Novel targeted therapy shows better response than chemo in BRAF V600-mutant paediatric LGG

The combination of two targeted therapies, dabrafenib and trametinib, significantly improves the overall response rate (ORR) in paediatric patients with low-grade glioma (LGG) with BRAF V600 mutations compared with the combination of standard chemotherapy drugs, according to a study presented at ASCO 2022.

“For paediatric patients with BRAF V600-mutant LGG, dabrafenib plus trametinib may offer an improved standard of care. This represents an important advance for the youngest patients with brain cancer, as this is the first combination of targeted therapies developed for patients as young as one year of age,” said lead author Dr Eric Bouffet from The Hospital for Sick Children in Toronto, Ontario, Canada.

“[Previous studies have shown that] BRAF V600 mutations have been detected in approximately 15–20 percent of all paediatric LGGs (pLGGs), … and dabrafenib monotherapy has shown clinical benefit in BRAF V600-mutant pLGG. [A]dding trametinib in adult patients with solid tumours has led to additional benefit and fewer cutaneous adverse events [AEs],” Bouffet noted. [Lancet Oncol 2022;23:53-64; Clin Cancer Res 2019;25:7303-7311]

This double-blind, phase II trial involved 110 children (aged 1–18 years) with BRAF V600-mutant LGG who were recruited from 57 investigative centres in 20 countries. Participants were randomized to receive either dabrafenib* plus trametinib** (experimental arm; n=73; median age 10 years) or standard dosing of carboplatin plus vincristine (chemotherapy arm; n=37; median age 8 years). Nine patients who had disease progression on chemotherapy were switched to receive dabrafenib plus trametinib. [ASCO 2022, abstract LBA2002]

At a median follow-up of 18.9 months, the ORR, as assessed by IRC***, was significantly higher in the dabrafenib plus trametinib arm compared with the chemotherapy arm (47.0 percent vs 11.0 percent; odds ratio [OR], 7.2; p<0.001), with a notable partial response rate of 44.0 percent vs 8.0 percent.

Patients on dabrafenib plus trametinib also demonstrated a higher clinical benefit rate (CBR) than those on chemotherapy (86.0 percent vs 46.0 percent; OR, 7.4).

The 12-month progression-free survival (PFS) rate was higher among those treated with dabrafenib plus trametinib compared with chemotherapy (66.6 percent vs 26.2 percent), with a significantly longer median PFS of 20.1 vs 7.4 months (hazard ratio, 0.31; p<0.001).

Quality of life (QoL) was essentially stable in the experimental arm, whereas a worsening QoL, as indicated by a gradual decrease in the global health score, was observed in the chemotherapy arm, said Bouffet.

Grade ≥3 AEs occurred at a lower rate in the dabrafenib plus trametinib than chemotherapy arm (47.0 percent vs 94.0 percent), with fewer AEs leading to treatment discontinuation (3.0 percent vs 9.0 percent). Pyrexia, headache, and vomiting were the most common AEs reported in the dabrafenib plus trametinib arm.

No deaths were reported in either treatment arm.

“This is a big milestone for the paediatric neuro-oncology community, because for the first time, we see a combination of … targeted therapy that demonstrates a significant improvement compared to the standard of care in the first-line setting, with a higher ORR, CBR, and longer median PFS,” Bouffet said.

“[T]hese findings [also] demonstrate the importance of early molecular testing in pLGG and support the use of dabrafenib plus trametinib as a new potential standard of care in patients with BRAF V600-mutant pLGG requiring first systemic treatment,” Bouffet stressed.

*Dabrafenib twice daily 5.25 mg/kg/day for patients aged <12 years and 4.5 mg/kg/day for patients aged ≥12 years

**Trametinib once daily 0.032 mg/kg/day or 0.025 mg/kg/day for patients aged <6 years and ≥6 years, respectively

***IRC: Independent review committee