14 CLINICAL STUDIES

BRAFTOVI in combination with binimetinib was eva luated in a randomized, active-controlled, open-label,multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or

V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID™BRAF assay. 

Patients were permitted to have received immunotherapy in the adjuvant setting andone prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAFinhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on

Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group(ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease

(yes versus no).

Patients were randomized (1:1:1) to receive BRAFTOVI 450 mg once daily in combination with binimetinib45 mg twice daily (BRAFTOVI in combination with binimetinib), BRAFTOVI 300 mg once daily, or

vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

Only the results of the approved dosing (BRAFTOVI 450 mg in combination with binimetinib 45 mg) aredescribed below.

The major efficacy outcome measure was progression-free survival (PFS) of BRAFTOVI in combinationwith binimetinib compared with vemurafenib as assessed by a blinded independent central review. PFS was

defined as the time from the date of randomization to the date of the first documented disease progression ordeath due to any cause, whichever occurred first. Other outcome measures included overall survival (OS),

objective response rate (ORR), and duration of response (DoR) as assessed by central review.

A total of 577 patients were randomized, 192 to the BRAFTOVI in combination with binimetinib arm,194 to the BRAFTOVI arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the

BRAFTOVI in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-

five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1,or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate

dehydrogenase (LDH), 45% had ≥ 3 organs with tumor involvement at baseline, and 3% had brainmetastases. Based on centralized testing, 100% of patients’ tumors tested positive for BRAF mutations;

BRAF V600E (88%), BRAF V600K (11%), or both (<1%).

BRAFTOVI in combination with binimetinib demonstrated a statistically significant improvement in PFScompared to vemurafenib. Efficacy results are summarized in Table 5 and Figure 1. 

Table 5: Efficacy Results for COLUMBUS

BRAFTOVI

with binimetinib

N=192

Vemurafenib

N=191

Progression-Free Survival

Number of events (%) 98 (51) 106 (55)

 Progressive disease 88 (46) 104 (54)

Death 10 (5) 2 (1)

Median PFS, months (95% CI) 14.9 (11, 18.5) 7.3 (5.6, 8.2)

HR (95% CI)a 0.54 (0.41, 0.71)

P-valueb <0.0001

Overall Response Rate

ORR (95% CI) 63% (56%, 70%) 40% (33%, 48%)

CR 8% 6%

 PR 55% 35%

Duration of Response