Phase II dose optimization update with EZH2/EZH1 inhibitor tulmimetostat in patients with <i>ARID1A</i> -mutated ovarian clear cell carcinoma or endometrial carcinoma.

3102 Background: EZH2 inhibition antitumor activity occurs through various mechanistic pathways in multiple tumor types, including via synthetic lethality in advanced ARID1A -mutated ovarian clear cell carcinoma (OCCC) and endometrial carcinoma (EC). Oral, next-generation, dual EZH2/EZH1 inhibitor tulmimetostat is in Phase II evaluation in multiple disease cohorts (NCT04104776; Oaknin et al. ASCO 2024, ESMO 2024). We report updated efficacy and safety data from the ARID1A -mutated OCCC/EC cohorts, including dose optimization and expansion arms. Methods: Phase II Stage 1 evaluated tulmimetostat 350 mg once daily (QD). Stage 2 dose-optimization design randomizes further patients with OCCC (M2) or EC (M3) to 200 mg or 300 mg tulmimetostat QD in Stage 2a, with an efficacy gateway for each arm to open Stage 2b. Primary endpoint is objective response rate (complete response [CR] + partial response [PR]), and secondary objectives include safety. Results: As of October 15, 2024, enrollment into the M2/M3 200 mg, 300 mg, and 350 mg arms included 20/10, 21/21 and 14/11 patients, respectively. A total of 56.4% M2 and 61.9% M3 patients received ≥3 prior lines of therapy. Most responses were seen in the M2 200 mg arm and in the M3 350 mg arm (n=4 each; Table). The safety profile across arms was consistent with the EZH1/2 drug class. In M2/M3 cohorts, treatment-emergent adverse events (TEAEs) leading to dose modifications were reported in 55.0%/60.0%, 71.4%/85.7%, and 92.9%/90.9% of patients at 200 mg, 300 mg, and 350 mg, respectively. TEAEs leading to treatment discontinuation were reported in 5.0%/20.0%, 4.8%/4.8%, and 14.3%/9.1%, respectively. Serious TEAEs considered at least possibly related (TRAEs) to tulmimetostat treatment were reported in 5.0%/0%, 9.5%/14.3%, and 21.4%/27.3%, respectively. Grade ≥3 TRAEs were mainly hematologic (Table); no TRAEs leading to death were reported. Conclusions: Tulmimetostat showed an improved and acceptable safety profile in OCCC and EC at 200 mg and 300 mg doses (versus 350 mg) with promising antitumor activity, supporting further clinical investigation. Clinical trial information: NCT04104776 . Best confirmed responses and most common grade ≥3 related TEAEs. Cohort M2: OCCC M3: EC Dose, mg 200 300 350 200 300 350 Efficacy evaluable*, N 20 20 14 10 15 11 Best confirmed response † , n CRPRStable disease 0410 0210 0 17 008 115 042 Progressive diseaseNo post-baseline response assessment 51 71 60 11 71 41 Safety evaluable, N 20 21 14 10 21 11 Grade ≥3 related TEAEs ‡ , n (%) Thrombocytopenia 1 (5) 3 (14) 4 (29) 0 4 (19) 2 (18) Anemia 3 (15) 0 7 (50) 0 5 (24) 1 (9)