Targeting chemoresistance: A phase II study of iadademstat (Iada) with paclitaxel (P) in extrapulmonary neuroendocrine carcinoma (epNEC) and small cell lung cancer (SCLC).

Abstract

633 Background: epNECs and SCLC are aggressive with poor prognosis where chemoresistance limits treatment benefit. Iada is an oral inhibitor of lysine-specific demethylase 1 (LSD1) via its flavin adenine dinucleotide cofactor. Preclinical data suggest LSD1 inhibition may reverse chemoresistance. We conducted an investigator-initiated, multicenter, phase II study of Iada plus P. Methods: With IRB approval, the study planned to accrue 42 pts in epNEC and SCLC cohorts. Treatment: Iada 150 μg oral (5day on/2 day off weekly) + P 80 mg/m² IV weekly in 21 day cycles. Eligible pts: metastatic/unresectable epNEC or SCLC, 1–3 prior lines, must include platinum. Primary endpoint: ORR. Secondary: G3+ toxicity, PFS, OS, clinical benefit rate (CBR), duration of response (DoR). Exploratory: cytokine/immune profiling, tumor and blood epigenomic/genomic analyses. Protocol preplanned futility analysis was at 12 pt for NEC and 16 pt for SCLC. Results: Between January 2023 and July 2024, twenty pts were enrolled into 2 cohorts, epNEC (N=10) and SCLC (N=10) with 17 evaluable; 65% males, median age 67 years. Rate of any G3+ toxicity was 64% (9 hematologic, 1 hypocalcemia were drug related). Iadademstat 150 μg initial lead-in dose was decreased to 100 μg given 5d on/2d off to reduce myelosuppression. Preliminary results for efficacy are summarized in the table. The study stopped early given low probability of reaching the threshold for no-futility after enrolling 10 pts in each cohort. Both doses reached the intended 80% LSD1 target engagement, and there were no apparent drug interactions with P. Correlative studies are underway. Conclusions: Iada 100 μg in combination with P 80 mg/m² was feasible and achieved consistent LSD1 target engagement, but efficacy was insufficient to meet the prespecified threshold. This investigator-initiated study is the first prospective clinical trial to evaluate LSD1 inhibition as a strategy to overcome chemoresistance in epNEC and SCLC, and correlative analysis will provide critical pharmacodynamic and epigenetic insights to guide future therapeutic development. Clinical trial information: NCT05420636 . Cohort N evaluable PR (n,%) SD (>6 wk) (n,%) PD (n,%) CR+PR+SD (n,%) PFS (m) OS (m) DoR (m) NEC 9/10 0 3 (33.3%) 6 (66.7%) 3/9 (33.3%) 1.6 4.4 2.07 SCLC 8 / 10 1 (12.5%) 2 (25%) 5 (62.5%) 3/8 (37.5%) 1.3 8.4 3.15