ID #361 Superior tumour control with targeted therapy relative to conventional chemotherapy for BRAF-altered relapsed paediatric low-grade gliomas

Abstract Background Although targeted therapies for paediatric low-grade gliomas (pLGG) have shown efficacy, comparisons of alteration-specific long-term outcomes between targeted therapies and conventional chemotherapy are lacking. Methods We performed a population-based study of BRAF-altered pLGG treated at relapse with trametinib (for BRAF fused pLGG) or dabrafenib +/- trametinib (BRAF V600E), compared with chemotherapy-treated pLGG. Imaging responses (RAPNO) were assessed by neuroradiologists. Results The initial cohort comprised 267 BRAF fused and 161 BRAF V600E pLGG. Across alterations and lines of therapy, imaging responses for chemotherapy-treated pLGG were similar. Clinician-determined progression-free survival (PFS) was poor and, importantly, equivalent between first/second-line chemotherapy. For BRAF fused pLGG treated with chemotherapy or trametinib, there was a higher objective response rate (25% reduction) with trametinib – 60% (18/30) versus 36% (8/22) second-line versus 39% (22/56) first-line. Trametinib yielded significantly more partial responses. Moreover, 56% of tumours refractory/non-responsive to first-line chemotherapy responded to trametinib. These responses translated to superior disease control with 18-month PFS of 91% (n = 34) versus 52% for second-line chemotherapy (n = 27) (p 0.001). At 3.5 years, PFS for patients who remained on therapy was 82% versus 19% for chemotherapy. These differences narrowed for patients who discontinued trametinib, with 49% progressing within 2 years. Interestingly, disseminated tumours were more likely to progress on therapy – 67% probability at 5 years (p = 0.001). BRAF V600E pLGG treated with targeted therapy (n = 19) also showed superior disease control with 5-year PFS of 82% versus 33% for second-line chemotherapy (n = 9) (p = 0.02). With prolonged treatment times (median 5.5 years 1-10.9), tumour control persisted – only 16% of patients progressed on therapy. Review of V600E imaging responses is ongoing. Conclusion Acknowledging variation in treatment courses and follow-up, targeted therapy for relapsed BRAF-altered pLGG yields superior tumour control relative to chemotherapy. Ongoing work will help elucidate optimal treatment schedules and long-term functional outcomes.