BRAFTOVI is a kinase inhibitor indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Eligible patients were 18 years and older with a histologically confirmed diagnosis of locally advanced, unresectable/metastatic cutaneous melanoma or unknown primary melanoma (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV) and the presence of BRAFV600E and/or BRAFV600K mutation in tumor tissue....The median PFS (95% CI) was 12.9 months (10.9 to 14.9) for COMBO300 versus 9.2  months (7.4 to 11.1) for ENCO300 (parts 1  and  2) and 7.4  months (5.6 to 9.2) for ENCO300 (part 2)....COMBO300 improved PFS, ORR, and tolerability compared with ENCO300, confirming the contribution of binimetinib to efficacy and safety.

COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study...Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF V600E or BRAF V600K mutation;...1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191)….median progression-free survival was 14·9 months (95% CI 11·0–18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6–8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41–0·71; two-sided p<0·0001)....Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.

...Molecular Pre-screening 1.Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations; 2.Male or female ≥ 18 years of age; 3.Surgically resected, with tumor free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT3b-pT4bN0) cutaneous melanoma per AJCC 8th edition; 4.Sentinel node (SN) staged node negative (pN0); 5.Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma; 6.Available tumor sample for central determination of the BRAFV600E/K mutation. ...

...Presence of BRAFV600 mutation in tumor tissue previously determined by a local PCR or NGS-based assay at any time prior to Screening or by a central laboratory during Screening.5. ...

...Participants must meet the following key inclusion criteria to be eligible for enrollment into the study:- Male or female participants ≥18 years of age at the time of informed consent.- Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic(Stage IV) cutaneous melanoma, according to the AJCC 8th edition.- Documented evidence of a BRAF V600E or V600K mutation.- Submission of adequate tumor tissue for central laboratory testing of BRAF V600E/K mutation and biomarkers is required for all participants during the screening period and prior to randomization.- Must have received only 1 prior line of systemic therapy for melanoma (either adjuvant therapy or first-line anti-PD-1 monotherapy (ie, nivolumab orpembrolizumab).- Must have anti-PD-1 resistant disease (primary or secondary) with confirmed diseaseprogression per RECIST v1.1 either during or after receipt of an approved anti-PD-1monotherapy (ie, nivolumab or pembrolizumab) for melanoma, defined according tothe SITC Immunotherapy Resistance Taskforce (Kluger et al, 2020).- Have at least 1 measurable lesion per RECIST v1.1.- ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50%by cardiac imaging.`...

...- Confirmed BRAF V600E/V600K activating mutation reported in the data based on laboratory or genetic analysis results....

...- Documented evidence of a BRAF V600E or V600K mutation....

...- Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay (eg, US FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent), obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory....

...- Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization...

...- Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation...

...- Available tumour sample for central determination of the BRAF V600E/K mutation....

...- Presence of a BRAF V600E or V600K mutation, or both, in their tumour tissue....

...- Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or central laboratory -...

...Presence of BRAF V600E or V600K mutation in tumour tissue prior to enrolment, as previously determined using a local test at any time prior to Screening...

...Melanoma determined locally to be V600E/K mutation-positive. ...

...- Male or female 12 to < 18 years of age at the time of consent/assent.- Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer Stage IIIB, IIIC, or IV.- Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or central laboratory.- Evidence of at least one evaluable lesion (measurable or non-measurable) as detected by radiological or photographic methods based on RECIST v1.1.- Adequate cardiac function:a. ...

…phase 1b/2 study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E-mutant solid tumors…In the phase 2 cohorts, confirmed responses were seen in 2 of 11 (18%) evaluable mCRC patients, 11 of 26 (42%) evaluable BRAFi-pretreated melanoma patients, and 28 of 42 (67%) BRAFi-naïve melanoma patients…The combination of encorafenib (450 mg) plus binimetinib (45 mg) showed acceptable tolerability and encouraging activity in patients with BRAF V600-mutant tumors…

CONTRADICTING EVIDENCE: A 51-year-old woman....The pleural biopsy confirmed the diagnosis as pleural metastasis of BRAFV600E mutated melanoma….Although melanoma treatment was changed to PD-1 and CTLA-4 combination blockade with nivolumab (80mg/body) and ipilimumab (3mg/kg) for second line therapy, and was changed again to BRAF/MEK double blockade with dabrafenib (300mg/day) and trametinib (2mg/day) for third line therapy, she eventually died of respiratory failure due to exacerbation of melanoma lung metastases.