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Verticillins are epipolythiodioxopiperazine alkaloids isolated from a fungus with nanomolar anti-tumor activity in high-grade serous ovarian cancer (HGSOC). HGSOC is the fifth leading cause of death in women, and natural products continue to be an inspiration for new drug entities to help tackle chemoresistance. Verticillin D was recently found in a new fungal strain and compared to verticillin A. Both compounds exhibited nanomolar cytotoxic activity against OVCAR4 and OVCAR8 HGSOC cell lines, significantly reduced 2D foci and 3D spheroids, and induced apoptosis. In addition, verticillin A and verticillin D reduced tumor burden in vivo using OVCAR8 xenografts in the peritoneal space as a model. Unfortunately, mice treated with verticillin D displayed signs of liver toxicity. Tolerability studies to optimize verticillin A formulation for in vivo delivery were performed and compared to a semi-synthetic succinate version of verticillin A to monitor bioavailability in athymic nude females. Formulation of verticillins achieved tolerable drug delivery. Thus, formulation studies are effective at improving tolerability and demonstrating efficacy for verticillins.

Background: In 2014, UNICANCER, composed of 18 French Comprehensive Cancer Centers, launched the Epidemiological Strategy and Medical Economics (ESME) program to investigate real-world data in oncology. Real-world data give the opportunity to assess the activity of specific products outside the framework of clinical trials. Oral vinorelbine (OV) is one of the therapeutic options available for metastatic breast cancer (mBC). Few data are available regarding its real clinical efficiency in current practice. We aimed at evaluating such activity within the ESME population. Methods: The ESME-mBC database was built from information systems, treatment databases and patients' electronic files, with homogenous on-site collected information and high-level quality-control (Delaloge et al, Ann. Oncol 2016 (in press)). All patients having started a systemic treatment for mBC in a cancer center participating in the ESME program between 01-Jan-2008 and 31-Dec-2013 have been selected into the database. For the purpose of the current analyses, data cut-off was July, 2015 and all patients who received OV at any time during the course of their disease were selected and analyzed. Primary end point was progression-free survival (PFS) from initiation of OV. Secondary end points were descriptive and prognostic analyses, and overall survival (OS). Results: Among 13.853 patients recorded in the ESME-mBC database, 1402 received OV as a monotherapy or in combination (809 and 593 patients / 57.7% and 42.3% respectively). Most frequent combinations were with capecitabine (368 patients) and anti-HER2 therapy (165 patients). De-novo mBC was observed in 282 patients (20.1%) and 569 patients (40.6%) had only non-visceral metastases. At metastatic diagnosis, 221 patients (16.9%) had HER2-positive and 298 patients (22.9%) triple-negative tumors respectively. At OV initiation, median age was 59.0 [IC95%: 50-67] years. Endocrine therapy was given prior OV in 769 patients (54.9%). For PFS analysis, 1345 patients were evaluable. The following table summarizes PFS results according to the treatment patterns and the OV-line. PFS results according to the treatment patterns and the OV-line  OV-line  1st line2nd line3rd line4th line and moreOverall populationN320414313270Overall populationPFS (months, [IC95%])4.7 [4.2-5.5]3.3 [3.0-3.5]2.9 [2.6-3.2]2.3 [2.1-2.4]OV monotherapyN118223207202OV monotherapyPFS (months, [IC95%])4.3 [3.1-5.3]3.2 [2.9-3.5]2.8 [2.5-3.2]2.2 [2.0-2.4]OV in combination with capecitabineN1531294925OV in combination with capecitabinePFS (months, [IC95%])5.1 [3.9-6.1]3.5 [2.8-4.6]3.0 [2.4-4.7]2.0 [1.4-5.2]OV in combination with anti-HER2N41503826OV in combination with anti-HER2PFS (months, [IC95%])6.0 [4.1-7.9]3.1 [2.4-3.8]3.3 [2.4-6.0]2.7 [1.9-3.7] Following diagnosis of mBC, median OS was 38.2 months [IC95%: 36.1-40.0] in the cohort of patients who received OV at any time. Conclusions:This study allows large scale assessment of real life benefit of OV over subsequent lines and shows that OV yields clinical benefit even in heavily pre-treated mBC patients. Citation Format: Pierre H, Mahasti S, Damien P, Nicolas M, Chritelle L, Florence D, Mony U, Lionel U, William J, Paule A, Audrey M, Claudia L, Mario C, Marie-Paule S, Marie-Ange M-R, Marianne L, Jean-Christophe E, Thierry P, Jean-Marc F, Bruno C, Anthony G, Christian C, Gaëtane S, David P. Real-life activity of oral vinorelbine in metastatic breast cancer patients in the Unicancer ESME database [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-12.