Encorafenib is indicated:...in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Table 3. ESMO-MCBS table for new therapies/indications in melanoma...Adult patients with unresectable or metastatic melanoma with the BRAF V600 mutation.

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

With a median duration of follow-up of 100 mo, the 7-year analysis from COLUMBUS part 1 confirms the long-term, sustained efficacy and known safety profile of enco + bini, with no new safety signals emerging, in pts with BRAF V600–mutant metastatic melanoma.

With a median duration of follow-up of 100 mo, the 7-year analysis from COLUMBUS part 1 confirms the long-term, sustained efficacy and known safety profile of enco + bini, with no new safety signals emerging, in pts with BRAF V600–mutant metastatic melanoma.

Overall, this 5-year update confirmed that people with BRAF V600-mutant melanoma that has spread to other parts of the body and who took encorafenib plus binimetinib were alive for longer without their disease getting worse than those who took vemurafenib or encorafenib alone.

The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients….In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with BRAF V600-mutant melanoma.

In COLUMBUS Part 1, 577 pts with advanced/metastatic BRAF V600 melanoma...randomized 1:1:1 to enco 450 mg once daily + bini 45 mg twice daily, enco 300 mg once daily, or vem 960 mg twice daily...In the enco + bini arm, the 5-year OS rate (95% CI) in all pts (n=192)...

Part 1 of COLUMBUS, 577 pts with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to encorafenib 450 mg QD + binimetinib 45 mg BID (COMBO450)...For COMBO450, ENCO300, and VEM, the 5-year PFS rate was 22.9%, 19.3%, and 10.2%; ORR (95% CI) was 64.1% (56.8–70.8), 51.5% (44.3–58.8), and 40.8% (33.8–48.2); and the median duration of response (DOR) was 18.6, 15.5, and 12.3 mo, respectively.

Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67])….In the COLUMBUS trial, results for updated PFS and OS with COMBO450 continue to demonstrate long-term benefits in patients with BRAF V600‒mutated melanoma.

The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib.

...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.`...

...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. ...

...- Unresectable advanced or metastatic malignant melanoma with BRAF [Rapidly Accelerated Fibrosarcoma isoform B] V600 mutation;...

...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. ...

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

...- Presence of B-RAF proto-oncogene, V600 mutant (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....

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

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

...- Patient must have BRAF V600 mutation positive based on report from Clinical Laboratory Improvement Act (CLIA) certified laboratory...

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

...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...

...- Histologically confirmed diagnosis of metastatic melanoma with the presence of the B-Raf proto-oncogene, serine/threonine kinase (BRAFV600) mutation...

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

...- Presence of BRAFV600 mutation in tumor tissue previously determined by a local assay (including immunohistochemistry [IHC]) at any time prior to Screening or during Screening...

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

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

BECARE is a retrospective study of EB in unresectable advanced/metastatic BRAFV600-mut melanoma in 21 sites from Spain….The median PFS and OS for pts with brain metastasis treated with EB in the 1st line was 6.3 m (95% CI: 6.2-12) and 10 m (95% CI: 7.4-NR), respectively.

BECARE is a retrospective, non-interventional study that investigates real-world effectiveness and tolerability of encorafenib plus binimetinib in unresectable advanced / metastatic BRAFV600-mut melanoma...The ORR to EB was 80.4%. With a median follow up of 13 m (range: 1.1-26.7), median PFS was 11.4 m (95% CI: 9.9-21.6) and 6.6 m (95% CI: 4.4-NR) for pts in first-line and after ICI, respectively. The 12-m OS rate was 72.3% (95% CI: 60.1-87) and 30% (95% CI: 11.6-77.3) for pts in first-line and after ICI, respectively.

This two-stage, single-center phase 2 trial investigated T 2 mg QD in patients (pts) with advanced BRAFV600/NRASQ61R/K/L wt melanoma...LD-D (50 mg BID) was added to T (pre-amend)....The ORR in 14 evaluable pts is 42.9% (5 confirmed and 1 unconfirmed partial response), the disease control rate is 71.4%.

Consistent survival improvements for encorafenib and binimetinib in BRAF V600 mutated melanoma have been confirmed in clinical trials, with over 4 years of median follow up.

A 50-year-old woman with history of left chest wall stage IA (T1aNx) and left leg stage IB (T1bN0) melanoma...Biopsy of a lung lesion confirmed metastatic BRAF V600 melanoma. She was treated with steroids, tapered over 6 weeks, and whole-brain radiation therapy (WBRT) before transitioning to bridging targeted therapy with encorafenib and binimetinib (Table 1). Restaging scans after 6 weeks demonstrated significant treatment response...