27 septiembre 2018
Zepsyre ( Lurbinectedin ) Combo Induces Clinical Activity in Chemo-Sensitive SCLC .
¡PM01183 Tiene Actividad Clínica en Cáncer de Pulmón Microcítico ( SCLC ) !!. Esta actividad fue particularmente significativa en pacientes sensibles (intervalo libre de quimioterapia [CTFI]> 90 días), que indujeron una ORR del 100% (n = 11; PR, 82%; CR, 18%; IC 95%, 71,5% - 100%).
Cristie L. Kahl
Published: Wednesday, Sep 26, 2018
Lurbinectedin (Zepsyre; PM1183) plus doxorubicin demonstrated significant clinical activity as a second-line therapy for patients with small cell lung cancer (SCLC), especially when excluding refractory patients.
In particular, patients with chemotherapy-free intervals (CTFIs) of 90 days or more induced a 53% overall response rate (ORR) and PFS of 5.7 months, according to findings that were presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada.1
Lurbinectedin is an investigational agent that received FDA orphan drug designation to treat patients with SCLC in August 2018. The agent inhibits RNA polymerase II, and by blocking trans-activated transcription, it induces apoptosis.2
“In transcriptionally addicted tumors, like SCLC, [lurbinectedin] cause a detachment of transcription factors from their promoters inhibiting its transactivity,” Martin Forster, MD, medical oncologist, University College London Hospitals, and colleagues wrote.
In a multicenter, phase Ib, 3+3 dose-escalation study, investigators administered 3-mg to 5-mg full-dose lurbinectedin plus 50 mg/m2 doxorubicin, followed by dose expansion at radiotherapy dose to patients with select advanced diseases, including SCLC.
Findings of cohort A of this trial demonstrated clinical activity in the second-line setting among patients with SCLC with an objective response rate (ORR) of 67%. The partial response (PR) rate was 57% and the complete response (CR) rate was 10% (95% CI, 43%-85%). This activity was particularly significant in sensitive patients (chemotherapy-free interval [CTFI] >90 days), who induced an ORR of 100% (n = 11; PR, 82%; CR, 18%; 95% CI, 71.5%-100%).
The researchers conducted an expansion cohort with a reduced dose to improve efficacy and safety in the endometrial cancer and SCLC subgroups, which were also presented at this meeting (cohort B).
The trial included 28 patients aged <75 years with an ECOG performance score of 0 or 1 and with no more than 1 prior chemotherapy line and stable brain metastases who were treated with 2 mg/m2 lurbinectedin plus 40 mg/m2doxorubicin on day 1 of each cycle every 3 weeks. Patients continued on 4 mg/m2lurbinectedin after the doxorubicin cumulative dose of 450 mg/m2 was reached.
The majority of patients were male (75%), with a median age of 64 years (49-77). In addition, 68% had an ECOG performance score of 1, 4% had central nervous system (CNS) involvement, and 75% has bulky disease (>50 mm).
Median CTFI was 3.4 months (0-15.9), of which 36% were resistant (CTFI <90 days), and 64% were sensitive (CTFI >90 days). Median time to progression to the first-line platinum-based combination was 6.8 months (1.4-18.9).
The overall ORR was 37%—11% in resistant patients (n = 9) and 50% in the sensitive cohort (n = 18). When patients with CTFI <30 days were excluded, overall ORR was 48%, 33% in resistant patients (n = 3) and 50% in sensitive patients (n = 18).
Overall median progression-free survival (PFS) was 3.4 months (95% CI, 2-6), 1.5 months in the resistant cohort (95% CI, 1-5), and 5.7 months in the sensitive cohort (95% CI, 3-8). Overall 6-month PFS was 37% (95% CI, 19-55), 11.1% in resistant patients (95% CI, 0%-32%) and 50% in sensitive patients (95% CI, 27%-73%).
When the investigators excluded patients with CTFI <30 days, median PFS in the overall population improved to 5.3 months (95% CI, 2-7), and to 1.9 months (95% CI, 1-6) in the resistant cohort. Similarly, 6-month PFS improved to 47.6% in the entire cohort, and to 33.3% in resistant patients (95% CI, 0%-87%).
Overall median OS was 7.9 months (95% CI, 5-12), 4.9 months in resistant patients (95% CI, 2-7), and 11.5 months in sensitive patients (95% CI, 6-17). Moreover, overall 6- and 12-month OS rates were 59.2% (95% CI, 40%-79%) and 22.4% (95% CI, 4%-41%), respectively, 33% (95% CI, 3%-64%) and 0% (95% CI, 0%-0%) in resistant patients, and 75.4% (95% CI, 54%-97%) and 33.9% (96% CI, 8%-60%) in sensitive patients.
Excluding patients with CTFI <30 days, overall OS was 10.2 months (95% CI, 6-12), 6.7 months in resistant patients (95% CI, 5-8) and 11.5 months in sensitive patients (95% CI, 6-17). Overall 6- and 12-month OS was 73.6% (95% CI, 54%-95%) and 27.8% (95% CI, 5%-50%), respectively, 66.7% (95% CI, 13%-100%) and 0% (95 CI, 0%-0%) in the resistant group, and 75.4% (95% CI, 54%-96%) and 33.9% (95% CI, 8%-60%) in the sensitive group.
“OS shows a remarkable improvement in this second-line setting, especially when excluding refractory patients,” the researchers wrote.
The most common grade 4 adverse events (AEs) included neutropenia (68%), thrombocytopenia (11%), febrile neutropenia (7%), and aspartate aminotransferase (4%).
“Main hematological toxicity was myelosuppression, (which was) well-managed with (granulocyte colony-stimulating factor) and dose reductions,” the researchers added.
Cristie L. Kahl
Published: Wednesday, Sep 26, 2018
Martin David Forster, MD, PhD
In particular, patients with chemotherapy-free intervals (CTFIs) of 90 days or more induced a 53% overall response rate (ORR) and PFS of 5.7 months, according to findings that were presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada.1
Lurbinectedin is an investigational agent that received FDA orphan drug designation to treat patients with SCLC in August 2018. The agent inhibits RNA polymerase II, and by blocking trans-activated transcription, it induces apoptosis.2
“In transcriptionally addicted tumors, like SCLC, [lurbinectedin] cause a detachment of transcription factors from their promoters inhibiting its transactivity,” Martin Forster, MD, medical oncologist, University College London Hospitals, and colleagues wrote.
In a multicenter, phase Ib, 3+3 dose-escalation study, investigators administered 3-mg to 5-mg full-dose lurbinectedin plus 50 mg/m2 doxorubicin, followed by dose expansion at radiotherapy dose to patients with select advanced diseases, including SCLC.
Findings of cohort A of this trial demonstrated clinical activity in the second-line setting among patients with SCLC with an objective response rate (ORR) of 67%. The partial response (PR) rate was 57% and the complete response (CR) rate was 10% (95% CI, 43%-85%). This activity was particularly significant in sensitive patients (chemotherapy-free interval [CTFI] >90 days), who induced an ORR of 100% (n = 11; PR, 82%; CR, 18%; 95% CI, 71.5%-100%).
The researchers conducted an expansion cohort with a reduced dose to improve efficacy and safety in the endometrial cancer and SCLC subgroups, which were also presented at this meeting (cohort B).
The trial included 28 patients aged <75 years with an ECOG performance score of 0 or 1 and with no more than 1 prior chemotherapy line and stable brain metastases who were treated with 2 mg/m2 lurbinectedin plus 40 mg/m2doxorubicin on day 1 of each cycle every 3 weeks. Patients continued on 4 mg/m2lurbinectedin after the doxorubicin cumulative dose of 450 mg/m2 was reached.
The majority of patients were male (75%), with a median age of 64 years (49-77). In addition, 68% had an ECOG performance score of 1, 4% had central nervous system (CNS) involvement, and 75% has bulky disease (>50 mm).
Median CTFI was 3.4 months (0-15.9), of which 36% were resistant (CTFI <90 days), and 64% were sensitive (CTFI >90 days). Median time to progression to the first-line platinum-based combination was 6.8 months (1.4-18.9).
The overall ORR was 37%—11% in resistant patients (n = 9) and 50% in the sensitive cohort (n = 18). When patients with CTFI <30 days were excluded, overall ORR was 48%, 33% in resistant patients (n = 3) and 50% in sensitive patients (n = 18).
Overall median progression-free survival (PFS) was 3.4 months (95% CI, 2-6), 1.5 months in the resistant cohort (95% CI, 1-5), and 5.7 months in the sensitive cohort (95% CI, 3-8). Overall 6-month PFS was 37% (95% CI, 19-55), 11.1% in resistant patients (95% CI, 0%-32%) and 50% in sensitive patients (95% CI, 27%-73%).
When the investigators excluded patients with CTFI <30 days, median PFS in the overall population improved to 5.3 months (95% CI, 2-7), and to 1.9 months (95% CI, 1-6) in the resistant cohort. Similarly, 6-month PFS improved to 47.6% in the entire cohort, and to 33.3% in resistant patients (95% CI, 0%-87%).
Overall median OS was 7.9 months (95% CI, 5-12), 4.9 months in resistant patients (95% CI, 2-7), and 11.5 months in sensitive patients (95% CI, 6-17). Moreover, overall 6- and 12-month OS rates were 59.2% (95% CI, 40%-79%) and 22.4% (95% CI, 4%-41%), respectively, 33% (95% CI, 3%-64%) and 0% (95% CI, 0%-0%) in resistant patients, and 75.4% (95% CI, 54%-97%) and 33.9% (96% CI, 8%-60%) in sensitive patients.
Excluding patients with CTFI <30 days, overall OS was 10.2 months (95% CI, 6-12), 6.7 months in resistant patients (95% CI, 5-8) and 11.5 months in sensitive patients (95% CI, 6-17). Overall 6- and 12-month OS was 73.6% (95% CI, 54%-95%) and 27.8% (95% CI, 5%-50%), respectively, 66.7% (95% CI, 13%-100%) and 0% (95 CI, 0%-0%) in the resistant group, and 75.4% (95% CI, 54%-96%) and 33.9% (95% CI, 8%-60%) in the sensitive group.
“OS shows a remarkable improvement in this second-line setting, especially when excluding refractory patients,” the researchers wrote.
The most common grade 4 adverse events (AEs) included neutropenia (68%), thrombocytopenia (11%), febrile neutropenia (7%), and aspartate aminotransferase (4%).
“Main hematological toxicity was myelosuppression, (which was) well-managed with (granulocyte colony-stimulating factor) and dose reductions,” the researchers added.
Cáncer de Pulmón No Microcítico (CPNM) en Estadio III . La Comisión Europea aprueba Imfinzi (durvalumab), la primera inmunoterapia en demostrar un beneficio significativo en la supervivencia global en CPNM estadio III irresecable .
Durvalumab redujo el riesgo de muerte cerca de un tercio en comparación con el tratamiento estándar en el ensayo Fase III PACIFIC, según los últimos datos presentados en el WCLC de Toronto .
Datos actualizados reafirman una mejora sin precedentes en la supervivencia libre de progresión superior a 11 meses.
Madrid, 26 de septiembre de 2018.
AstraZeneca y MedImmune, su división global de investigación y desarrollo de biológicos, han anunciado que la Comisión Europea ha concedido la autorización de comercialización de Imfinzi (durvalumab) para el tratamiento del cáncer de pulmón no microcítico (CPNM) estadio III irresecable en adultos con tumores que expresen PD-L1 en ?1% de las células tumorales y que no hayan progresado después de haber recibido un tratamiento de quimiorradioterapia (QRT) basada en platino. La aprobación se basa en los resultados del ensayo Fase III PACIFIC. Durvalumab es la primera inmunoterapia en demostrar un beneficio significativo en la supervivencia global para este tipo de pacientes.
Los resultados del estudio Fase III PACIFIC han sido presentados durante el 19º Congreso Mundial de Cáncer de Pulmón (WCLC, por sus siglas en inglés) organizado por la Asociación Internacional para el Estudio del Cáncer de Pulmón (IASCL, por sus siglas en inglés) en Toronto. Además, estos datos se han publicado simultáneamente en la revista New England Journal of Medicine, y entre los autores se encuentran tres investigadores españoles. Los resultados muestran que durvalumab mejoró significativamente la supervivencia global (SG), la segunda variable primaria del ensayo, en comparación con el tratamiento estándar, con independencia de la expresión de PD-L1, reduciendo el riesgo de muerte en un 32% (HR 0,68; 99,73% IC 0,47-0,997; p=0,0025).
El Dr. Luis Paz-Ares, co-investigador principal del estudio PACIFIC, del Hospital Universitario 12 de Octubre de Madrid, ha indicado que “el cáncer de pulmón es la principal causa de muerte por cáncer en Europa y aproximadamente un tercio de los pacientes con CPNM presentan la enfermedad en estadio III. Durante décadas, el tratamiento estándar ha sido quimioterapia con radioterapia seguida de vigilancia activa, después de lo cual la mayoría de los pacientes progresan a enfermedad avanzada. Durvalumab ha demostrado un contundente beneficio en la supervivencia para estos pacientes en un área con una significativa necesidad no cubierta”. ...