The combination of the two targeted anti-cancer drugs is unprecedented “clinically meaningful” in patients with highly malignant brain tumors with rare genetic mutations, according to a clinical trial report by researchers at the Dana-Farber Cancer Institute. Showed activity.
Combinations of drugs that blocked excessive cell proliferation signaling pathways shrank tumors by more than 50% in one-third of 45 Patience Cumbersome High-grade gliomaIncludes glioblastoma, the most aggressive brain tumor. The patient was selected for the study because the patient’s tumor had a gene mutation in the BRAF gene known as v600E. This mutation is found only in 2-3% of patients with high-grade glioma, but in up to 60% of certain types of low-grade glioma. This study included 13 patients with low-grade glioma. Nine of those patients responded objectively to treatment. Drug combination, 69% response rate.
“This is the first time I’ve targeted drag Clinical trials have shown that it works with glioblastoma, “said Dr. PatrickWen, the first author of the report. Lancet Oncology Director of the Center for Neuro-Oncology in Dana-Farber. He said that with all current chemotherapeutic treatments for glioblastoma, the response rate is less than 5%, in contrast to the 33% response rate achieved by this combination. According to Wen, the response rate was even higher in patients younger than 40 years (about 40%).
The two drugs paired in this study were dabrafenib and trametinib. Both drugs target proteins in the MAPK pathway. It is a signaling strand of protein that acts as a switch for cell proliferation, stays in the “on” position, and can cause uncontrolled proliferation and cause tumors.
Three patients showed a complete response — their tumors were no longer visible on image scans — and 12 had partial shrinkage of their tumors. Patients did not heal, but patients who responded to the drug experienced a very lasting effect. In one assessment, the median response period was 13.6 months, and in another, it was 36.9 months.
The findings are from an ongoing Phase 2 study called ROAR (Rare Oncology Agnostic Research), which has enrolled patients in 27 community and academic institutions since 2014. cancer Centers in 13 countries. This study is a so-called “basket” study that seeks to enroll patients who share common tumor characteristics (BRAF v600E mutations in this case), but patients may have a variety of cancers. The ROAR trial includes patients with thyroid and biliary tract cancer, gastrointestinal stromal tumors, hairy cell leukemia, multiple myeloma, low-grade and high-grade malignancy. Glioma Brain tumor etc. This study is designed to determine the overall response rate of dabrafenib in combination with trametinib in patients with BRAF V600E mutant cancer. BRAF proteins are growth signaling protein kinases that play a role in the regulation of MAPK signaling pathways. BRAF V600E mutations cause cancer and become uncontrollable by activating the MAPK pathway, which is composed of many proteins. Cell proliferation Development with tumor..
The drugs used in this study, dabrafenib and trametinib, are oral drugs that block some of the overactive MAPK signaling pathways. Dabrafenib inhibits the enzyme B-Raf, and trametinib inhibits molecules called MEK1 and MEK2 that are part of the MAPK pathway. They have been used in combination to treat melanoma, non-small cell lung cancer, and thyroid cancer.
Gliomas are cancers that are caused by glia, the sustentacular cells of the brain, rather than the neurons themselves in the brain.Gliomas make up about 80 percent of the total Malignant brain tumor.. Some low-grade gliomas grow slowly, while others are aggressive, high-grade gliomas, including glioblastomas that are difficult to remove and most often recur. According to the authors of the report, there have been no significant advances in the treatment of glioma in recent years, but reports of the combination of dabrafenib and trametinib, which are active in glioma, are isolated. Their report from the ROAR trial shows that the combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has historically shown resistance to treatment, including glioblastoma, which is difficult to treat. This is the first time that glioblastoma has shown remarkable activity. “”
The drug only helped patients with rare V600E mutations in their tumors, but Wen said the results were promising “because people began to think that there would never be a targeted therapy for glioblastoma.” rice field. He added that there is new evidence that there may be other targets for glioma that may be blocked by designer drugs.
Patrick Y Wen et al, BRAFV600E Mutant low-grade and high-grade glioma (ROAR) patients with dabrafenib and trametinib: multicenter, open-label, single-arm, phase 2, basket study, Lancet Oncology (2021). DOI: 10.1016 / S1470-2045 (21) 00578-7
The ROAR trial was originally designed and sponsored by GlaxoSmithKline and is now sponsored by Novartis.
Dana-Farber Cancer Institute
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Targeted drug combinations show unprecedented activity in some highly aggressive brain tumors
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