Dabrafenib + Trametinib in BRAF V600-Mutant Pediatric Low-Grade Glioma

glioma: gliomaIn a study spanning 20 countries and 58 investigative centers, an international team found that children with low-grade mutant BRAF V600 glioma experienced far greater survival and lifestyle benefits with a new oral targeted drug combination than those treated with standard-of-care chemotherapy. Results of this Phase II/III trial, presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrate the use of targeted drugs—dabrafenib twice daily plus trametinib once daily—provides a new standard therapy for children with low-grade mutant BRAF V600 glioma (Abstract LBA2002). “This study shows higher overall survival, a longer median progression-free survival, higher clinical benefit rate, a good safety profile, and manageable side effects,” said Eric Bouffet, MD, Director of Pediatric Neuro-Oncology at the Hospital for Sick Children in Toronto, who described the study during an ASCO press briefing. “Importantly, we were able to use a liquid formulation, and this is important because no child was left behind.” Melissa Hudson, MD, Director of the Cancer Survivorship Division at St. Jude Children Research Hospital in Memphis, TN, said the study's results should allow pediatric oncologists to personalize treatment of these children with targeted therapies that not only are highly effective, but also improve the quality of their long-term survival. “The current standard therapy involves cytotoxic agents that cause the need for follow-up in the clinic and are associated with health problems later in life,” said Hudson, who was asked by ASCO to provide commentary about this study. “So having availability of a targeted therapy that can be delivered orally to patients with such an excellent safety profile and early outcomes is quite exciting, as well as showing these very impressive outcomes related to objective and clinical responses.” Treatment Pathways An estimated 4,170 new cases of childhood brain tumors are expected to be diagnosed in the United States in 2022, with gliomas accounting for about half of these. As such, gliomas are the most common form of pediatric brain cancer, with 15-20 percent of childhood gliomas housing a BRAF V600 mutation. Surgical resection generally is often the first line of therapy, but the tumor's location may make it difficult to remove entirely. With residual and progressive disease, chemotherapy represents the next line of therapy, with a drug combination of carboplatin plus vincristine representing a standard used particularly for low-grade glioma. With current therapies, 5-year survival rates are about 95 percent, though most patients require multiple lines of treatment often linked to harsh side effects that affect quality of life. Further, patients with the BRAF V600 mutation generally have a poorer response to chemotherapy and are at greater risk for recurrence, thus representing an unmet need for a new regimen. Combining dabrafenib with trametinib was viewed as a possible candidate to help meet this goal. In a Phase I/II trial, dabrafenib yielded clinically meaningful outcomes as a stand-alone therapy for BRAF V600 low-grade glioma. When trametinib was combined with dabrafenib to treat adult patients with BRAF V600 melanoma in another trial, patients experienced an improved response rate with limited side effects over standard care. Dabrafenib targets the V600-mutant form of BRAF, found in several cancer types, while trametinib targets the kinase MEK within the same signaling pathway. If used in tandem, the researchers believed the drug duo would provide an effective weapon to combat BRAF V600 mutant low-grade pediatric glioma by inhibiting growth of cancer cells stemming from this genetic miscue. Study Details To test this hypothesis, children with low-grade gliomas with BRAF V600 mutations were enrolled in a Phase I/II trial to investigate the safety, tolerability, and efficacy of the target drug combination against their disease. Results of this early trial, initiated in 2014, showed promising clinical outcomes with low-grade side effects. Based on these findings, Bouffet and colleagues launched what he termed “the next logical step”: a study that would compare this targeted drug combination to treat children with low-grade BRAF V600 glioma mutations against a chemotherapeutic regimen that's been the standard of care for a few decades. This Phase III trial represents the first combination of targeted therapies developed for patients as young as 1 year of age. In all, 110 children from 20 countries ages 1-18 years were enrolled in the trial, which took place in 58 treatment sites in Europe, Asia, United States, and Australia. Eligible patients with BRAF V600 mutation, progressive disease after surgery, or non-surgical patients requiring immediate systemic treatment were randomly assigned (2:1) to receive either the experimental targeted drug combination or standard chemotherapy. Patients on the experimental drug regimen received the drug as long as clinical benefit was seen, while those on chemotherapy were on a fixed time of 14 months. Children in the chemotherapy arm, whose disease progressed, were given the option to cross over to the targeted regimen. With a cutoff date on August 23, 2021—a median follow-up of 18.9 months—61 patients or 84 percent of the patients on the targeted drug combination remained on treatment, while eight or 22 percent of those receiving chemotherapy stayed the course. The study showed that patients receiving the targeted drug combination of dabrafenib plus trametinib had an overall response rate—defined as the proportion of patients who had a complete or partial response—of 47 percent compared to 11 percent for those receiving standard chemotherapy of carboplatin plus vincristine. For secondary endpoints, the clinical benefit—defined as the proportion of patients who had a complete response, partial response, or stable disease after 6 months—was 86 percent for patients on the targeted combination versus 46 percent for those receiving standard chemotherapy. Median progression-free survival was 21.1 months compared to 7.4 months for patients on chemotherapy. All patients had at least one adverse event, Bouffet said during the press briefing, but patients receiving the targeted drug combination had fewer Grade 3 or greater harsh side effects than those on chemotherapy, 47 percent versus 94 percent, respectfully. Most common side effects included pyrexia, headache, and vomiting. Bouffet said he and other members of the research team noted that the differences in quality-of-life among children in both arms of the study initially was not significant, though children on the targeted drug regimen appeared to do better with the passing of time. “We see these children during the course of our consultation; not only do they not have hair loss, but also they have a normal life,” Bouffet noted. “They are often in a rush because they want to go back to their normal activities during this treatment.” He also added that the study highlighted the need to identify specific mutations as a critical early step to help guide optimal therapies for this specific type of glioma. “This study demonstrates how important it is to document as early as possible the molecular alteration that are present in this type of tumor.” The study is ongoing with the research team still collecting data on long-term safety in addition to assessing an optimal duration of treatment. Warren Froelich is a contributing writer.

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