trametinib (Mekinist) is accepted for restricted use within NHSScotland....in combination with dabrafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Trametinib as monotherapy or in combination with dabrafenib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation...Dabrafenib in combination with trametinib is indicated for the adjuvant treatment of adult patients with Stage III melanoma with a BRAF V600 mutation, following complete resection.

MEKINIST in combination with dabrafenib is indicated for the treatment of patients with BRAF V600 mutation positive unresectable Stage III or metastatic (Stage IV) melanoma

...Other regimens (for patients with BRAF V600-activating mutation) with the following agents - Dabrafenib/trametinib...vemurafenib/cobimetinib...Encorafenib/Binimetinib...

Table 3. ESMO-MCBS table for new therapies/indications in melanoma...Adjuvant treatment of melanoma after surgical resection with BRAF V600 mutation

In a phase III trial, patients with treatment-naïve BRAFV600-mutant metastatic melanoma were randomized to receive either combination nivolumab/ipilimumab (Arm A) or dabrafenib/trametinib (Arm B)…Median duration of response was not reached for Arm A and 12.7 months for Arm B (p<0.001)....Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

...- Patient must have BRAF V600E or BRAF V600K tumor genotype based on a Clinical Laboratory Improvement Act (CLIA) approved assay...

...Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive by the central laboratory....

...- BRAF (proto-oncogene B-Raf) V600E/K mutation-positive confirmed by a local laboratory....

...- Histologically confirmed acral lentiginous or cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and BRAF V600 mutation-positive....

...- Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma...

...1) Patients of either sex aged = 18 years;2) Histologically confirmed stage III (unresectable) or stage IV melanoma;3) Tissue BRAFWT signature and a molecular shift to circulating free DNA BRAF mutated positive melanomas upon progression to anti PD-1 therapy;4) Tumor biopsy, if feasible, to confirm the BRAFV600 mutation at progression;5) Previous adjuvant treatment, including checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 is allowed, except for stage IV (if completed at least 6 months prior to enrollment, and all related adverse events have either returned to baseline or stabilized). ...

...- Signed written informed consent - Recheck the results of histological studies and paraffin blocks - Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E or V600K mutation-positive by the local laboratory. ...

...to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2...

...Tumor biopsy, if feasible, to confirm the BRAFV600 mutation at progression; 5....

...• Signed informed consent• Age ≥18 years old• Histologically or cytologically confirmed BRAFV600 mutant stage 3 unresectable or metastatic melanoma• Measurable disease by RECIST • ECOG performance status 0-2• Minimum life expectancy 12 weeks• Adequate bone marrow, renal and liver function• Received no prior BRAF or MEK inhibitor therapy for metastatic disease• Willing and able to comply with the scheduled visits, treatment plans, laboratory tests, completion of QoL questionnaires and other study procedures• Archival tumour tissue sample available • Women of child-bearing potential and all sexually active male patients must agree to use effective contraception methods throughout treatment...

...- Histologically confirmed AJCC Stage IIIB or IIIC (Tx, T1-4, N1b, N2b, N2c, N3, Mo) cutaneous melanoma or unknown primary determined to be BRAF V600 mutation positive, with sufficient nodal or in-transit disease to enable biopsies prior to surgery.Patients must have disease that is measurable per RECIST version 1.1...

...- Histologically or cytologically confirmed Stage IV or unresectable Stage III BRAF V600E or BRAF V600K mutant melanoma - BRAF mutation must be determined by FDA approved BRAF mutation detection assay - BRAFV600 mutant status must be documented by a CLIA-certified laboratory - CT scan of neck, chest, abdomen and pelvis within 28 days prior to registration - A whole body PET/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis within 28 days prior to registration. ...

...- Patients must have histologically confirmed melanoma unresectable Stage III or Stage IV positive for BRAF V600E, V600K, V600R or V600D by a CLIA approved assay....

The median PFS and OS were 9.1 (95% CI, 7.1–10.3) months and 17.9 (95% CI, 12.7–27.8) months, respectively. The 12- and 24-month OS rates were 62.7% and 26.8%, respectively….DATUM-NIS confirms the efficacy of dabrafenib–trametinib in patients with melanoma in daily clinical practice in the real-world setting.

We included adult patients with resected stage III BRAF V600-mutant melanoma who received either adjuvant D/T or PD-1...In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS.

At a median follow-up of 33 months (IQR 21-43), the median RFS was 51.0 months (95% CI 41.0-not reached [NR]) in the D/T group, significantly longer than PD-1 (44.8 months [95% CI 28.5-NR]) (univariate: HR 0.66, 95% CI 0.50-0.87, P = 0.003; multivariate: HR 0.58, 95% CI 0.39-0.86, P = 0.007)...In patients with stage III BRAF V600-mutant melanoma post definitive surgery, D/T yielded better RFS than PD-1, with higher transient but lower persistent toxicity, and comparable OS.

This was a retrospective, multicenter chart review study of BRAF V600-mutated stage III/IV melanoma patients... Median (95% confidence interval [CI]) RFS-2 was 18.9 (14.9 – 28.1) months, with 91% and 81% remaining relapse-free at 12 and 18 months, respectively; most patients also remained distant metastasis-free at 6 months (97%) and 12 months (85%).

mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively)….Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAFV600-mutated melanoma and BM at baseline...

...we designed a phase I trial combining phen with dabrafenib/trametinib (dab/tram) in patients (pts) with metastatic BRAF V600-mutated mel….There were 8 PRs and 2 CRs. Responses were observed in 2/7 pts who had received prior therapy with BRAFi. One CR lasted > 1 year. There were 8/11 (73%) responders among the BRAFi-naïve pts.

Data from the ELDERLYMEL study demonstrate that dabrafenib plus trametinib is safe and effective in at least 75 y.o. patients with advanced BRAF V600-mutated melanoma without increasing toxicity.

We identified 40 patients with BRAFV600-mutated metastatic melanoma...Most common BRAF/MEKi regimen was dabrafenib plus trametinib (n = 34, 85%)....Best response to BRAF/MEKi was CR (n = 4, 10%), PR (n = 26, 65%), SD (n = 4, 10%) and PD (n = 6, 15%)…Predictive and prognostic biomarkers for long-term response to both immunotherapy and BRAF/MEKi are needed to optimize treatment strategies and patient outcomes.

This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma...The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm...

Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of 7 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type)....Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively.

We conducted a phase I/II clinical trial in 4 centers of HCQ+D+T in advanced BRAFV600-mutant melanoma patients….The one-year PFS rate was 48.2% (95% CI = 31.0-65.5%), median PFS was 11.2 months (95% CI = 5.4-16.9 months), and response rate (RR) was 85% (95% CI=64-95%). The complete response rate was 41% and median overall survival (OS) was 26.5 months.

Dabrafenib combined with trametinib confer long-term survival in Chinese patients with BRAF V600-mutant, unresectable or metastatic acral/cutaneous melanoma.

BRAFV600mut metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Median PFS reached 11.4 months, and overall response rate 70%.

We performed a retrospective descriptive analysis of elderly (≥75 years old, y.o.) and non-elderly (<75y.o.) BRAFV600+ advanced melanoma patients treated with D+T or D monotherapy in 10 Spanish academic centers...159 patients were included, 130 <75y.o. and 29 ≥75y.o. Clinical features were similar between groups, except in number of comorbidities, number of metastatic sites, ECOG-PS, and BRAFV600 mutation type. 5 patients per group received D monotherapy (p=0.019) and this decision was only influenced by age...D+T is safe and effective in ≥75 y.o. patients with advanced BRAF600+ melanoma.

Enrolled patients were diagnosed unresectable or metastatic BRAF V600 mutant melanoma, non-treated or pretreated, but no prior treatment with BRAF or MEK inhibitors. Patients were assigned to receive dabrafenib 150 mg q12h and trametinib 2 mg once daily. Primary endpoint was the ORR by investigator assessment using RECIST v1.1. Secondary endpoints included PFS, duration of response and OS...This analysis demonstrates meaningful efficacy of dabrafenib plus trametinib in Chinese patients with advanced BRAF V600 mutant melanoma, including acral melanoma patients.

The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive advanced melanoma in our hospital….The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression-free survival (PFS) was 12 months, and median overall survival (OS) was 23 months.