Purpose of Review: H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy. RecentFindings: Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response.Summary: While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.

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Combination dabrafenib (D) and trametinib (T) is an FDA approved adjuvant therapy for patients with resected stage III BRAF-mutant melanoma. We describe treatment-related toxicities with adjuvant D+T in a real-world population through a retrospective case series. The primary endpoint was development of toxicities.ResultsEighteen of the 20 patients (90%) required at least one treatment interruption due to adverse events (AEs), 11 patients (55%) required a dose reduction and 13 (65%) permanently discontinued therapy due to an AE. The nine patients who did not require dose reduction had been initiated on a lower starting dose of dabrafenib. The most common treatment-limiting AEs were recurrent pyrexia and chills (85%) and liver laboratory abnormalities (50%). The median total time on therapy was 148.5 days (range 19-383), 40.7% (range 5.2-100%) of the intended one-year duration.ConclusionAdjuvant treatment of melanoma with combination D+T is associated with treatment-limiting toxicities in the majority of this patient group. Patients should be carefully monitored throughout therapy.

e22086 Background: Patients with stage III melanoma are at high risk for recurrence after resection of the primary lesion. The Combi-AD study showed adjuvant therapy with BRAF inhibitor, dabrafenib (D), and MEK inhibitor, trametinib (T), in patients with resected stage III BRAF mutant melanoma offers recurrence free survival benefit at 3 and 4 years compared to placebo. In this study, adverse events led to dose interruption in 66% of patients, dose reduction in 38% of patients, and permanent discontinuation in 26% of patients. This is a retrospective case series of patients with resected stage III melanoma treated with adjuvant BRAF and MEK inhibition reporting toxicities in a real-world population. Methods: Medical records of all patients with resected Stage III melanoma treated with adjuvant D+T by multiple, independent oncologists at our institution between November 2017 and December 2019 were reviewed. Planned treatment was dabrafenib 150 mg bid and trametinib 2 mg daily for 1 year. Primary outcome of interest was development of toxicities. Secondary outcomes included number of treatment interruptions, dose reductions, and total time on combination therapy. Results: Twenty patients were treated with adjuvant D+T during the study period. Eighteen patients (90%) required at least 1 treatment interruption due to adverse events. Eleven patients (55%) required a dose reduction and 14 (70%) permanently discontinued therapy due to an adverse event. The 9 patients who did not require dose reduction had been initiated on a lower dose of dabrafenib (75 mg BID) due to physician experience with toxicities in prior patients. The most common treatment-limiting adverse events were recurrent pyrexia (85%) and liver laboratory abnormalities (50%). Permanent discontinuation was secondary to recurrent pyrexia in 9 patients (45%) and liver laboratory abnormalities in 5 patients (25%). For the 16 patients who completed or discontinued therapy, the median total time on therapy was 76 days, 20.8% of the intended duration. The majority of these patients never reached the FDA labeled combination dose. Conclusions: We report our findings of the side effects of adjuvant D+T to demonstrate the frequency and severity of treatment limiting toxicities in a real-world population, which exceeds what has been reported in clinical trials. Adjuvant D+T is an approved treatment for resected stage III melanoma but requires diligent toxicity assessment and management.

The original version of this review article unfortunately contained a mistake in the author group section. Author Viveka Nand Yadav's name was inadvertently captured as "Vivek Yadav".

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