Regorafenib Plus Temozolomide and RT Shows Early Signs of Tolerability in MGMT-Methylated, IDH Wild-Type Glioblastoma

Regorafenib (Stivarga) in combination with temozolomide (Temodar) and radiotherapy was tolerable for the treatment of patients with MGMT-methylated, IDH wild-type glioblastoma, according to data from the phase 1 REGOMA-2 study (NCT06095375) presented during the 2025 Society of Neuro-Oncology Annual Meeting.1

In cohort A (n = 9), no patients experienced a dose-limiting toxicity (DLT) at any dose level of regorafenib. Two patients in cohort B (n = 12) who were treated at dose level 3 (n = 6) experienced a DLT, consisting of 1 instance of grade 3 hypertransaminasemia and an instance of grade 4 thrombocytopenia on the last day of radiotherapy.

“The maximum tolerated dose [MTD] of regorafenib was 160 mg in cohort A and 120 mg in cohort B, with a weak pharmacokinetic interaction between the 2 drugs,” Giuseppe Lombardi, MD, PhD, a medical oncologist at Veneto Institute of Oncology IOV-IRCCS in Padova, Italy, and his coauthors wrote in a poster presentation of the findings.

How was the REGOMA-2 trial designed?

REGOMA-2 was a dose-finding study that enrolled adult patients with MGMT-methylated, IDH wild-type glioblastoma at 2 centers in Italy.2 In order to be eligible for enrollment, patients needed to have grade IV disease, adequate laboratory values, and have recovered from the effects of surgery; patients in cohort B (concomitant therapy cohort) needed to have undergone prior tumor resection up to 7 weeks before the first dose of regorafenib. Patients in cohort A (adjuvant/maintenance therapy cohort) were required to have completed standard courses of temozolomide and chemotherapy, have MRI-documented stable disease prior to the first dose of regorafenib, a life expectancy of at least 6 months, and an ECOG performance status of 0 or 1 (or a Karnofsky performance status of at least 70).

The trial used a 3+3 design to explore regorafenib at doses of 80 mg (level 1), 120 mg (level 2), and 160 mg (level 3).1 Patients in cohort A also completed concurrent chemoradiotherapy and received regorafenib plus temozolomide for 6 to 12 cycles; at the end of the combination treatment, regorafenib monotherapy could be administered at the standard dose of 160 mg.

After the MTD was determined in the adjuvant dose-escalation cohort, cohort B examined escalating doses of regorafenib in combination with temozolomide and radiotherapy. Regorafenib was administered for a total of 2 cycles (56 days) from the beginning of the concomitant phase.

The primary end points were the incidence of DLTs, the number of patients who experienced at least 1 adverse effect (AE), and the number of patients who discontinued treatment due to an AE.2 Secondary end points included pharmacokinetic measures, best response to treatment, progression-free survival, quality of life, and overall survival.

At baseline, the median ages in cohorts A and B were 52 years and 53 years, respectively.1

What were the pharmacokinetic and additional safety data observed with the combination?

Additional findings from REGOMA-2 showed that regorafenib when given as monotherapy or in combination with temozolomide displayed a significant reduction in the area under the concentration curve (P = .038), with a geometric mean ratio of 80% (90% CI, 64%-98%) when given with temozolomide.

Further safety data revealed that 1 patient in cohort A treated at dose level 2 had regorafenib treatment delayed and their dose of temozolomide delayed due to grade 2 thrombocytopenia. One patient treated at dose level 3 had a grade 3 gastrointestinal toxicity.

In cohort B, 1 patient had grade 3 hypertension, and another experienced grade 3 hypertransaminasemia. Regorafenib was reduced in a patient due to grade 2 pain; however, this was not deemed to be a DLT. There was 1 case of grade 3 hyperbilirubinemia. There were no grade 3 to 4 AEs at dose level 1.

“The MTD of 120 mg can be considered the RP2D of regorafenib for combination with standard Stupp therapy in a phase 2 trial,” Lombardi and his coauthors wrote in their conclusion. “Preliminary activity analyses are ongoing.”

Disclosures: Lombardi listed no relevant disclosures.

References

1. Padovan M, Simonelli M, De Nicolo A, et al. A phase 1, first-in-human study of regorafenib plus temozolomide with or without radiotherapy in patients with newly diagnosed MGMT methylated, IDH wildtype glioblastoma: the REGOMA-2 trial. Presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract CTNI-04.
2. Regorafenib with temozolomide with or without RT in MGMT-methylated, IDH wild-type GBM patients (REGOMA-2). ClinicalTrials.gov. Updated December 24, 2024. Accessed November 21, 2025. https://clinicaltrials.gov/study/NCT06095375