13 febrero 2022

Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study

 Received: 21 December 2021 / Revised: 8 February 2022 / Accepted: 11 February 2022 / Published: 12 February 2022

Genomic instability (GI) is a transversal phenomenon in oncology, constituting a hallmark of cancer. In gynecological malignancies, the predictive value of GI has been described and is mainly caused by alterations in the homologous recombination repair (HRR) genes, such as BRCA1/2. The POLA clinical trial constitutes an ideal substrate used to study the correlation between GI and response to combined therapy of lurbinectedin plus olaparib in solid tumors. In this context, we developed an approach based on next-generation sequencing, capable of shedding information about Copy Number Variations (CNV) as a surrogate of GI and genotyping of homologous recombination repair genes. Additionally, some algorithms used to extract GI parameters were tested and benchmarked, selecting the most informative mutational and GI features as potential predictive biomarkers for the drug combination explored in the POLA trial.

Abstract

We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1–5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. 

Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0–5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3–4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively.

 Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses. ...


PharmaMar Recuerda a la Crisis de las Puntocom . Los Títulos de Pharmamar Han Perdido Más de un 60 % Desde los Máximos Históricos de Hace Año y Ofreciendo un Gráfico Semejante a una Pirámide . Post By Finanzas .com

 Carlos Galán , Director de la Escuela de Trading de Las Rozas .

El Peligroso Dibujo de la Pirámide .


Galán aseguró sin tapujos que la cotización de la biofarmacéutica de origen gallego le recuerda “a los valores de la crisis de las puntocom con subidas espectaculares y bajadas igual de espectaculares dibujando la figura de una pirámide”.

Estoy harto de ver este tipo de gráficos y no me gustan, no me atraen como inversor y aquel inversor tradicional que quiera estar tranquilo debe huir de este tipo de valores”, sentenció Galán.

“Se crean demasiadas expectativas sobre un negocio que sí, que es muy bonito, pero que no se corresponde con la negociación”, consideró el experto.

Galán fija una resistencia en los 68,80 euros con un objetivo teórico en los 90 euros, pero ves más probable un escenario negativo por el valor dado los antecedentes .

Los Títulos de Pharmamar Llevan Varias Semanas de Lateralidad y Galan Ve el Soporte Más Relevante en los 49,80 euros “ Y Si lo Pierde con Solvencia No es Descartable Que se Pueda Ir, Perfectamente, Hasta los 20 euros Porque es Demasiado Volátil ”, Aseguró el Experto. ...

New York Times Admits Unvaxxed People Have ‘Lower Rates of Infection And Hospitalization’ Of COVID19 Than The Vaxxed .





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