In this randomized, open-label, 2-part, 2 × 2 crossover, phase 1 study, the effect of a low-fat low-calorie (LFLC) meal on the relative bioavailability of a trametinib 2-mg tablet or dabrafenib 150-mg capsule was evaluated in healthy participants. Trametinib adjusted geometric mean ratios (90%CI) of fed : fasted for area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity were 0.76 (0.71-0.82) and 0.82 (0.77-0.88), respectively. For dabrafenib, the adjusted geometric mean ratios of AUC from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity (90%CI) for fed:fasted were 0.85 (0.79-0.91) and 0.86 (0.80-0.92), respectively. Consumption of an LFLC meal delayed trametinib and dabrafenib absorption, with an increase in time to maximum concentration of ≈15 and ≈30 minutes, respectively, compared to the fasted state. These findings indicate that consumption of an LFLC meal reduced the bioavailability and delayed the absorption of trametinib and dabrafenib, supporting current recommendations to administer both drugs in the fasting state; however, an occasional LFLC meal is unlikely to affect the pharmacokinetics of the drugs once steady state is reached and, by consequence, not likely to alter the overall intended efficacy.

OBJECTIVE: Anaplastic thyroid carcinoma (ATC) has a poor survival. The combination of Dabrafenib plus Trametinib (DT) had a significant impact in survival of BRAF p.V600E patients. However, durable responses may be compromised by resistance. We aim to present our experience with DT in BRAF positive ATC patients and compare the outcomes with usual therapy, and to study tumor molecular alterations in the DT group.
METHODS: Patients treated between May 2018 and April 2022 in a tertiary referral center, assessed for BRAF status were included. Patients were divided in three groups: BRAF p.V600E treated with DT, BRAF wild type (WT) under multimodal therapy (MT), and BRAF WT under compassionate care (CC). Response was assessed monthly in the first 6 months and every 3 months afterwards, by RECIST 1.1. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method and compared with the log-rank test.
RESULTS: Twenty-seven ATC patients were included (DT = 9, MT = 8, and CC = 10). Median OS was 475 days for DT, 156 days for MT, and 39 days for CC (P < .001). At 12 months, only patients in the DT group were alive (71%). Median PFS was 270 days, in the DT group, compared with less than 32 days in BRAF WT (P < .001). No severe adverse events were reported. Molecular profiling showed that in one of the four clinical progressions, a pathogenic NRAS mutation was found.
CONCLUSIONS: Our results show a significant real-world efficacy of Dabrafenib plus Trametinib in both survival and recurrence compared with standard treatment, with a good safety profile.

Anaplastic thyroid cancer (ATC) is a rare but lethal thyroid cancer. Dabrafenib and trametinib has been the standard treatment for the patients with BRAF mutation based on phase II study. This study aimed to exam the impact of dabrafenib and trametinib in ATC patients. ATC patients treated in three institutes in Taiwan were retrospectively reviewed. The clinical features, BRAF status, and survivals were collected. Multivariate analysis was performed to determine the independent prognostic factors. A total of 44 ATC patients were enrolled in current study. Twelve (50%) out of 24 detected patients had BRAF V600E mutation and eleven received dabrafenib and trametinib treatment. Patients treated with dabrafenib and trametinib had longer overall survival (OS) than the patients without treatment with dabrafenib and trametinib (median OS: 10.4 months vs. 3.3 months, P=0.05). The objective response rate was 81.8% and progress-free survival was 7.4 months. Multivariate analysis identified prior surgery, treatment with dabrafenib and trametinib and metastasis to lung, brain, and bone were significant prognostic factors for OS. The benefit of prior surgery was significant in patients receiving dabrafenib and trametinib (P=0.017) rather than those without dabrafenib and trametinib (P=0.067). The current study provides the real-world evidence that targeted therapy with dabrafenib and trametinib was effective and significantly improved the OS for ATC patients. The role of prior surgery became important in the era of targeted therapy. Future studies should focus on resistance mechanisms and combination with immunotherapy for ATC patients.

BACKGROUND: Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T).
METHODS: This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05.
RESULTS: Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors.
CONCLUSIONS: This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.