Trotabresib Plus CRT Fails to Improve PFS in Newly Diagnosed Glioblastoma

At the 2026 European Society for Medical Oncology (ESMO) Congress, results from a randomized phase 2 trial (NCT04324840) demonstrated that adding trotabresib (CC-90010) to postoperative chemoradiotherapy did not improve progression-free survival (PFS) in patients with newly diagnosed IDH wild-type glioblastoma. The experimental regimen was evaluated against temozolomide plus radiotherapy alone. The findings were presented by Angelo Dipasquale, MD, a medical oncologist in the division of neuro-oncology and early-phase clinical trials at IRCCS Humanitas Research Hospital in Milan, Italy.

What did the trial show for PFS and OS?

With a median follow-up of 15.9 months (IQR, 13.8-20.0), among 184 patients, median PFS was 7.9 months (95% CI, 6.5-8.6) with trotabresib vs 8.2 months (95% CI, 7.2-16.4) with radiotherapy and temozolomide alone (log-rank P = .048). The 12-month PFS rate was 22.2% vs 38.9%, respectively. Median overall survival (OS) was 16.9 months (95% CI, 13.9-not estimable [NE]) vs 16.7 months (95% CI, 13.3-NE; log-rank P = .898).

In subgroup analyses of PFS, HRs favored the control arm among patients with MGMT-methylated tumors (HR, 2.24; 95% CI, 1.02-4.92; P = .045) and those with complete resection (HR, 1.95; 95% CI, 1.09-3.50; P = .025). No significant OS differences were seen in subgroups.

How did safety and dose modifications compare?

In the safety population, grade 3 or 4 thrombocytopenia occurred in 37.0% of patients in the trotabresib arm vs 15.3% of the control arm, and grade 3 or 4 neutropenia in 16.8% vs 8.5%. Treatment reductions occurred in 43.7% vs 18.6% (OR, 3.39; 95% CI, 1.64-7.02; P = .001), and interruptions occurred in 49.6% vs 28.8% (OR, 2.43; 95% CI, 1.25-4.74; P = .009). Treatment withdrawal was similar across arms (5.9% vs 5.1%; OR, 1.17; 95% CI, 0.29-4.72; P = .99).

Dipasquale concluded that the “late PFS curve separation suggested different therapy exposure” because of more dose interruptions and reductions with trotabresib. He said safety and dose optimization in early-phase glioblastoma trials should be explored beyond conventional dose-limiting toxicity assessment.

What was the design of the phase 2 trial?

The trial enrolled patients with newly diagnosed glioblastoma after complete or partial resection who had a Karnofsky performance status of 70 or higher, dexamethasone use of 3 mg or less, and eligibility for standard care. Patients were randomly assigned 2:1 to either the experimental arm or the control arm, stratified by extent of resection and MGMT status. Median age was 55 years (range, 20-75), 64.1% were male, and 66.8% had MGMT-unmethylated tumors.

In arm A, patients received trotabresib 30 mg once daily on days 1 to 4 with radiotherapy and temozolomide for 6 weeks, followed by a 4-week break. Adjuvant therapy consisted of trotabresib 30 mg daily on days 1 to 4 with 6 cycles of maintenance temozolomide, then trotabresib 45 mg monotherapy. In arm B, patients received radiotherapy and temozolomide, 6 cycles of maintenance temozolomide, and best supportive care. Primary end points were PFS by investigator assessment in the intention-to-treat population and safety; OS was a secondary end point.

What is trotabresib and how does it work in glioblastoma treatment?

Trotabresib is an oral BET (bromodomain and extraterminal) inhibitor that has demonstrated blood-brain barrier penetration and target engagement in gliomas. In part A of the phase 1/2 study, trotabresib with radiotherapy and temozolomide had a manageable safety profile and a 6-month PFS rate of 69.2% in newly diagnosed glioblastoma. The investigators noted that standard treatment, maximal safe resection followed by temozolomide-based chemoradiotherapy, has seen limited innovation over the past 20 years.

References

Dipasquale A, Sepulveda Sanchez JM, Lombardi G, et al. Randomized phase II trial investigating addition of trotabresib (CC-90010) to radiotherapy and temozolomide in patients with newly diagnosed IDH wild-type glioblastoma. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 692O.