500PAre epigenetic therapies modifying sensitivity to conventional chemotherapy

Abstract Background Epigenetic therapies (epidrugs) modify cancer cells transcriptional programmes and influence all hallmarks of cancer. Thus, epidrugs have been reported to modulate sensitivity to conventional chemotherapy (CCT) preclinically. We explored whether sensitivity to CCT differed before and after epidrug therapy. Methods Patients (pts) enrolled in phase 1 trials evaluating epidrugs at the Drug Development Department (DITEP) in Gustave Roussy between March 2010 and May 2017 who received at least one CCT just before and after epidrug therapy were eligible. Progression free survival (PFS) of the CCT line before (PFSpre) and after (PFSpost) epidrug were compared using Wilcoxon signed rank in a paired data subset (uncorrected α-risk). Results 69% of the 93 eligible pts had haematological malignancies. Epidrug treatments consisted of: IDH inhibitors (IDHi) (30%), HDACi (19%), protein degradation modulators (20%), EZH2i (17%), BETi (12%) and LSD1i (2%); 52 (56%) pts derived clinical benefit (CB) from epidrugs (objective response or SD > 2 months). Median PFSpre and PFSpost were 4.2 and 3.8 months (NS), respectively; PFSpost was significantly worse for pts who did not derive CB from epidrugs (1.8 vs 5.6 months, p = 0.01), whereas significance was lost for pts who derived CB (5.1 vs 3.6 months, NS). Analysis stratified on the CCT type evidenced that PFSpost was significantly worse for pts receiving anthracyclines, topoisomerase inhibitors and alkylating agents (excluding platinum salts) (p = 0.004, p = 0.02 and p = 0.01, respectively), whereas no significant difference was observed for platinum, antimetabolites, anti-microtubule agents or antiangiogenic agents. Conclusions Epidrug therapy might modify sensitivity to certain CCT; patients who derive clinical benefit from epidrugs tend to have better PFS on CCT after epidrug treatment than patients who do not benefit from epidrugs. Further studies on larger and homogeneous series are warranted. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure P. Romano-Martin: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Jannsen; Research grant / Funding (self): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Roche. C. Baldini: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. S. Champiat: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. A. Varga: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Honoraria (self): MSD; Honoraria (self): AstraZeneca; Honoraria (self): Roche. A. Gazzah: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. R. Bahleda: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. P. Vuagnat: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. A. Hollebecque: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. J. Michot: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. V. Ribrag: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. C. Massard: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Lilly; Advisory / Consultancy: MedImmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Jannsen. S. Postel Vinay: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (self): Roche; Research grant / Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.