Abstract 1806P
Background
Iadademstat (iada) is a potent and selective LSD1 inhibitor. In SCLC, it re-activates the NOTCH pathway resulting in the repression of the tumor driver ASCL1. In chemoresistant PDX models, iada produces robust, and in some cases, complete and durable tumor regression. In a First-in-Man Ph I study in acute leukemia, iada was safe and well tolerated, showing it is a meaningful candidate for combinations in oncology.
Methods
CLEPSIDRA (EudraCT nº 2018-000469-35) is an open-label, single-arm, multicenter Ph II study of iada in combination with platinum-etoposide (PtEt) in 2L ED-SCLC patients who are candidate to re-challenge chemotherapy and had confirmed positive expression of for iada responsive biomarkers. Patients receive 4-6 PtEt cycles followed by iada monotherapy. The study comprised a dose/regime finding phase and a second phase to assess clinical activity.
Results
14 patients were enrolled. Iada-PtEt showed high hematotoxicity despite different combination dosing schemes were evaluated, including skipping iada and/or dose reductions. Yet, no signs of liver, renal or neuronal toxicity were observed. Furthermore, patients treated with iada alone before or after chemotherapy dosing did not show any hematotoxicity (accounting for a total number of weeks dosed with iada alone > 60) confirming the excellent tolerability of iada in monotherapy. Despite the difficulties to find a favorable combo dosing scheme and the skipping of several doses, iada-CbEt resulted in a relevant clinical benefit rate (40% PR and 20% long-lasting SD in BM-positive patients with available CT-Scan) suggesting that patient stratification by biomarkers might be useful. The longest PFS was 15 months, of which 10 months as iada monotherapy during which the response continued to improve for an additional tumor reduction of 53%, leading to a final tumor reduction of 90% in this patient.
Conclusions
LSD1 inhibition is an emerging approach in personalized medicine for several tumors including ED-SCLC. Iada is a promising drug, with a favorable safety profile and with clinical benefit in SCLC, including long-lasting therapeutic efficacy in one patient. Combination of iada with non-hemotoxic agents in ED-SCLC as I/O drugs represents a future strategy of interest.
Clinical trial identification
EudraCT n° 2018-000469-35.
Editorial acknowledgement
Legal entity responsible for the study
Oryzon Genomics SA.
Funding
Oryzon Genomics SA.
Disclosure
A.F. Navarro Mendivil: Advisory/Consultancy: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy, member of the Safety Monitoring Committee of CLEPSIDRA Trial: Oryzon Genomics; Advisory/Consultancy: Astra Zeneca. S. Gutierrez, R. Bullock: Full/Part-time employment: Oryzon Genomics. C. Buesa: Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Oryzon Genomics.