center, in New York City, who is an ASCO spokesperson.
In his discussion of the paper, Dr Judson noted that the results with eribulin in sarcoma follow the same pattern that was seen with this drug in breast cancer (in the pivotal EMBRACE trial), which also showed an improvement in OS of around 2 months but also no improvement in PFS.
This contrasts with what is usually seen with drugs active against cancer, he commented ― usually they prolong PFS and are also shown to improve OS. This is the opposite, and "we don't know quite what is going on here," he said, adding that it might be due to a different mechanism of action. Eribulin acts as an inhibitor of microtubule dynamics, and it may be affecting the tumor microenvironment, he suggested. "It does look like a true biological effect," he added.
However, eribulin was more toxic than dacarbazine, Dr Judson noted. Treatment-emergent adverse events (TEAEs) were more frequent in patients treated with eribulin than in those treated with dacarbazine. TEAEs included neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%), and alopecia (35% vs 3%). Also more frequent were TEAEs of grade 3 (63% vs 53%) and grade 4 (26% vs 20%), as well as fatal TEAEs (4% vs 1%), the researchers noted.
Dr Judson commented that eribulin was not more active that dacarbazine on conventional measures of efficacy, such as percentage of responses or stable disease, and that it has no apparent effect on disease control. Previous studies have shown that effective chemotherapy improves pain and sleeplessness, but there appeared to be no effect on symptoms with eribulin.
In addition, it is very much more expensive. Eribulin costs $5511 per cycle of treatment, whereas the comparator and standard therapy, dacarbazine, costs $78 per cycle. So there is a question mark over its cost-effectiveness, he said.
"Is it affordable for a 2-month increase in survival with no reduction in tumor burden, in spite off significant toxicity?" he asked. "Without tumor shrinkage or improved quality of life, is a small increase in survival meaningful?"
Trabectedin Improvement in PFS
The trabectedin trial is the first phase 3 study of this drug in sarcoma, but the drug is already known to be active in sarcoma (it was approved in Europe in 2007 on the basis of a randomized phase 2 trial [J Clin Oncol. 2009;27:4188]).
The phase 3 study, presented by George D. Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute, in Boston, was conducted in 518 patients and showed that trabectedin had "improved efficacy" compared with dacarbazine.
There was a highly statistically significant difference in PFS (4.2 months with trabectedin vs 1.5 months with dacarbazine; HR = .55; P < .0001).
Also, the results for time to postprotocol therapy show a significant difference (6.9 months with trabectedin vs 3.7 months with dacarbazine; HR = 0.47; P < .0001).
"Trabectedin offers a meaningful treatment option for patients with advanced liposarcoma or leiomyosarcoma," the researchers concluded.
However, this trial found no improvement in OS (12.4 months with trabectedin vs 12.9 months with dacarbazine). In his discussion, Dr Judson noted that the median OS in the dacarbazine group exceeded by 3 months what had been expected, so the lack of a difference is "perhaps not so surprising." He also commented that posttrial chemotherapy was likely a confounder.
Dr Judson congratulated the researchers for conducting a phase 3 study with trabectedin, and he noted that this study shows the same benefit that has been seen in "every other trial with trabectedin": about 20% to 30% of patients show a prolonged clinical benefit.
Unfortunately, there is as yet no way of identifying which patients will have the prolonged benefit. "Further research is needed to find a biomarker that would identify these patients," he added.
Trabectedin was "somewhat more toxic" than dacarbazine, Dr Judson noted, with patients reporting more nausea, vomiting, fatigue, and diarrhea.
Because trabectedin is not available in the United States, there is no US price to consider. But Dr Judson noted that trabectedin is considered to be cost-effective in the United Kingdom; it was approved for reimbursement by the National Institute of Clinical Excellence in 2010.
Dr Judson also commented that an OS benefit is difficult to show from a clinical trial in sarcoma, because a number of drugs can be used post protocol that may affect survival in both arms of the study. But overall, the drugs are making a difference in survival, he said: for patients with metastatic sarcoma who receive no treatment, the median OS is around 12 months, whereas the median OS is now approximately 20 months for patients who have received various drug treatments.
In recent years, the targeted agent pazopanib (Votrient, Novartis Pharmaceuticals Corporation) was approved for use in sarcoma on the basis of a trial showing a PFS improvement (but no OS benefit) and is considered by experts to be of benefit in controlling the disease.