FDA Grants Fast Track Status to Tulmimetostat for Endometrial Cancer

FDA

The FDA has granted fast track designation to tulmimetostat (CPI-0209) for use as a potential therapeutic option in patients with advanced, recurrent, or metastatic endometrial cancer harboring ARID1A mutations and whose disease had progressed on at least 1 prior line of therapy.¹

The second-generation EZH2/EZH1 inhibitor was designed to achieve comprehensive target coverage through extended on-target residence time, according to MorphoSys AG.² It is known that EZH2 serves as an epigenetic writer that places methyl groups on a histone protein, which results in gene expression suppression. Cancers that depend on an irregular pattern of gene expression and redirect EZH2 to genes that become abnormally repressed are likely to be more resistant to treatment.

The designation was supported by preclinical data, which have showcased that tulmimetostat had stronger antitumor activity than other first-generation EZH2 inhibitors spanning several cancer types,^1,2 and early clinical data from an ongoing phase 1/2 trial (NCT04104776).³

“Receiving fast track designation from the FDA for tulmimetostat in ARID1A-mutated endometrial cancer underscores this investigational therapy’s potential in a patient population with limited treatment options,” Tim Demuth, MD, PhD, chief research and development officer at MorphoSys, stated in a press release.¹ “The preliminary results from our phase 1/2 study of tulmimetostat are very promising. We will continue to generate data from this study across tumor types to inform our future development plans for tulmimetostat, both as a monotherapy and in combination with other treatments.”

The first-in-human, open-label trial enrolled patients with advanced solid tumors and lymphomas that has progressed on applicable previous lines of therapy.^3,4 Patients needed to have a life expectancy of 12 weeks or more, an ECOG performance status of 0 or 1, and acceptable bone, renal, and liver function.³

Patients were divided into 6 disease-specific cohorts: those with other ARID1A-mutant solid tumors (M1), those with ARID1A-mutant ovarian clear cell carcinoma (M2), those with ARID1A-mutant endometrial carcinoma (M3), those with lymphoma (M4), those with pleural or peritoneal mesothelioma and BAP1 loss (M5), and those with metastatic castration-resistant prostate cancer (M6).⁴

In the dose-escalation phase, tulmimetostat was evaluated at 5 dose levels. Phase 1 findings supported a recommended phase 2 dose of 350 mg once daily. The Simon 2-stage design requires 1 objective response in stage 1 (n = 10) for expansion to the second stage of the trial (+ n = 19), which includes all cohorts except M4.

The primary end point of phase 2 is objective response rate per investigator assessment and key secondary end points include progression-free survival, time to progression, duration of response, time to response, disease control rate, overall survival, safety, and changes in laboratory values with regard to pharmacokinetics and pharmacodynamics.

At a data cutoff date of February 14, 2023, 81 patients had received at least 1 dose of the agent (safety population) and 75 underwent at least 1 post-baseline response assessment or had discontinued treatment before their first post-baseline assessment (efficacy-evaluable population). All cohorts completed enrollment to the first stage of the trial.

In the overall safety analysis set, the median age was 65 years (range, 34-88) and the median time since diagnosis was 2.8 years (range, 0-19.6). Most patients had an ECOG performance status of 1 (66.7%). Regarding prior lines of treatment, 13.6% had 1 prior line, 32.1% had 2 prior lines, 49.4% had 3 or more prior lines, and 4.9% were not defined. The median duration of treatment was 57 days (range, 2-438).

Three of the 5 cohorts that utilized the Simon 2-stage design achieved eligibility for stage 2 expansion: M2, M3, and M5. In the 14 efficacy-evaluable patients who comprised M2, 4 had a partial response (PR) as their best response (confirmed or unconfirmed) and 4 had stable disease (SD). Six patients experienced disease progression. In the M3 cohort (n = 8), 2 patients achieved a complete response (CR) as their best response and 1 had SD. Two experienced disease progression, 1 was not evaluable for response, and 1 discontinued treatment. In M5 (n = 21), 3 patients had a PR as their best response and 10 had SD. Six patients experienced disease progression and 2 discontinued treatment.

In M1 (n = 10), 1 patient achieved an unconfirmed PR and 3 had SD; 2 had disease progression and 4 discontinued treatment. In M4 (n = 12), which utilized a single-stage enrollment, 2 patients had a CR as their best response, and 1 patient experienced a PR. In this group, 4 experienced progressive disease and 5 discontinued treatment. In M6 (n = 10), 6 patients had a best response of SD, 3 had disease progression, and 1 discontinued treatment; this cohort will not move to stage 2.

Regarding safety, 98.8% of evaluable patients experienced at least 1 treatment-emergent adverse effect (TEAE), with 37% experiencing at least 1 serious TEAE and 65.4% experiencing at least 1 grade 3 or higher TEAE. Notably, 91.4% of TEAEs were considered to potentially be related to the study treatment.

The most common TEAEs that were considered to potentially be related to tulmimetostat included thrombocytopenia (any grade, 50.6%; grade ≥3, 24.7%), diarrhea (45.7%; 11.1%), anemia (35.8%; 14.8%), nausea (33.3%; 1.2%), fatigue (32.1%; 0%), alopecia (27.2%; 1.2%), dysgeusia (24.7%; 0%), vomiting (22.2%; 1.2%), reduced appetite (14.8%; 1.2%), neutropenia (16%; 13.6%), and weight decrease (12.3%; 0%).

Moreover, 77.8% of patients had TEAEs that resulted in dose modifications, 38.3% had TEAEs that required dose reductions, and 70.4% had AEs that needed dose interruptions. A total 11.1% of patients discontinued treatment and 17.3% experienced TEAEs that resulted in study discontinuation. Notably, 6.2% of discontinuations were potentially related to the study drug. Five patients died from TEAEs although none were determined to be related to tulmimetostat.

References

1. MorphoSys receives US FDA fast track designation for tulmimetostat in endometrial cancer. News release. MorphoSys AG. September 12, 2023. Accessed September 13, 2023. https://www.morphosys.com/en/news/morphosys-receives-us-fda-fast-track-designation-tulmimetostat-endometrial-cancer
2. Tulmimetostat. MorphoSys AG website. Accessed September 13, 2023. https://www.morphosys.com/en/our-pipeline/tulmimetostat
3. A study of CPI-0209 in patients with advanced solid tumors and lymphomas. ClinicalTrials.gov. Updated October 16, 2022. Accessed September 13, 2023. https://clinicaltrials.gov/study/NCT04104776
4. Drescher C, Walter HS, Gastinne T, et al. EZH2/EZH1 inhibitor tulmimetostat (CPI-0209) in patients with advanced solid tumors or hematologic malignancies: preliminary phase II results. J Clin Oncol. 2023;41(suppl 16):3094. doi:10.1200/JCO.2023.41.16_suppl.3094