Regorafenib conferred an encouraging OS benefit compared with lomustine among patients with recurrent glioblastoma, according to a randomized, open-label phase 2 study published in The Lancet Oncology.
“The standard of care for newly diagnosed glioblastoma is a maximally safe resection followed by concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide,” Giuseppe Lombardi, MD, oncologist and PhD fellow at Veneto Institute of Oncology and University of Padua, and colleagues wrote. “At recurrence, the standard of care is less well defined and efficacy is poor; in this setting, a nitrosourea regimen is an option, and lomustine (Gleostine, NextSource), a synthetic alkylating agent, has been widely used as a control in phase 2 and 3 trials in patients with recurrent glioblastoma.”
Lombardi and colleagues randomly assigned 119 patients with recurrent glioblastoma at 10 centers in Italy to receive regorafenib (Stivarga, Bayer) — a mutikinase inhibitor that interferes with the tumor vasculature — or lomustine.
Patients in the regorafenib arm (n = 59; median age, 54.8 years; 69% men) received a 160-mg dose orally once a day for the first 3 weeks of each 4-week cycle. Patients in the lomustine arm (n = 60; median age, 58.9 years; 72% men) received a 110 mg/m2 dose orally once every 6 weeks until disease progression, death, unacceptable toxicity or withdrawal of consent.
OS served as the primary endpoint.
At the time of the analysis cut-off, median follow-up was 15.4 months.
A total of 99 patients (83%) had died, including 42 (71%) in the regorafenib group and 57 (95%) in the lomustine group.
7.4 months (95% CI, 5.8-12) with regorafenib vs. 5.6 months (95% CI, 4.7-7.3) with lomustine (HR = 0.5; 95% CI, 0.33-0.75).
“The statistically significant HR of 0.5 suggests that patients receiving regorafenib had a substantial and clinically meaningful reduction in the risk [for] death compared with those treated with lomustine,” Lombardi and colleagues wrote.
Researchers reported median PFS of 2 months (95% CI, 1.9-3.6) with regorafenib vs. 1.9 months (95% CI, 1.8-2.1) with lomustine.
Researchers observed grade 3 to grade 4 treatment-related adverse events among 56% of patients in the regorafenib group, including hand-foot skin reaction, increased lipase and increased blood bilirubin in six patients each.
Grade 3 to grade 4 adverse events observed among 40% of the lomustine group included decreased platelet count (n = 8), decreased lymphocyte count (n = 8) and neutropenia (n = 7).
None of the deaths that occurred appeared to be drug related.
Limitations included the occurrence of a few potentially more favorable prognostic factors, despite randomization, among patients in the regorafenib group.
“Specifically, they were about 4 years younger, slightly more had MGMT (O-6-methylguanine-DNA methyltransferase) methylation at diagnosis, fewer used steroids at baseline, and they had longer median time between diagnosis and first recurrence compared with patients in lomustine group,” researchers wrote.
The study also did not have an independent and central neuroradiology and histopathology review.
“To our knowledge, [this trial] is the first study to assess the role of regorafenib as a monotherapy in patients with relapsed glioblastoma who had received treatment with first-line chemoradiation, with OS as the primary endpoint,” Lombardi and colleagues wrote. “This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study.”
Although the results appear to be impressive, there are caveats that need to be researched before the phase 3 trial begins, Roger Stupp, MD, of Malnati Brain Tumor Institute of Lurie Comprehensive Cancer Center at Northwestern University, wrote in an accompanying editorial.
Stupp noted that patients in previous randomized trials who received lomustine as reference treatment had median OS of 8 to 10 months, whereas patients in this trial had median OS of 5.6 months.
“There is no easy explanation for this fact,” Stupp said. “Indeed, the dose of lomustine was identical to other trials, toxicity was not excessive, and patient characteristics were similar between the two groups.”
Stupp added that trials looking at the integration of treatment into the first-line setting could be more successful.
“Patients with recurrent glioblastoma have a heterogenous and often difficult clinical course, are likely to require concomitant high doses of steroids, and drug metabolism might be altered by frequent use of antiepileptic drugs,” Stupp wrote. “Exposure to the novel agent is probably too short because patients often progress within 2 months, thus not really allowing the new drug to show efficacy.” – by John DeRosier
Disclosures: Bayer provided funding and editorial assistance for the study. Lombardi reports personal fees from Bayer outside of the submitted work. Please see the study for all other authors’ relevant financial disclosures. Stupp reports advisory board roles with AbbVie, Boehringer Ingelheim, Celgene, EMD Merck, Novartis and Roche, and travel assistance from NovoCure.