The Discovery and Development of Binimetinib for the Treatment of Melanoma

Abstract

Introduction:

Binimetinib is an uncompetitive, small molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2) and was recently approved in 2018 in combination with encorafenib for the treatment of metastatic melanomas. Preclinical and clinical trial data on the drug demonstrate its potent efficacy in cancers, especially melanomas with BRAF and NRAS mutations.

Areas Covered:

The authors review the preclinical as well as clinical Phase 1, 2 and 3 trial data leading to its FDA approval in 2018 for metastatic melanoma. Phase 3 data in combination with encorafenib demonstrated double the PFS (14.9 months) compared to vemurafenib alone (7.3 months) in patients with BRAF-mutated metastatic melanoma.

Expert Opinion:

No longer-term data is available yet to demonstrate any durable complete responses to therapy with binimetinib or improvements in overall survival compared to other FDA approved therapies including immunotherapy or vemurafenib. Treatment approaches to patients with BRAF mutated metastatic melanoma should be individualized and binimetinib in combination with encorafenib is a reasonable oral strategy with a reasonably tolerated toxicity profile. Cost of treatment and durability of response should be incorporated into the discussion as part of the overall medical decision making.

I. Introduction:

Binimetinib (Mektovi®) is an uncompetitive, small molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2). This MEK inhibitor was originally developed by Array Biopharma Inc. for the treatment of autoimmune diseases where it was discontinued for lack of efficacy in a Phase 2 clinical trial for rheumatoid arthritis. However, given the role of MEK inhibition as an anti-cancer therapeutic strategy, this drug was later evaluated and repurposed for a cancer therapeutic indication with more success completing Phase 1, 2, and even Phase 3 cancer clinical trials. This led to the FDA approving binimetinib in combination with encorafenib for treatment of metastatic cutaneous melanoma on June 27, 2018.

Cutaneous melanoma is the uncontrolled proliferation of melanocytes due to genetic mutations primarily driven by UV-mediated exposure.¹ Although melanoma only accounts for about 1% of all skin cancers, it is the most aggressive form of skin cancer and is the leading cause of skin cancer-related mortality. It is estimated that of all melanoma cases worldwide, about 76% were attributed to excess exposure to UV radiation.² Given its increasing prevalence year over year, in 2016 the American Cancer Society (ACS) reported that melanoma of the skin had now become the fifth and seventh most common cancer in males and females, respectively.³ The ACS also estimates that in 2019 there will be approximately 96,480 new melanoma diagnoses (57,220 men and 39,260 women) and about 7,230 deaths (4,740 men and 2,490 women). Despite public health campaigns to reduce UV exposure, there has a been a global rise in incidence in the past several decades which is projected to continually increase in European countries and in U.S. whites.^{4, 5} While UV exposure is one of the most important causes of malignant melanoma, other risk factors such as family history, lifestyle and diet, and melanocytic nevi also lead to increased risk of melanoma.^6–8 It is predicted that due to the rising incidence and the ability for melanoma to metastasize quickly that the national healthcare cost will rise to $4.58 billion by 2020.⁹

Cutaneous melanoma has one of the highest rates of somatic mutations of any cancer.^{10, 11} These mutations occur in genes encoding for enzymes responsible for the control of cell survival, proliferation, and differentiation leading to uncontrolled proliferation of melanocytes.^{1, 12, 13} One such pathway is the mitogen-activated protein kinase (MAPK) pathway. The MAPK signaling cascade consisting of RAF-RAS-MEK-ERK, a pathway comprised of G-coupled protein receptors and receptor tyrosine kinases that have been implicated in many cancers including melanoma.¹³ The most frequent mutation in this pathway affects BRAF, one of three RAF protein family members and occurs in approximately 50% of all melanomas.^{14, 15} Further downstream in the MAPK pathway is NRAS, one of three RAS protein (H-, K-, N-RAS) family members that is mutated in ~25% of melanomas.^{14, 15} Less common are NF1-mutant (~15% of melanomas) and wild-type melanomas that don’t harbor any of the previous three mutations (~10% of melanomas).^{14, 15} Under normal physiological conditions, the MAPK pathway is activated by a variety of extracellular signals such as growth factors, hormones, and cytokines via receptor tyrosine kinases to maintain cellular homeostasis.^{16, 17} However, the constitutive activation of the ERK kinase is due to gain-of-function mutations in RAF and RAS, resulting in oncogenic activity and neoplasia.^{18, 19}

Due to the central role of MAPK cascade dysregulation in cancer, modulation of this pathway is highly sought as an anti-cancer strategy. Small molecules targeting RAF and MEK proteins have now been evaluated in numerous clinical trials. Currently, there are four MEK inhibitors that are FDA-approved for the treatment of cancers. These include: trametinib for BRAF-mutant melanoma (approved in 2013), cobimetinib for BRAF-mutant melanoma (approved in 2015), selumetinib for stage III or IV differentiated thyroid cancer (approved in 2016), and binimetinib for BRAF-mutant melanoma (approved in 2018). This review will focus solely on the clinical development of binimetinib.

II. Preclinical discovery and development of binimetinib

First developed by Array Biopharma for treatment of rheumatoid arthritis, binimetinib (ARRY-162 or ARRY-438162) is an ATP-uncompetitive, selective, and potent inhibitor of MEK1/2. MEK activation is downstream from both BRAF and NRAS which are both mutated in melanomas, however it is upstream and a regulator of ERK making it an ideal target for inhibition in cancer treatment.²⁰ Binimetinib is a potent MEK inhibitor with an IC50 concentration of 12 nM in melanomas. It is highly selective for MEK with no off-target inhibition against 220 other serine/threonine and tyrosine kinases up to 20 μM. In BRAF- and NRAS-mutant cell lines such as HT29, Malme-3M, SKMEL2, SKMEL28, COLO205, and A375, binimetinib has an IC50 range of 30 to 250 nM in inhibition of cell proliferation.²¹ In mice xenograft tumor models, binimetinib exhibits dose-dependent inhibition of tumor growth at ranges of 3 to 30 mg/kg daily for 21 days.²¹

Pharmacokinetic (PK) data for binimetinib in humans demonstrates a maximal tolerated dose of 60mg BID and a maximal proposed clinical dose of 45 mg BID. For this clinical dose, PK analysis demonstrates a maximal concentration in the serum (Cmax) of 458 ng/mL with an area under the curve(AUC) of 1648 hr * ng/mL. For exposures at maximal dose tested in a single dose (80 mg), Cmax = 687 ng/mL with an AUC of 2960 hr * ng/mL Metabolites of the drug detected in human hepatocyte incubations showed products of direct glucuronidation of binimetinib as well as an N-desmethylated metabolite. Following a single oral dose with C-14 labeled binimetinib, 60% of the circulating radioactivity was from the parent drug and not metabolites. In vitro liver cytochrome enzymes CYP1A2 and CYP2C19 catalyze the formation of the active metabolite representing <20% of the clinical binimetinib exposure. Regarding absorption, binimetinib is 50% orally available and its serum half-life (t_1/2) = 1.5 hours with a volume of distribution (Vd) of 384L. Elimination of the drug is approximately 2/3 in the feces and 1/3 in the urine (Detailed in Table 1 which is summarized from the NDA #210498, Array BioPharma, Inc. submission to the FDA for binimetinib in 2018).

Table 1.

Dosing, Pharmacokinetics, and Clearance for Binimetinib in Humans⁴⁴

Maximum Tolerated Dose (MTD)	Single Dose	80 mg
	Multiple Dosing	60mg BID
Exposure at MTD (60 mg BID)	Multiple Dosing	Cmax: 687 ng/mL
		AUC: 2960 hr*ng/mL
Maximum Recommended Dose (MRD)	Multiple Dosing	45mg BID
Exposure at MRD	Multiple Dosing	Cmax: 458 ng/mL (46.1%)
		AUC: 1648 hr*ng/mL (35.3%)
		Cmax at steady state: 439 ng/mL (53.9%)
		AUC at steady stateL: 2103 hr*ng/mL
Metabolites		The most abundant metabolites produced from human hepatocyte incubations were products of direct glucuronidation of binimetinib.Additional metabolites detected include an amide formed by cleavage of the N-O bond in the aliphatic side chain. and an N-desmethylated entity (active metabolite AR00426032 or M3). The maximum contribution of direct glucuronidation to the clearance of binimetinib was estimated to have been 61.2%. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, approximately 60% of the circulating radioactivity AUC in plasma was attributable to binimetinib. In vitro, CYP1A2 and CYP2C19 catalyzes the formation of the active metabolite, which represents < 20% of the binimetinib exposure clinically.
Absorption	Bioavailability	Based on human ADME study, oral absorption isestimated to be at least 50%.
Terminal half-life	Terminal t½	The median (range) binimetinib terminal half-life (t1/2) was 8.66 hours (Range of 8.10 to 13.6 hours)
Volume of Distribution	Vd	Human ADME mean Vd = 384 L (29.3% of circulating volume)
Elimination	Fecal	mean of 62.3%
	Urine	mean of 31.4%

⁴⁴Summarized from the 2018 PATIENT LABELING REVIEW from the Food and Drug Administration NDA Application #210498, Array BioPharma, Inc. 2018.

III. Clinical Studies Supporting Binimetinib

1. Phase 1 Clinical Studies:

A multicenter, open-label Phase 1 study was performed to first determine the maximum tolerable dose (MTD) of binimetinib and was carried out in two parts in subjects with advanced solid tumors (NCT00959127).^{22, 23} The primary goal of the study was to determine the MTD, safety, and pharmacokinetic profile followed by a secondary goal to identify anti-tumor activity. Adverse events were assessed based on severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and all patients that received at least one dose of drug were included in the safety analysis. Subjects were enrolled in the first part of the study based on a 3 + 3 dose escalation trial design where binimetinib was administered twice daily (BID) in 21-day treatment cycles. Four dose levels were evaluated: 30 mg BID, 45 mg BID, 60 mg BID, and 80 mg BID in a total of 19 subjects. The dose-limiting toxicity was observed in two of three evaluable subjects at 80 mg BID and the MTD was determined to be 60 mg BID in the first portion of the study.

In the second, expansion phase of the study, 74 additional subjects were enrolled which included 28 subjects with biliary cancer (treated at 60 mg BID), 31 subjects with KRAS-mutant colorectal cancer (6 treated at 60 mg BID and 25 treated at 45 mg BID), and 15 subjects with BRAF-mutant colorectal cancer (45 mg BID). In the patients in the expansion phase receiving 60 mg BID (34 subjects), an unexpected number of ocular toxicities were observed which prompted a dose-reduction of the MTD to 45 mg BID for the remaining incoming subjects. Adverse events were collected and reported for all 93 subjects in both parts of this Phase 1 study regardless of causality and these are summarized in Table 2. The most prevalent adverse events were rash, nausea, vomiting, and diarrhea recorded in 81%, 56%, 52%, and 51%, respectively. Response rates to treatment were evaluated in 91 (98%) subjects in this study and three (3%) had measurable objective responses, one complete response and two partial responses recorded at 11.3, 10.2, and 17.9 months, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated for the subjects in the expansion phase subjects at 1.4/7.1 months (PFS/OS) for BRAF-mutant colorectal cancer subjects, 1.5/4.7 months in the KRAS-mutant colorectal cancer 45 mg BID cohort, 3.5/9.1 months in the KRAS-mutant colorectal cancer 60 mg BID cohort, and 2.1/4.8 months in the biliary tract cancer 60 mg BID cohort.

Table 2.

Patient Symptom and Adverse Event Frequency for Binimetinib Trial

Symptom/Adverse Event	COLUMBUS Binimetinib + Encorafenib arm Phase 3	NEMO Binimetinib Monotherapy Phase 3	Binimetinib Monotherapy Phase 2	Binimetinib + Encorafenib Phase 1b/2	Binimetinib Phase 1 MTD + 1b Expansion
	NCT01909453	NCT01763164	NCT01320085	NCT01781572	NCT00959127
	N = 192	N = 269	N = 71	N = 55	N = 93
Nausea	84 (44%)	79 (29%)	14 (20%)	54%	52 (56%)
Diarrhea	72 (38%)	108 (40%)	26 (37%)	44%	47 (51%)
Dermatitis acneiform	NR	95 (35%)	33 (46%)
Vomiting	61 (32%)	57 (21%)	9 (13%)	31%	48 (52%)
Fatigue	56 (29%)	60 (22%)	16 (23%)	33%	40 (43%)
Arthralgia	54 (28%)			33%
Blood CKP increase	49 (26%)	113 (42%)	34 (48%)
Headache	48 (25%)
Constipation	47 (24%)	37 (14%)
Asthenia	40 (21%)
Pyrexia	38 (20%)	28 (10%)		31%	17 (18%)
Abdominal pain	33 (17%)				20 (22%)
Anemia	31 (16%)	19 (7%)			24 (26%)
Dry skin	31 (16%)
Myalgia	31 (16%)
Blurred vision	31 (16%)
Increase GGT	30 (16%)	8 (3%)
Hyperkeratosis	29 (15%)
Rash	29 (15%)	98 (36%)	22 (31%)		75 (81%)a
Hypertension	28 (15%)	37 (14%)
Alopecia	27 (14%)
Back pain	26 (14%)
Muscle spasms	25 (13%)
Upper abdominal pain	24 (13%)
Cough	24 (13%)
Nasopharyngitis	24 (13%)
Pruritus	24 (13%)	32 (12%)	9 (13%)
Peripheral edema	22 (11%)	97 (36%)	26 (37%)		43 (46%)
Pain in extremity	22 (11%)
Increased ALT	21 (11%)	22 (8%)
Insomnia	19 (10%)
Decreased appetite	18 (9%)	31 (12%)
Palmoplantar keratoderma	18 (9%)
Increased AST	17 (9%)	35 (13%)		31%
Erythema	15 (8%)
Musculoskeletal pain	15 (8%)
Skin papilloma	15 (8%)
Hyperglycaemia	14 (7%)
PPE syndrome	14 (7%)
Dysgeusia	11 (6%)		8 (11%)
Keratosis pilaris	9 (5%)
Photosensitivity reaction	7 (4%)

^aReported as combined rash which includes dermatitis acneiform, acne, skin exfoliation, and any term containing rash.

Adverse events with frequency >30% are denoted in BOLD.

2. Phase 1B/2 and Phase 2 Studies:

With encouraging data from the Phase 1 study and lack of treatments for NRAS-mutant specific melanoma, an open-label, non-randomized Phase 2 study (NCT01320085) of binimetinib monotherapy in adults with metastatic BRAF- or NRAS-mutant cutaneous melanoma was initiated. The study enrolled subjects into one of three cohorts: BRAF-mutant tumors treated at 45 mg BID binimetinib, NRAS-mutant tumors treated at 45 mg BID binimetinib, or BRAF-mutant tumors treated at 60 mg BID binimetinib. The study’s goal was to retrospectively investigate efficacy of binimetinib in NRAS-mutant subjects in addition to those with BRAF-mutations. Primary endpoints were objective responses and secondary endpoints were progression-free survival (PFS), time to response (TTR), and duration of response (DOR). The study enrolled 30 subjects in the 60 mg BID NRAS-mutant cohort and 41 subjects in the 45 mg BID BRAF-mutant cohort. The 60 mg BID BRAF-mutant cohort data was not reported due to a lack of statistically significant numbers at the time of data cutoff for the study. Subjects in this Phase 2 study were analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 and were assessed at every second cycle of treatment with each cycle lasting 28 days.²⁴ Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) version 4 and were observed 30 days following last treatment or until resolution.²⁵

Resulting median PFS was 3.7 months and 3.6 months for NRAS-mutant and BRAF-mutant subjects, respectively. Median TTR was 7.9 weeks and 8.5 weeks and median DOR was 7.6 weeks and 9.2 weeks for NRAS-mutant and BRAF-mutant subjects, respectively. Interestingly, the study also found that seven subjects having prior BRAF inhibitor treatment did not show any response to MEK inhibition by binimetinib, similar to what was observed in a Phase 1 study with trametinib, another MEK inhibitor. Regarding safety, most treatment discontinuations occurred due to treatment-toxicities including peripheral edema (33%), rash (31%), acneiform dermatitis (46%), or pruritus (13%). Dose-reductions were permitted and 17 (57%) subjects in the NRAS–mutant cohort and 16 (39%) subjects in the BRAF-mutant cohort had at least one dose reduction.

A multicenter, open-label, Phase 1B/2 study (NCT01543698) was initiated to investigate dual inhibition of BRAF and MEK through combination treatment with the BRAF inhibitor, encorafenib (LGX818 or BRAFTOVI) and the MEK inhibitor, binimetinib.^26–28 The primary objective of the Phase 1B study was to determine the recommended Phase 2 dose for the combination. A range of 50 to 600 mg encorafenib daily and 45 mg of binimetinib twice daily were studied in patients with BRAF-mutant tumors. No serious adverse events were observed in Phase 1B and three doses of encorafenib would be explored in phase 2: 400, 450 (current single dose recommendation), or 600 mg encorafenib QD in combination with 45 mg BID of binimetinib. Between these three arms, a total of 48 subjects were treated out of 55 enrolled: 9 in the 400 or 450 mg encorafenib dose cohort and 39 subjects in the 600 mg encorafenib dose cohort. Adverse event rates observed in the 600 mg encorafenib group included nausea (54% of patients), diarrhea (44%), fatigue (33%), arthralgia (33%), and vomiting, pyrexia, and AST elevation (31% each). The 400/450 mg encorafenib cohort adverse event rates were 44% for nausea, 44% for fatigue, and 33% each for elevated AST, vomiting, and diarrhea. Grade 3 and 4 adverse events occurred in 64% of 600 mg encorafenib cohort subjects and in 67% of 400/450 mg encorafenib cohort, however, the only adverse event occurring in more than one patient was increased lipase for the lower (400/450 mg encorafenib) dose group. Due to the safety and tolerability of the 450 mg encorafenib plus 45 mg BID binimetinib group, this dose was chosen for the phase 3 COLUMBUS trial.

A second multicenter, open-label, phase 1B/2 study (NCT01781572) was also conducted with binimetinib in combination with ribociclib (LEE011, a CDK4/6 inhibitor) following the phase 2 study that investigated its potential efficacy in NRAS-mutant melanoma.^{29, 30} The primary goal of the 1B portion of this study was to determine the MTD and recommended Phase 2 dose for the combination in NRAS-mutant melanoma with a secondary objective to observe safety, pharmacokinetics, and efficacy. Subjects were randomized to either a 28-day (N=29) or a 21-day (N=32) cycle dosing regimen where they received 200–450 mg of ribociclib QD and 30 or 45 mg of binimetinib BID in combination. The MTD for the 21-day and 28-day phases were determined to be 600 mg QD ribociclib + 45 mg BID binimetinib, and 200 mg QD ribociclib + 45 mg BID binimetinib, respectively, with the 28-day cycle MTD selected as the recommended Phase 2 dose.

Although Phase 2 results have not been published and results submission has been extended at the sponsor’s request, the phase 1B portion of the study has reported efficacy and safety results for 16 patients. For this group, median PFS was 6.7 months. A confirmed PR was observed in 25% of patients while stable disease was observed in 44% of patients during the study period. Grade 3 or 4 adverse events observed in the Phase 1B included AST and ALT elevation (25% of patients), nausea (19%), rash (19%), vomiting (12%), and neutropenia (12%).

3. Phase 3 Clinical Studies:

Two Phase 3 trials were conducted prior to FDA’s approval of binimetinib in 2018. The first Phase 3 study (NEMO, NCT01763164) was a randomized, open-label study of binimetinib monotherapy compared to dacarbazine.³¹ The study enrolled a total of 402 patients with histologically confirmed locally advanced unresectable or metastatic cutaneous and NRAS-mutant melanoma. Enrollment was obtained at a 2:1 ratio with 269 subjects in the binimetinib cohort and 133 in the dacarbazine cohort. Binimetinib subjects were treated 45 mg orally BID and dacarbazine was administered at 100 mg/m² intravenously once every three weeks. Dose reductions to 30 mg BID of binimetinib and 500 mg/m² for dacarbazine were permitted in the study for adverse events without reescalation. The primary outcome of this study was progression free survival while secondary outcomes included OS, OR, disease control, TTR, and DOR. Patients in the study were evaluated based on RECIST version 1.1.²⁴ For patients treated with binimetinib monotherapy median PFS was 2.8 months (95% CI 2.8–3.6), while this was only 1.5 months (95% CI 1.5–1.7) for the dacarbazine treated patients. Median OS was 11.0 months (95% CI 8.9–13.6) for binimetinib treatment and 10.1 months (95% CI 7.0–16.5) with dacarbazine treatment. A significantly higher (p=0.015) confirmed OR of 15.2% (N=41, 95% 11–20) was observed in the binimetinib group compared to 6.7% (N=9, 95% 3–13) with dacarbazine. Additionally, a higher proportion of patients achieved disease control with binimetinib, 58.4% (N=157, CI 52.2–64.3), compared to dacarbazine, 24.8% (N=33, CI 17.7–33.0). The DOR for both confirmed and partial responses was 6.9 months for binimetinib treatment (95% CI 4.2–11.1) and was unknown for dacarbazine. Common adverse events (>20% occurrence) in the binimetinib cohort across all grades were elevated blood creatine phosphokinase (42%), diarrhea (40%), rash (36%), peripheral edema (36%), and dermatitis acneiform (35%). Overall, serious adverse events associated with binimetinib treatment were experienced by 34% (N=91) of patients and dose reductions occurred in 61% (N=163), while 25% (N=66) of patients discontinued treatment due to toxicity or progression.

A second Phase 3 trial of binimetinib (COLUMBUS, NCT01909453) investigated the combination of binimetinib and encorafenib compared to vemurafenib and encorafenib monotherapies in advanced unresectable or metastatic BRAF-mutated melanoma.^{32, 33} Vemurafenib was the first FDA-approved BRAF inhibitor to show efficacy in PFS for treatment of BRAF-mutant melanoma.^{34, 35} Although PFS was increased with BRAF inhibitor monotherapy, resistance to treatment developed within 6–7 months in most melanoma patients.^{36, 37} Combination approaches targeting both MEK and BRAF were thought to improve PFS as seen in a Phase 3 study of dabrafenib and trametinib.^{38, 39} Encorafenib and binimetinib were evaluated in this study as a more tolerable alternative to other MAPK inhibitor combinations. The COLUMBUS study was a randomized, open-label study consisting of two parts. Part 1 of the study was to compare a combination of 450 mg QD encorafenib and 45 mg BID of binimetinib to a 300 mg encorafenib QD monotherapy or to a 960 mg vemurafenib BID monotherapy. The study was expanded to part 2 at the request of the US Food and Drug Administration (FDA) to include two additional cohorts comparing a combination of 300 mg encorafenib QD and 45 mg binimetinib BID to 300 mg encorafenib QD alone in order to compare equivalent encorafenib doses for monotherapy and combination treatment. Part 1 of the study was randomized at a 1:1:1 ratio for each arm for a total of 577 patients: 192 assigned to the binimetinib and encorafenib combination, 194 to encorafenib monotherapy, and 191 to vemurafenib monotherapy. Tumor response in the study was evaluated based on RECIST version 1.1 at baseline, every 8 weeks for the first 24 months, and every 12 weeks thereafter.²⁴ The primary endpoint for this study was the comparison of PFS of binimetinib and encorafenib versus vemurafenib alone. Secondary endpoints included drug safety profiles of the combination as well as the PFS of binimetinib and encorafenib in combination versus encorafenib or vemurafenib alone, OR, confirmed OR, disease control, confirmed CR, DOR, TTR, and the safety profile. Median PFS assessed by blinded independent central review was observed as 14.9 months (95% CI 11.0–18.5) for the combination group and 7.3 months (95% CI 5.6–8.2) for vemurafenib alone indicating a significant decrease in progression with combination therapy (p<0.0001). This difference approaches significance when comparing the encorafenib alone PFS of 9.6 months (95% CI 7.5–14.8) to combination therapy (p<0.051). Confirmed OR was observed in 63% (N=121) of patients in the encorafenib and binimetinib combination group, 51% (N=194) of the encorafenib monotherapy group, and 40% (N=77) of the vemurafenib group. Median confirmed DOR was 16.6 months (95% CI 12.2–20.4) for combination treatment, 14.9 months (95% CI not established) for encorafenib only, and 12.3 months (95% CI 6.9–16.9) for the vemurafenib group. In the encorafenib and binimetinib combination group, common adverse events (>20% occurrence) were nausea (44%), diarrhea (38%), vomiting (32%), fatigue (29%), arthralgia (28%), increased CPK (26%), headache (25%), constipation (24%), asthenia (21%), and pyrexia (20%). In the combination group, 29 subjects (15%) of 192 dropped out due to drug related adverse events. The Key Melanoma Binimetinib Trials by Phase and endpoints are summarized in Table 3.

TABLE 3.

Summary of Key Clinical Regimens and Efficacy for Binimetinib Trials

Study Title	A study of ARRY-438162 (MEK162) in patients with advanced cancer, Phase 1	A phase II study of single agent MEK162 in patients with advanced melanoma	A phase Ib/II study of LGX818 in combination with MEK162 in adult patients with BRAF dependent advanced solid tumors	A phase Ib/II study of LEE011 in combination with MEK162 in patients with NRAS mutant melanoma	Study comparing the efficacy of MEK162 versus dacarbazine in unresectable or metastatic NRAS mutation-positive melanoma (NEMO), phase III	Study comparing combination of LGX818 plus MEK162 versus vemurafenib and LGX818 monotherapy in BRAF mutant melanoma (COLUMBUS), phase III
NCT Number	NCT00959127	NCT01320085	NCT01543698	NCT01781572	NCT01763164	NCT01909453
Study Start Date	August 2009	March 2011	May 2012	June 2013	July 2013	September 2013
Completion Date	January 2013	January 2014 Biomarker study completed 2019	Ongoing	February 2018, results submission delayed as of December 2018	December 2015	Part 1 completed September 2016 Part 2 ongoing
Study Arms	Dose-finding phase: •30 to 80 mg binimetinib BID until MTD observed Expansion phase: •45–60 mg binimetinib BID	•45 mg binimetinib BID, patients with BRAF-mutant tumors •45 mg binimetinib BID, patients with NRAS-mutant tumors •60 mg binimetinib BID, patients with BRAF-mutant tumors	•50– 400 mg encorafenib (LGX818) QD + 45 mg binimetinib BID in phase 1b •450 or 600 mg encorafenib QD + 45 mg binimetinib BID in phase 2 •200 mg encorafenib QD + 45 mg binimetinib BID + 100–600 mg ribociclib (LEE011) QD	Phase 1b: •28-day cycle:  ⚬200 to 300 mg ribociclib QD + 30 to 45 mg binimetinib BID •21-day cycle:  ⚬200 to 450 mg ribociclib QD + 30 to 45 mg binimetinib BID Phase 2: •RP2D is 200 mg ribociclib QD + 45 mg binimetinib BID	•45 mg binimetinib BID or •1000 mg dacarbazine IV Q3W	Part 1: •450 mg encorafenib QD and 45 mg binimetinib BID •300 mg encorafenib QD •960 mg vemurafenib BID Part 2: •300 mg encorafenib QD and 45 mg binimetinib BID •300 mg encorafenib
# Subjects	Dose-finding phase: N = 19 Expansion phase: N = 74	N = 71 (30 in the 45 mg NRAS and 41 in BRAF arms) N = 10 in 60 mg BRAF arm (not included in final analysis)	Dual combo (encorafenib + binimetinib): N = 13 in phase 1 and N = 42 in phase 2 Triple combo (encorafenib + binimetinib + ribociclib): N = 21 in phase 1b and N = 42 in phase 2	Phase 1b: N = 61 (29 and 32 patients in 28-day and 21-day cycles, respectively) Phase 2: N = 41	N = 402 (269:133) Randomized 2:1 binimetinib to dacarbazine	Part 1: N = 577 (192:194:191) Randomized 1:1:1 combo to encorafenib monotherapy to vemurafenib monotherapy Part 2: Not yet reported
Study Endpoints	Primary outcome to establish MTD, safety, and pharmacokinetics profile Secondary outcome was to assess tumor response and duration of response	Primary outcome of OR (CR or PR) Secondary outcomes included PFS, TTR, DOR, safety and tolerability, PK.	Phase 1b/2 primary outcome to determine RP2D, efficacy, and tolerable dose for phase 3 trial	Phase 1b primary outcome to determine RP2D and secondarily focus on safety, tolerability, and clinical efficacy	Primary outcome of PFS Secondary outcomes include: OS, ORR, TTR, DOR, DCR	Primary outcome of PFS Secondary outcomes include OS, ORR, TTR, DOR, DCR
Efficacy Results	MTD determined to be 60 mg in the dose-finding phase and was reduced to 45 mg in the expansion phase after an unexpected increase in ocular toxicities in the expansion phase. Efficacy results were reported for biliary tract cancer and colorectal cancer.	Total PR: 6 (21%) in NRAS arm and 8 (23%) in BRAF arm ORR: 3 (11%) and 2 (6%) in NRAS and BRAF arms, respectively. Stable disease: 13 (46%) and 13 (37%) in NRAS and BRAF arms, respectively. DCR: 19 (68%) and 21 (60%) in NRAS and BRAF arms, respectively.	Phase 1b: MTD in phase 2 determined to be either 450 mg or 600 mg encorafenib QD + 45 mg binimetinib Phase 2: Determined tolerated dose for phase 3 to be 450 mg encorafenib QD + 45 mg binimetinib BID Median PFS 11.3 months (all subjects) Confirmed RR 78% for 400/450 mg and 72% for 600 mg encorafenib + binimetinib	Phase 1b: MTD was determined to be 200 mg LEE011 QD + 45 mg binimetinib BID Median PFS: 6.7 and 4 months for 28-day and 21-day cycles, respectively Confirmed PR: 8 (18%) ORR: 13 (30%) Phase 2 results have not yet been published.	Binimetinib vs dacarbazine Median PFS: 2.8 months vs 1.5 months Confirmed OR: 41 (15.2%) vs 9 (6.7%) patients Stable disease: 109 (40.5%) vs 23 (17.3%)	Part 1: Median PFS: 14.9 months in combination vs 9.6 months with encorafenib alone vs 7.3 months with vemurafenib alone Confirmed OR: 122 (664%) vs 100 (52%) vs 78 (41%) respectively

MTD = Maximum tolerated dose; PFS = Progression-free survival, OR = Objective response; PR = Partial response; CR = Complete response; RR = Relative response; TTR = Time to response, DOR = Duration of objective response; DCR = Disease control rate

PK = Pharmacokinetics, RP2D = Recommended phase 2 dose

IV. Ongoing studies:

Currently, Array is conducting a new Phase 2 open label, randomized multicenter trial of Encorafenib + Binimetinib evaluating a standard-dose and a high-dose regimen in patients with BRAF-V600-mutant melanoma brain metastasis (POLARIS). This trial opened in June 2019 and anticipates enrolling approximately 100 patients. (NCT03911869, POLARIS). Two previous Phase 2 studies both found favorable safety data supporting dual inhibition of BRAF/MEK. The first was by Drago and Lawrence et al.^{40, 41} and treated brain metastases patients with BRAF/MEK dual inhibitors (binimetinib/encorafenib, vemurafenib/cobimetinib, and vemurafenib/trametinib). The other trial was COMBI-MB, and combined dabrafenib and trametinib in patients with brain metastases from melanoma. An inclusive overview of the clinical trials conducted with binimetinib (alone or in combination treatment regimens) for melanoma and other malignancies is included as Table 4.

Table 4.

Overview of Clinical Cancer Trials Investigating Binimetinib

Indication	Phase*	Status*	Interventions
Melanoma, Brain Metastasized Melanoma (21)	Phase 3: 2 Phase 2: 16 Phase 1: 3	Completed: 3 Recruiting/Active: 14 Withdrawn/Terminated: 4	Binimetinib monotherapy or in combination with encorafenib, pembrolizumab, nivolumab+ipilumab, dacarbazine, ribociclib
Colorectal Cancer (16)	Phase 3: 2 Phase 2: 9 Phase 1: 5	Completed: 2 Recruiting/Active: 12 Withdrawn/Terminated: 1	Binimetinib monotherapy or in combination with encorafenib, cetuximab, pembrolizumab, bevacizumab, nivolumab, ipilimumab, panitumumab, palbociclib, leucovorin, fluorouracil, ganitumab
Non-small Cell Lung Cancer (11)	Phase 3: 0 Phase 2: 5 Phase 1: 6	Completed: 2 Recruiting/Active: 8 Withdrawn/Terminated: 1	Binimetinib monotherapy or in combination with palbociclib, encorafenib, cisplatin, pemetrexed, erlotinib, carboplatin
Pancreatic Cancer (6)	Phase 2: 3 Phase 1: 3	Completed: 2 Recruiting/Active: 3 Withdrawn/Terminated: 1	Binimetinib monotherapy or in combination with hydroxychloroquine, avelumab, talazoparib, AMG479, BEZ235, BKM120
Colorectal Cancer (4)	Phase 2: 2 Phase 1: 2	Completed: 3 Withdrawn/Terminated: 1	Binimetinib monotherapy or in combination with capecitabine, gemcitabine, cisplatin, oxaliplatin
Ovarian and Peritoneal Cancer (4)	Phase 3: 1 Phase 2: 1 Phase 1: 2	Completed: 2 Recruiting/Active: 2	Binimetinib monotherapy or in combination with paclitaxel, chemotherapy, buparlisib
Triple Negative Breast Cancer (4)	Phase 2: 3 Phase 1: 1	Completed: 1 Recruiting/Active: 2 Withdrawn/Terminated: 1	Binimetinib monotherapy or in combination with pembrolizumab, avelumab, dactolisib

^*As of February 2020.

V. Conclusions:

Binimetinib is an uncompetitive, small molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2) and was recently approved in 2018 in combination with Encorafenib for the treatment of metastatic melanomas. Preclinical and clinical trial data on the drug demonstrate its potent efficacy in cancers, especially melanomas with BRAF and NRAS mutations. Phase 1 and Phase 2 data demonstrate it is reasonably well tolerated at a dose of 45 mg BID and Phase 3 data in combination with encorafenib demonstrated double the PFS (14.9 months) compared to vemurafenib alone (7.3 months) in patients with BRAF-mutated metastatic melanoma. Additional trial data including the new POLARIS trial is being gathered to define its efficacy in melanoma brain metastases. Given it is only approved in combination a not as a monotherapy, it currently is not a first line treatment for metastatic melanoma. It is important therefore when considering which patients should be considered for this regimen compared to standard of care immunotherapy or vemurafenib regimens that an individualized approach should be exercised. The treating clinician must evaluate several factors in the patient’s risk--benefit analysis including drug side effects, cost, and tumor benefit-as no durable complete responses have yet been observed with binimetinib combination therapy in this disease compared to immunotherapy regimens.

VI. Expert Opinion:

For most patients with early stage melanoma, treatment and prognostic options are excellent with surgery alone however once metastatic disease is present, survival decreases significantly. While the incidence of melanoma in the population is growing year over year, the proportion of melanoma-related deaths has declined due to the remarkable breakthroughs in therapy this disease has witnessed in the last decade. While not the focus of this review, immunotherapy regimens for patients with advanced metastatic melanoma have revolutionized the treatment of this disease with observation-for the first time ever-of some patients having durable complete responses with treatment. The challenges associated with immunotherapy treatment however are also not trivial and include several, even life-threatening toxicities, significant costs associated with some of these treatments, and the need for intravenous delivery of some of these agents.

With improvements in genetic and molecular profiling of tumors, our understanding of mutation-drivers for melanoma have led to a variety of small molecule inhibitors being developed that target kinases in the MAPK pathway including inhibitors of BRAF and MEK. With the approval of vemurafenib by the FDA in 2011 as the first targeted BRAF inhibitor for V600E mutated metastatic melanoma, this opened the door for the subsequent development of several other MAPK-focused inhibitors that have moved through clinical trials. It also became evident that monotherapy inhibition of BRAF was not quite as effective as combination therapy with BRAF and MEK inhibitors for many patients and binimetinib is the latest MEK inhibitor approved in combination for treating metastatic melanoma that is BRAF mutation positive. In evaluating the role of this new combination in the existing options for patients with metastatic melanoma several factors have to be taken into account. The Phase 3 COLOMBUS study was the main driver for FDA’s decision for binimetinib’s approval in combination with the BRAF inhibitor encorafenib in 2018 based largely on the data showing that the combination doubled the PFS to 14.9 months compared to 7.3 months with vemurafenib alone. Other important points to note are that no significant improvement in overall response was found between the groups and no complete responses were observed in any of the study arms. Also, overall survival data was not reported for the study. The original study design also compared 450 mg dose of encorafenib in combination with binimetinib vs. a 300mg QD dose of encorafenib as monotherapy and additional arms in the study were asked from FDA to evaluate this 300 mg QD encorafenib dose in combination so that an equivalent dose could be compared more easily.

Another important consideration is cost. The cost for a binimetinib oral tablet 15 mg is around $12,014 for a supply of 180 tablets (roughly $66.74 per tablet), depending on the pharmacy.⁴² The cost for encorafenib oral capsule 75 mg is around $12,014 for a supply of 120, also depending on the pharmacy. This equates to an average cost of $100.12 per pill. At the binimetinib dose used in the FDA approved trial (45 mg BID), this would add up to 6 tablets a day or a daily cost of around $400. Taken over a year this would add up to $146,170 just for binimetinib alone. Since the approved regimen is binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, in addition to the $146,170/yr cost for binimetinib, patients would also be paying for 6 encorafenib tablets daily (or around $600 daily cost for encorafenib) or another $219,262.80 for the encorafenib yearly bringing the total cost for the combination out of pocket to: $365,432.80 yearly. Since the PFS time was 14.9 months, this would add up to a combined treatment cost of $447,000 until average disease progression is observed. While several insurance carriers offset some of this cost and the manufacturer also offers patient assistance programs, patients paying the full amount out of pocket would be expected to cover around $1000 a day for their treatment costs, which is prohibitive to many patients.

Originally vemurafenib cost about $13000 a month for treatment and currently is $5296 for a supply of 112 of the 240mg tablets at most pharmacies. If using the dose from the COLUMBUS trial at 960mg BID this would be 8 tablets a day or 240 tablets a month = $11349 a month or approximately $136,182 a year for the treatment. Comparatively, vemurafenib, the first drug in this class, originally cost $13,000 per month ($207,000 for a patient with median survival). Patients failing vemurafenib are often given ipilimumab, an immunomodulator, at $150,000 per course. The incremental cost-effectiveness ratio (ICER) for vemurafenib compared with dacarbazine was $353,993 per QALY gained (0.42 QALYs added, $156,831 added). The ICER for vemurafenib followed by ipilimumab compared with vemurafenib alone was $158,139.⁴³

Another important point to consider is combination drug toxicity compared to monotherapy with vemurafenib or immunotherapy. In the encorafenib and binimetinib combination group, common adverse events (>20% occurrence) were nausea (44%), diarrhea (38%), vomiting (32%), fatigue (29%), arthralgia (28%), increased CPK (26%), headache (25%), constipation (24%), asthenia (21%), and pyrexia (20%). In the combination group, 29 subjects (15%) of 192 dropped out due to drug related adverse events – which is the same % observed dropping out with another BRAF inhibitor sorafenib in its Phase 3 trial in patients with advanced differentiated thyroid cancer. This is a reasonably well tolerated profile compared to some of the more severe or life-threatening toxicities reported with immunotherapies. An obvious benefit of BRAF/MEK inhibitor combination treatment is that it is an oral regimen that can be taken daily by the patient at home without having to come in to a center to get an infusion or have a port placed for therapy.

Of the adjuvant treatment options available to patients with advanced BRAF mutated metastatic melanomas, binimetinib in combination with encorafenib appears to be a reasonable option compared to vemurafenib alone as it significantly improved progression-free survival in the disease. However, at almost 3 times the cost as vemurafenib alone, this also has to factor into the physician-patient discussion. It is unknown however how this combination regimen compares to standard of care immunotherapy that generated more durable responses as well as a number of durable complete responses that have not been seen with targeted BRAF or MEK inhibitors. While immunotherapy costs are lower than this combination therapy of binimetinib and encorafenib, this discussion must also be balanced with the need for infusions or injections with immunotherapy as well as its significant toxicity risks. The clinician must therefore weigh all of these factors and have a balanced discussion with patients outlining these risks and benefits as part of an individualized approach for therapy choice and implementation. With ongoing melanoma research in the era of molecular and personalized medicine, novel treatments have catalyzed the field providing exciting new therapies with improved outcomes for patients with advanced melanomas. These novel drugs are improving outcomes and lowering the mortality of this devastating disease. Challenges, however, remain in minimizing toxicities and cost burden for more manageable long-term use of these exciting compounds.

Figure 1.

Targeting the MAPK Pathway with Binimetinib and other TKIs in Melanoma

Figure 2.

Chemical Structure of Binimetinib

Article Highlights:

• ▪ Binimetinib (Mektovi®) is an uncompetitive, small molecule inhibitor of selective mitogen-activated protein kinase (MEK1/2).

• ▪ Binimetinib is highly potent in BRAF- and NRAS-mutated melanomas, has 50% oral bioavailability, and its maximum recommended dose is 45 mg twice daily.

• Binimetinib demonstrated safety and early efficacy in metastatic melanomas in Phase 1 and II trials at a dose of 45 mg BID and was shown in combination with encorafenib to be superior to vemurafenib in the COLUMBUS Phase III trial.

• ▪ Binimetinib has currently been evaluated in over 70 clinical trials in a variety of cancers and was FDA approved in 2018 in combination with encorafenib for the treatment of metastatic melanomas where it demonstrated double the progression-free survival (14.9 months) compared to vemurafenib alone (7.3 months) in patients with BRAF-mutated metastatic melanoma.

• ▪ Factors including binimetinib side effects, high cost, and limited durable tumor benefits must be considered in clinical decision making as no durable complete responses have yet been observed with binimetinib combination therapy in melanoma compared to immunotherapy regimens.