A phase 3 clinical trial has shown that a regimen consisting of lomustine and temozolomide in combination with radiotherapy can improve survival for patients with previously untreated glioblastoma with MGMT promoter methylation.
Glioblastoma, the most common form of primary brain tumor, is highly aggressive and extremely deadly, with a five-year survival rate of only 5.6%. Standard treatment is radiotherapy followed by chemotherapy with temozolomide, an alkylating agent (a drug that interferes with cancer cells' DNA and therefore inhibits the tumor's growth). This treatment tends to halt tumor growth for some time, but patients often experience a return of the cancer.
Patients whose glioblastomas exhibit a methylated MGMT promoter, a distinct genetic sequence that occurs in approximately one third of glioblastoma tumors, have a stronger response to temozolomide than other patients. MGMT promoter methylation causes the MGMT gene—which creates a DNA repair protein involved in cellular defense against mutagenesis and toxicity from alkylating agents—to be read less frequently, enabling temozolomide to attack the tumor. However, temozolomide is limited in its efficacy, even in patients with MGMT promoter methylation.
Various attempts were made to combine temozolomide with other drugs in order to increase its effectiveness, all without success. This changed several years ago when researchers at University Hospital Bonn in Germany ran a pilot study combining temozolomide with lomustine.
"At the time, we found first indications that this combination might be able to significantly improve the prognosis," commented lead researcher Ulrich Herrlinger, MD, Professor in the Department of Neurology and Center for Integrated Oncology at University Hospital Bonn. "In order to confirm these results, we started a large patient trial with funding from the Federal Ministry of Education and Research. We have now been able to show that the administration of [lomustine] and [temozolomide] actually significantly prolongs the survival time of our patients… with well-tolerated side effects."
For this open-label, phase 3 trial, results of which have now been published in The Lancet, 141 adults with newly diagnosed glioblastoma with MGMT promoter methylation and a Karnofsky Performance Score of 70% or higher were randomized 1:1 to receive standard temozolomide chemoradiotherapy followed by six 4-week courses of temozolomide or to receive up to six 6-week courses of lomustine/temozolomide in addition to radiotherapy. The study's primary end point was overall survival in the modified intention-to-treat population, which consisted of the 129 patients who started their assigned chemotherapy.
In the modified intention-to-treat population, lomustine/temozolomide improved median overall survival compared with temozolomide (48.1 vs 31.4 months). A secondary analysis also showed a significant improvement in overall survival in the original intention-to-treat population of 141 patients. Lomustine/temozolomide did result in an increase in grade 3 or higher adverse events (59% for lomustine/temozolomide vs 51% for temozolomide). No treatment-related deaths occurred.
Dr. Herrlinger emphasized the importance of the lomustine/temozolomide combination for patients with MGMT promoter methylation. "This is a tailor-made therapy for this subgroup," he said. "Ultimately, this is an initial step toward personalized cancer medicine for glioblastoma patients."
For More Information
Herrlinger U, Tzaridis T, Mack F, et al (2019). Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trial. Lancet, 393(10172):678-688. DOI:10.1016/S0140-6736(18)31791-4
Image credit: KGH