XXIV Riunione Nazionale MITO Ginecologia Oncologica: dai geni alla terapia Cristiana Sessa Oncology Institute of Southern Switzerland Bellinzona MECCANISMI DI AZIONE INNOVATIVI DELLA TRABECTEDINA E DELL’ANALOGO LURBINECTEDINA Pisa, 4-5 Dicembre 2014

Lurbinectedin (PM01183) Preclinical data  New DNA minor groove covalent binder  In vitro / in vivo activity against a broad tumor panel  Antitumor activity in orthotopic primary grafts of cisplatin – resistant epithelial ovarian cancer (EOC)

Trabectedin Lurbinectedin (PM01183) The structural difference is in the part of the molecule that does not bind DNA but interacts with DNA binding proteins (e.g. transcription factors, proteins involved in DNA repair) Chemical structures

Ecteinascidins’ mode of action  Direct effect on cancer cells by binding in the DNA minor groove, causing DNA damage and modulating the transcription of cancer relevant genes  Indirect effect on tumor microenvironment by decreasing the number of tumor associated macrophages by inhibiting the transcription and production of cytokines (e.g. IL6, IL2) chemokines (e.g. CCL2) and angiogenic factors (e.g. VEGF, Angiopoietin 2)

Ecteinascidins and DNA repair system  Cell lines deficient in different NER proteins are less sensitive to trabectedin and lurbinectedin  Cell lines deficient in HR proteins are much more sensitive to trabectedin and lurbinectedin  Lack of correlation between in vitro and in vivo sensitivity to trabectedin and lurbinectedin Romano, IJC 2013

Pro-tumor functions of Tumor-Associated Macrophages Solinas, Jounal of Leukocyte Biology, Vol. 86, Nov. 2009

Yondelis inhibits CCL2 and IL-6 production in TAM and tumor cells from patients with ovarian cancer ©2005 by American Association for Cancer Research

Response of OVA1XR to Lurbinectedin based treatments Vidal et al, CCR 2012 * < 0.05

Antitumor activity of Lurbinectedin and Cisplatin in A-2780 derived tumor xenografts Vidal et al, CCR 2012

Lurbinectedin Phase I overview  Myelosuppression DLT at clinically relevant doses  Nausea and vomiting requiring preventive antiemetics  Combination with other cytotoxic feasible and active in properly selected patients  PK different from trabectedin: long Ty 2 β, low central volume  AUC correlated with severity of neutropenia  High interpatient variability of PK to be further investigated

Lurbinectedin (PM1183), an active compound in platinum-resistant/refractory ovarian cancer (PRROC) patients: Results of a two-stage, controlled Phase II study A. Poveda et al, Abstr ASCO, 2014

Primary endpoint: Response Rate First Stage (n=22) Second Stage (ongoing) > 2 responses (by either RECIST and/or Rustin criteria) Randomization 1:1 PM mg FD q3wk IV N= 30 pts Topotecan Standard or weekly N= 30 pts Stratified by Resistant / Refractory PM mg FD q3wk IV PM1183-B Study Design CROSSOVER Second Stage (ongoing) PM mg FD q3wk IV

Lurbinectedin in platinum resistant/refractory ovarian cancer Efficacy PM1183 (n=52) % Topotecan (n=29) % p value Best overall response (%) CR PR SD PD 1(3) 10 (20 25 (50) 15 (26) 0 (0) 0 15 (52) 14 (48) ORR (%) (95% CI)22 (11-35) Pt resistant30 (16-49)-0.02 Pt refractory5 (0-26)-1 PFS (mo) 2 nd stage OS (mo)

 PM1183 is an active drug in Pt-res/Pt-ref ovarian cancer with an objective response rate of 30%  The study has met the primary endpoint, showing a statistically significant superiority over T in terms of ORR, PFS and OS.  The safety profile is predictable and manageable  A Phase III study in Pt-res ovarian cancer is planned. Lurbinectedin in platinum resistant/refractory ovarian cancer patients Conclusions

Lurbinectedin pharmacological features  Estensive microsomal-mediated metabolism in all animal species  Clearance is higher with increasing serum albumin and lower with increasing α 1 glycoprotein  Role of concomitant medications (aprepitant)  Caution in the concomitant use of LYP2C8 and CYP3A4 substrates  Also concomitant CYP2C19 substrates must be avoided

Clinical development of Lurbinectedin in ovarian cancer Additional preclinical data needed  comparison with trabectedin ± cisplatin in ovarian xenografts  potential causes of differences from trabectedin indirect effects on tumor microenvironment indirect effects on TAM Additional clinical data needed  confirmation of the preclinical results in resistant ovarian cancer  Phase III  combination studies  population PK profile

Ongoing combination studies with Lurbinectedin in ovarian cancer  Phase I multicenter clinical and pharmacokinetic study of lurbinectedin with weekly paclitaxel ± bevacizumab in patients with selected solid tumors  Phase I multicenter clinical and pharmacokinetic study of lurbinectedin with cisplatin in patients with advanced solid tumors