Tulmimetostat

Overview

Tulmimetostat (CPI-0209; DZR123) is an oral, next‑generation inhibitor of the polycomb repressive complex 2 (PRC2) catalytic subunits EZH2 and EZH1. It is being evaluated in an ongoing first‑in‑human phase 1/2 study (NCT04104776) across advanced solid tumors and lymphomas, with dose‑optimization under the FDA’s Project Optimus framework. (novartis.com)

Mechanism of action

• Target: Dual EZH2/EZH1 inhibitor that reduces H3K27me3 and reprograms PRC2‑regulated gene expression. Compared with first‑generation EZH2 inhibitors, tulmimetostat shows improved potency and prolonged target residence time, enabling durable target coverage. (aacrjournals.org)
• Rationale: Tumors with ARID1A loss-of-function and certain BAP1‑deficient contexts exhibit dependence on PRC2 activity; preclinical models of ARID1A‑mutant bladder, ovarian clear cell, and endometrial cancers showed antitumor activity, and a blood‑based pharmacodynamic gene signature correlated with drug exposure in patients. (aacrjournals.org)

Efficacy

Phase 1/2, multi‑cohort (monotherapy) preliminary findings:

• ASCO 2023 (data cutoff Nov 8, 2022; n=62 treated, n=48 efficacy‑evaluable): confirmed responses observed in multiple cohorts. Notably, in peripheral T‑cell lymphoma (PTCL), 2 complete responses (CR) and 1 partial response (PR) among 7 evaluable patients; ovarian clear cell carcinoma (OCCC, ARID1A‑mutant) 1 PR/10; endometrial carcinoma (ARID1A‑mutant) 2 PR/5; mesothelioma (BAP1‑loss) 1 PR/12. These results met stage‑expansion criteria for OCCC, endometrial carcinoma, and mesothelioma cohorts. (ascopubs.org)

• ASCO 2024 (dose‑optimization update; data cutoff Oct 15, 2023; n=117 treated, n=111 efficacy‑evaluable): continued signals of antitumor activity across cohorts while exploring lower once‑daily doses (≤350 mg). Pharmacodynamic gene‑expression changes increased with dose and plateaued at higher exposures (≈225–375 mg). (ascopubs.org)

• ESMO 2024 (OCCC, ARID1A‑mutant; data cutoff Feb 18, 2024): randomized dose‑optimization showed confirmed PRs at 200 mg (3/10; ORR 30%), 300 mg (2/10; 20%), and 350 mg (1/14; ~7%); stable disease was frequent across arms. Similar pharmacodynamic effects were seen across doses. (oncologypro.esmo.org)

The study remains ongoing and recruiting; additional cohorts include urothelial and mCRPC (with an enzalutamide combination cohort). (novartis.com)

Safety

• Phase 1 (ASCO 2021): tulmimetostat was generally well tolerated up to 275 mg once daily with no dose‑limiting toxicities observed at that time; common adverse events (mostly grade 1–2) included fatigue, diarrhea, nausea, alopecia, anemia, and thrombocytopenia. Pharmacodynamic target engagement (global H3K27me3 reduction) was observed across dose levels. (ascopubs.org)

• Phase 2 preliminary (ASCO 2023; 350 mg QD): most frequent treatment‑related adverse events (any grade/grade ≥3) were thrombocytopenia (51.6%/27.4%), diarrhea (45.2%/12.9%), nausea (37.1%/0%), anemia (30.6%/16.1%), fatigue (29.0%/0%), alopecia (25.8%/1.6%), vomiting (21.0%/0%), and neutropenia (17.7%/14.5%). Treatment‑emergent AEs led to dose modifications in 75.8%; discontinuation due to AEs in 8.1%. (ascopubs.org)

• Dose‑optimization update (ASCO 2024): safety profile consistent with EZH2‑class effects; dose modifications in 74.4%, serious AEs in 41.9%, and discontinuations due to AEs in 9.4%. Hematologic toxicities (thrombocytopenia, anemia) and diarrhea were the most common related events. (ascopubs.org)

Clinical development status

• Ongoing global phase 1/2 trial (NCT04104776) with monotherapy cohorts in ARID1A‑mutant solid tumors (urothelial/other, OCCC, endometrial), mesothelioma (BAP1‑loss), lymphoma (PTCL and EZH2‑mutant DLBCL), mCRPC, and a dose‑optimization schema for OCCC and endometrial cancer; includes an enzalutamide combination cohort in mCRPC. (novartis.com)

Further reading

• First‑in‑human phase 1 results (ASCO 2021 abstract). (ascopubs.org)
• Preliminary phase 2 results across cohorts (ASCO 2023 abstract). (ascopubs.org)
• Phase 2 dose‑optimization update (ASCO 2024 abstract). (ascopubs.org)
• OCCC randomized dose‑optimization data (ESMO 2024 poster 748P). (oncologypro.esmo.org)
• Mechanism and pharmacodynamics in preclinical and early clinical settings (peer‑reviewed, Cancer Research, 2024). (aacrjournals.org)
• Current trial listing and design overview (NCT04104776). (novartis.com)

Note: Reported clinical data are preliminary from conference abstracts and ongoing studies as of February–October 2024 cutoffs; peer‑reviewed clinical efficacy/safety publications have not yet been identified. (ascopubs.org)

Last updated: Oct 2025