MEK162

Safety and efficacy evaluation of encorafenib plus binimetinib for the treatment of advanced BRAF- mutant melanoma patients

Alice Indini & Mario Mandalà

Abstract

Introduction: Approximately 40-50% of patients with cutaneous melanoma harbour point mutations in BRAF. BRAF and MEK inhibitors in combination are now a standard therapy for advanced BRAF V600-mutated melanoma. Nevertheless, survival rates with the combination are limited, highlighting the need for further therapeutic improvement and strategies to overcome primary and acquired resistance.
Areas covered: Encorafenib, a highly selective BRAF inhibitor, was developed in combination with binimetinib, a potent, selective allosteric MEK1/2 inhibitor, to improve efficacy and tolerability over other approved combo-targeted therapies. This novel combination shows peculiar pharmacodynamic properties which translate in a higher on-target potency and paradox index. 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.
Expert opinion: the favorable survival results and the attractive toxicity profile suggest that encorafenib and binimetinib combination is an intriguing standard option when targeted therapies are considered as first line treatment in BRAF mutated melanoma patients. In the near future, results from ongoing clinical trials will provide information on the use of this novel combination in specific situation, including as adjuvant treatment or as a combination strategy.

Keywords: encorafenib, binimetinib, melanoma, BRAF, MEK, targeted therapy.

Chemical structure

Pivotal trial COLUMBUS Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF- mutant elanoma (COLUMBUS): a mult centre, open-label, randomised phase 3 rial. Lancet Oncol. 2018. 19(5):603-615.

Chemical structure

Pivotal trial COLUMBUS Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF- mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018. 19(5):603-615.

1. Introduction

Almost half of cutaneous melanomas harbor hotspot mutations in the B-Raf proto-oncogene kinase (BRAF), which constitutively activate the mitogen-activated extracellular signal regulated kinase (MEK). The RAS/RAF/MEK/ERK (i.e. the mitogen-activated protein kinase [MAPK] pathway) has a major role in many cellular processes, and is involved in tumor cell proliferation, survival, differentiation1 and an immunosuppressive modulation of the tumor microenvironment2. BRAF mutant melanomas most frequently show a BRAF V600 mutation (74-90%), the most common being V600E mutation (accounting for nearly 90% of the identified mutations), while others (e.g. V600K, V600D/R) account for the remaining 10% observed mutations. Approximately 15% of melanomas harbor loss or mutations in the NF1 gene, playing an inhibitory role on the MAPK signaling; the remaining 15%-30% harbor an activating mutation of neuroblastoma RAS (NRAS), which is always exclusive to BRAF mutation3.
The discovery of BRAF mutations as drivers of melanoma carcinogenesis, has led to the development of targeted therapies (BRAF inhibitors, BRAFi)4,5, which have subsequently been replaced by the dual MAPK pathway inhibition, with combined MEK inhibitor (MEKi) and BRAFi6,7,8. Targeted therapy with BRAFi and MEKi improved the efficacy and tolerability compared to BRAFi alone, leading to a dramatic improvement in the prognosis of metastatic BRAF mutant melanoma. Targeted therapy has now moved to the adjuvant setting, after the results of a randomized clinical trial, the COMBI-AD study, demonstrating a significant improvement in both disease-free (DFS) and overall survival (OS) in high-risk resected (i.e. stage III) BRAF mutant melanoma9. Thus, combined BRAFi and MEKi therapy is currently under investigation as neoadjuvant strategy, in combination with immunotherapy or in sequencing preplanned strategy in several randomized clinical trials10,11,12.
To date, one combo-targeted therapy (dabrafenib-trametinib) has been approved as adjuvant treatment for resected stage III BRAF mutant melanomas, and three combo-targeted therapies as treatments of unresectable/metastatic melanoma patients harboring BRAFV600 mutation: dabrafenib-trametinib, vemurafenib-cobimetinib, and encorafenib-binimetinib. Among these, encorafenib and binimetinib combination represents the most recent targeted-therapy strategy for melanomas harboring BRAFV600 mutation. In this review we focus on pharmacodynamic and pharmacokinetic properties of encorafenib and binimetinib, summarizing the toxicity profile and efficacy in the current landscape of targeted therapies in BRAFV600 mutated melanomas.

2 Mechanism of action

2.1 Pharmacodynamics

Encorafenib and binimetinib are both kinase inhibitors. Encorafenib targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays, and reduces ligand binding to several other kinases including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 in vitro at clinically achievable concentrations13. Encorafenib inhibits in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations, thus leading to tumor regression associated with MAPK pathway suppression13. Binimetinib is a reversible, non-competitive inhibitor of MEK1 and MEK2 activity, which are upstream regulators of the extracellular signal-related kinase (ERK) pathway14. MEK1/2 are threonine and tyrosine kinases, contributing to the activation of the RAS/RAF/MEK/ERK pathway. MEK inhibition prevents the activation of MEK1/2-dependent proteins and transcription factors, but also leads to a reduced production of inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF). Binimetinib inhibits ERK phosphorylation in in vitro cell-free assays, together with viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines14. Thus, encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway: compared with either drug alone, co-administration of encorafenib and binimetinib results in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity in BRAF V600E mutant human melanoma xenograft studies in mice13,14. Moreover, combined encorafenib and binimetinib delays the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice, compared to either drugs alone13,14. Notably, encorafenib inhibits BRAF V600E kinase activity in a biochemical assay at similar concentrations as dabrafenib and vemurafenib. However, the dissociation half-life (t½) is > 30 hours (compared with 2 hours for dabrafenib, and 0.5 hours for vemurafenib), resulting in improved pharmacodynamics and prolonged target suppression15. Furthermore, encorafenib is more potent at inhibiting proliferation than dabrafenib or vemurafenib in BRAF V600-mutant cell lines15. Encorafenib shows lower BRAF V600 and CRAF half maximal inhibitory concentration (IC50), thus translating into greater potency at inhibiting proliferation, and potential escape pathways, achieved with lower drug concentrations. Another relevant pharmacodynamic feature of encorafenib is the higher paradox index: this translates into a wider therapeutic window for achieving tumor inhibition without paradoxical ERK activation which, in turns, leads to the onset of cutaneous adverse events (AEs).

2.2 Pharmacokinetics

The pharmacokinetics of encorafenib and binimetinib were studied in healthy subjects and in patients with solid tumors15.

2.2.1. Encorafenib13

The systemic exposure of encorafenib is dose proportional over single doses (range-50-700 mg), but less than dose proportional after once-daily dosing 850-800 mg). The recommended therapeutic dose for encorafenib in association with binimetinib is 450 mg once daily (QD), while it is 300 mg QD for encorafenib monotherapy. The steady state is reached by Day 15, with a drug exposure 50% lower than that on Day 1. There is a moderate degree of inter-patient variability in exposure, with and area under the concentration-time curve (AUC) coefficient of variation (CV%), 12-69%. Following oral administration, ≥ 86% of encorafenib is absorbed, and the maximum concentration (Cmax) is reached in a median time of 2 hours. Encorafenib is primarily metabolized in the liver, by CYP3A4, CYP2C19, and CYP2D6. Co-administration of encorafenib with strong or moderate CYP3A4 inhibitors and inducers should be avoided, since the first may increase adverse reactions due to increased drug exposure, while the second might cause decreased encorafenib exposure and efficacy. Also, co-administration of encorafenib with sensitive CYP3A4 substrates (e.g. hormonal contraceptives) may result in decreased efficacy of such agents, or increased toxicity. If co- administration cannot be avoided, encorafenib modification may be considered. Encorafenib is excreted (primarily as metabolites) in equal proportions in faeces and urine, and has a mean terminal elimination t½ of 3.5 h. There is no clinically significant impact of age, sex, body weight, nor mild hepatic and renal impairment, on the pharmacokinetics of encorafenib. However, reduction of dose at 300 mg is recommended for patients with mild hepatic impairment, and treatment should not be started in patients with moderate to severe hepatic impairment.

2.2.2. Binimetinib14

The systemic exposure of binimetinib is approximately dose proportional. After twice-daily (BID) dosing, the accumulation of binimetinib is 1.5-fold and the CV% of the AUC is < 40% at steady state. Following oral administration, ≥ 50% of the binimetinib dose is absorbed, and the Cmax is reached in a median time of 1.6 hours. The recommended therapeutic dose for binimetinib is 45 mg BID. Binimetinib is primarily metabolized through glucuronidation by the uridine diphosphate glucuronosyl trasferase (UGT1A1) (61% of drug); secondary metabolism mechanisms include N- dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. Unchanged binimetinib represents ~60% of drug exposure in plasma, with the active metabolite M3 (produced by CYP1A2 and CYP2C19) representing 8.6% of exposure. Binimetinib has a mean t½ of 3.5 h: excretion is 62% in feaces (32% unchanged drug) and 31% in urine (6.5% unchanged). There is no clinically meaningful impact of age, sex, bodyweight, mild hepatic or severe renal impairment, on the pharmacokinetics of binimetinib. Binimetinib AUC appears to be increased twofold in subjects with moderate or severe hepatic impairment, compared with subjects with normal liver function. Thus, binimetinib is not recommended in patients with moderate or severe hepatic impairment. No clinically meaningful drug interactions involving binimetinib have been observed, including no significant impact of encorafenib co-administration. Caution is recommended for concomitant use of binimetinib with UGT1A1 inducers and inhibitors, in absence of dedicated drug-drug interaction studies. The recommended dosage of encorafenib is 450 mg (six 75 mg capsules) orally QD, in combination with binimetinib 45 mg (three 15 mg tablets) orally BID (approximately 12 hours apart), until disease progression or unacceptable toxicity. Both drugs may be taken with or without food. Dose reductions and modifications for specific adverse reactions during encorafenib and binimetinib therapies, as well as indications for treatment discontinuation are provided in both drugs’ prescribing information13,14. Importantly, if encorafenib is discontinued, binimetinib should be permanently discontinued. While, if binimetinib is withheld, encorafenib dose should be temporarily reduced to 300 mg QD, and subsequently discontinued in case of permanent binimetinib’s discontinuation13,14. 3 Clinical applications On June 27, 2018, the United States (US) Food and Drug Administration (FDA) approved encorafenib (LGX818) and binimetinib (MEK162) in combination, for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by a validated test16. Of note, encorafenib monotherapy is not approved for this indication16. The novel combination treatment received the European Medicines Agency (EMA) authorization in September 201817,18. The two drugs were approved based on the results of the pivotal two-part, phase III, randomized, open-label COLUMBUS trial8. Eligible participants were subjects aged ≥ 18 years, with unresectable or metastatic cutaneous melanoma, harboring a BRAF V600E or V600K mutation detected using the BioMerieux THxID™BRAF assay. Participants were treatment naive or have progressed on or after previous first-line immunotherapy. In COLUMBUS Part 1, enrolled subjects (n = 577) were randomized (1:1:1) to receive combination therapy with encorafenib plus binimetinib, versus vemurafenib or encorafenib monotherapy8. Study treatment was continued until disease progression or unacceptable treatment related toxicity, whichever occurred first. The study was originally designed to compare the efficacy of encorafenib 450 mg QD plus binimetinib 45 mg BID, with vemurafenib given at its clinically indicated dose (i.e. 960 mg QD), and with encorafenib given at 300 mg QD (which is the encorafenib maximum well tolerated dose as a monotherapy). On Nov 2014 the study protocol was amended upon request from the US FDA, and a new study phase (part 2) was added to better understand and isolate the contribution of binimetinib to the combination, by comparing encorafenib 300 mg plus binimetinib 45 mg against encorafenib 300 mg alone. The primary endpoint of COLUMBUS Part 1 was progression free survival (PFS) with the combo encorafenib plus binimetinib versus vemurafenib alone. At the primary analysis (median follow up of 16.6 months), median PFS was significantly longer in the encorafenib plus binimetinib group compared with the vemurafenib group (14.9 [95% CI 11.0-18.5] vs. 7.3 [95% CI 5.6-8.2] months, hazard ratio [HR] 0.54, 95% CI 0.41–0.71; two-sided p < 0.0001). The key secondary endpoint was comparison of PFS in the encorafenib plus binimetinib group versus the encorafenib group: median PFS was 14.9 (95% CI 11.0–18.5) vs. 9.6 (95% CI 7.5–14.8) months in the combination group and in the encorafenib monotherapy group, respectively (HR 0.75, 95% CI 0.56–1.00; p = 0.051). The confirmed overall response rate (ORR) by blinded independent central review (BICR) was 63%, 40% and 51% in the encorafenib plus binimetinib, vemurafenib and encorafenib groups, respectively. The median duration of confirmed objective response 16.6 months (12.2–20.4) for the encorafenib plus binimetinib group, 14.9 months (11.1–not estimable) for the encorafenib group, and 12.3 months (6.9–16.9) for the vemurafenib group. Key secondary endpoints of COLUMBUS trial also included the comparison of PFS in the vemurafenib group compared with those in the encorafenib group, favoring the latter compared to the vemurafenib group (0.68, 95% CI 0.52–0.90; p=0.0070)8. This result, which represents the first head-to-head comparison of two BRAFi, again supports the clinical relevance of encorafenib pharmacodynamics in warranting a better clinical activity and subsequent improved PFS results. At a planned OS analysis (median follow-up of 21.5 months), median OS was 33.6 months (95% CI 24.4–39.2) in the combination group, 16.9 months (95% CI 14.0–24.5) in the vemurafenib group, and 23.5 months (95% CI 19.6–33.6) in the encorafenib monotherapy group19. In this analysis, treatment with the encorafenib plus binimetinib combination reduced the risk of death by 39% compared with vemurafenib (HR 0.61, 95%CI 0.47–0.79; p < 0.001). OS did not significantly differ in the encorafenib plus binimetinib group compared with the encorafenib group (HR 0.81 [95% CI 0.61–1.06]; two-sided p=0·12). 1-year OS was 75.5% (95% CI 68.8–81.0) in the encorafenib plus binimetinib group, compared with 74.6% (95% CI 67.6–80.3) in the encorafenib group, and 63.1% (55.7–69.6) in the vemurafenib group. 2-year OS was 57.6% (95% CI 50.3–64.3) in the encorafenib plus binimetinib group, 49.1% (95% CI 41.5–56.2) in the encorafenib group, and 43.2% (95% CI 35.9–50.2) in the vemurafenib group. Updated results on the overall survival have recently been presented at the American Society of Clinical Oncology (ASCO) 2020 annual meeting20. A landmark analysis showed a higher rate of OS for the combination group at each year analyzed, with OS rates at 4 years of 39%, 26%, and 37% for the encorafenib plus binimetinib, vemurafenib, and encorafenib 300 mg, respectively. Updated safety analyses confirmed the beneficial long-term safety profile of the combination therapy, without new safety concerns20. Part 2 of the COLUMBUS trial was designed to specifically assess the contribution of binimetinib to the encorafenib plus binimetinib combination by maintaining the same reduced dose of encorafenib in the combination (i.e. 300 mg, the recommended phase II dose when used as monotherapy13), to enable a comparison of equal doses across treatment arms21. Results from Part 2 confirmed the contribution of binimetinib to the efficacy of the combination therapy for patients with advanced BRAF V600-mutant melanoma. In the primary endpoint analysis, median PFS for patients randomized to encorafenib 300 mg QD plus binimetinib 45 mg BID (n = 258) was 12.9 months (95% CI 10.1–14.0) compared with 9.2 months (95% CI 7.4–11.0) for patients treated with encorafenib 300 mg in COLUMBUS Parts 1 and 2 combined (n = 280) (HR 0.77, 95% CI 0.61–0.97; p = 0.029)8 . ORR by BICR was 66% for the encorafenib 300 mg plus binimetinib 45 mg, 45% for the encorafenib 300 mg monotherapy (COLUMBUS Parts 1 and 2 combined), and 50% for the encorafenib 300 mg monotherapy (COLUMBUS Part 2)8 . An update on OS and safety of COLUMBUS Part 1 has been recently released, with a median follow up for OS of 60.6 months across arms20. At 4 years, OS rates were 39% for the encorafenib 450 mg combination group, 26% for the vemurafenib group and 37% for the encorafenib 300 mg monotherapy group. Subgroup analyses for the comparison of encorafenib 450 mg combination with vemurafenib monotherapy showed a consistent benefit in favor of the combination group across various populations22. For patients with normal baseline lactate-dehydrogenase (LDH) levels and < 3 involved organ sites, the median OS for the encorafenib 450 mg combination group was not reached, whereas the median OS for the vemurafenib group was 28.1 months. The median OS for the subgroup with high LDH was 11.4 months for the combination group versus 9.6 months for the vemurafenib monotherapy group (HR,0.93; [95% CI, 0.62, 1.39]). Updated results of PFS and ORR (BICR assessed) confirmed the superiority of combination therapy compared with vemurafenib monotherapy19. Table 1 shows a comparison of the most relevant characteristics of the main clinical trials of BRAFi plus MEKi compared with BRAFi monotherapy in melanoma. Results presented in Table 1 derive from indirect comparisons and should therefore be interpreted consequently. Survival results in the COLUMBUS trial might be explained, at least partly, by a less proportion of patients with LDH levels >ULN compared with other trials’ populations. However, the median progression survival results of vemurafenib (7 months) is super-imposable in both the COMBI-V and COBRIM trials. Indeed, second line immunotherapy does not significantly differ among trials. In conclusion, despite the difference in median PFS and OS, the landmark analysis is not considerably different compared with that of other combinations.
The efficacy and safety of binimetinib monotherapy was investigated in the NEMO trial23. This was an open-label, randomized phase 3 trial investigating single-agent binimetinib versus dacarbazine, in patients with NRAS mutated melanoma. The rationale for binimetinib use in this subset of patients lies in the potential sensitivity of NRAS mutated melanoma cells to MEK inhibition24. Resuts from this trial suggested that binimetinib provided a PFS benefit compared with chemotherapy, without significant improvement in OS23. With the advent of immunotherapy and clinical trials of combined combo-immunotherapy, no further research focused on MEK inhibitors in NRAS mutated melanoma. Due to the limited efficacy of monotherapy, binimetinib did not receive treatment approval in this setting.
Current efforts in clinical trials are aiming to obtain the best results from the novel combination of BRAFi and MEKi. The main strategies consist in combining encorafenib and binimetinib with immunotherapy, either upfront or as sequential approaches, as well as using the new combination in the (neo)adjuvant setting for stage III melanoma. Another intriguing field is that of melanoma brain metastases, which still represents an unmet need and would deserve an effective and safe combination therapy. Table 2 displays the main clinical trials of encorafenib and binimetinib for BRAF V600-mutant melanoma currently ongoing.

4 Safety evaluation

Updated results on the safety of encorafenib 450 mg QD plus binimetinib 45 mg BID have recently been presentedError! Bookmark not defined.. Previous results had shown that common AEs reported more frequently in the combination group than in the encorafenib or vemurafenib groups were gastrointestinal toxicity (i.e. diarrhoea, constipation, nausea, vomiting, and abdominal pain), arthralgias, fatigue, headache and asymptomatic increase in creatine phosphokinase (CPK)8. Common AEs reported at a lower frequency in the encorafenib plus binimetinib group than in the encorafenib or vemurafenib groups were cutaneous toxicity (e.g., pruritus, hyperkeratosis, rash, keratosis pilaris, palmoplantar keratoderma, palmoplantar erythrodysaesthesia syndrome, dry skin, skin papilloma, macropapular rash), alopecia, photosensitivity reaction, pyrexia, and myalgias8.
Overall, a total of 68% of patients in both the encorafenib 450 mg combination group and the vemurafenib group, and 66% of patients in the encorafenib 300 mg monotherapy group experienced serious AEs (i.e. grade 3-4 according to the Common Terminology Criteria for Adverse Events [CTCAE])8,Error! Bookmark not defined.. Notably, the median time to the onset of first grade 3-4 AEs was longer in patients receiving the combination therapy compared to those treated with vemurafenib (8.4 vs 3.7 months, respectively). BRAFi and MEKi associated toxicity did not substantially increase over time, rather patients seem to experience less burden of toxicity later in the 2-year analysisError! Bookmark not defined.. The most common grade 3–4 AEs in the combination therapy group (i.e. seen in > 5% of patients) were increased γ-glutamyltransferase (GGT) (9%), increased CPK (7%), and hypertension (6%). AEs led to treatment discontinuation in 16%, 17% and 15% and dose reduction/interruption in 55%, 62% and 71% for the combination group, the vemurafenib group and the encorafenib 300 monotherapy group8,Error! Bookmark not defined.. The most frequent reasons for treatment discontinuation or dose modifications in the encorafenib plus binimetinib group were increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), while in the vemurafenib group were raised GGT, arthralgias and photosensitivity reactions.
Pyrexia, a BRAFi associated AE commonly observed during dabrafenib treatment, occurred in 20% of patients in the encorafenib plus binimetinib group, 29% of patients in the vemurafenib group and 17% of patients in the encorafenib monotherapy group. Skin toxicity occurred less frequently in the combination group compared to either monotherapy groups. Photosensitivity, a common AE during associated with vemurafenib with a significant impact on patients’ quality of life, was seen in 4% of patients in the combination group, 4% of patients in the encorafenib monotherapy group, compared with 25% of patients receiving vemurafenib. Secondary non-melanoma skin cancers occurred infrequently, the most common being squamous cell carcinomas, in 3% of patients in the encorafenib plus binimetinib group, 17% in the vemurafenib group and 8% in the encorafenib group8.
Specific MEKi toxic effects, including ocular and cardiac toxicity, were reasonably seen more frequently in the combination therapy group, than in either monotherapy groups. Serous retinopathy occurred in 20% of patients in the encorafenib plus binimetinib group, compared with 2% of patients in both monotherapy groups. Left ventricular dysfunction occurred in 8% of patients in the encorafenib plus binimetinib group, 1% of patients in the vemurafenib and 2% of patients in the encorafenib group. Most ocular and cardiac AEs observed in the combination treatment group were grade 1-2, rarely caused treatment interruptions or dose adjustments, and did not result in treatment discontinuation. Notably, the higher frequency of ocular AEs in the combination therapy group of the COLUMBUS trial was likely related to the intensive frequency of monitoring, which was mandatory for the combination group as per protocol. However, a high proportion of these ocular events were asymptomatic and detected through specialized eye examination. Despite the longer duration of exposure in the encorafenib plus binimetinib group (median duration of treatment was
51.2 weeks for encorafenib and 50.6 for binimetinib, compared with 27.1 weeks for vemurafenib and 31.4 for encorafenib monotherapy), the number of deaths occurring during treatment or within 30 days of the last dose was similar among treatment groups. Notably, none of the deaths due to AEs were considered likely to be related to study treatment8. Preliminary data on safety in COLUMBUS Part 2 suggested that safety profiles were consistent with those observed in Part 121. Overall, evidence suggests that combination therapy with encorafenib and binimetinib has a good tolerability, with a toxicity profile which seems the most manageable among the available BRAFi and MEKi combination treatments. This favorable tolerability might have relevant implications in the clinic: a wider proportion of patients with BRAF mutant melanoma could be treated, not only in first line, but also as an option in case of poor tolerance to other combinations of BRAFi and MEKi, or as a potential less toxic second line treatment after first line immunotherapy. Indeed, the combination therapy was associated with significant quality of life maintenance and improved patient reported outcomes, which were both secondary endpoints of the COLUMBUS trial25.

5 Conclusion

The therapeutic landscape of BRAF mutant melanoma has welcomed a new combo targeted strategy, encorafenib and binimetinib. Available results to date suggest that the novel combination not only provides good clinical outcomes for metastatic BRAF positive melanoma patients, but also that these results go together with a manageable safety profile. Ongoing clinical trials will further change the therapeutic strategies in the next future, specifically in the contexts of (neo)adjuvant therapy and combination with immunotherapy, either as a triple strategy or as sequential treatments.

6 Expert opinion

What, if any, improvement does the drug hold over other therapies? Although the COLUMBUS trial was not designed to compare encorafenib plus binimetinib with other BRAF/MEK inhibitor combinations, and no head to head comparisons are available, the results compare favourably to prior studies with other combinations. The median PFS in phase 3 trials evaluating dabrafenib- trametinib (COMBI-d and COMBI-v trials) and vemurafenib-cobimetinib (coBRIM) were 12.5 and 11.0 months, respectively6,7 (Table 1). Interestingly, the PFS of vemurafenib in those studies was 7 months similar to that reported in the COLUMBUS trial, suggesting that the patients’ populations did not substantially differ among these studies. Preclinical studies reported that encorafenib has a longer dissociation half-life than for dabrafenib or vemurafenib (>30 vs 2 vs 0.5 hours, respectively), resulting in a longer inhibition of pERK13. Increased antitumor activity in BRAF V600E- mutant cell lines was also observed for encorafenib in preclinical studies. These observations support the hypothesis that extended pathway inhibition can lead to improved clinical outcomes. Furthermore, in our experience most of the AEs reported with encorafenib and binimetinib are essentially biochemical toxicities and this represents an important element to be considered when counseling patients.

References

Papers of special note have been highlighted as:
* of interest
** of considerable interest
1 Farooq A, Zhou MM. Structure and regulation of MAPK phosphatases. Cell Signal. 2004; 16:769- 779.
2 Mandalà M, De Logu F, Merelli B, et al. Immunomodulating Property of MAPK Inhibitors: from Translational Knowledge to Clinical Implementation. Lab Invest. 2017;97(2):166-175. doi: 10.1038/labinvest.2016.132.
3 Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–96.
4 Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011: 30;364(26):2507-16.
5 Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicenter, open-label, phase 3 randomized controlled trial. Lancet. 2012. 28;380(9839):358-65.
6 Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double- blind, phase 3 trial. Lancet Oncol. 2016. 17(9):1248-60.
7 Robert C, Karaszewska B, Schachter J, et al. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N Engl J Med. 2015; 372(1):30-9. doi: 10.1056/NEJMoa1412690.
8 Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018. 19(5):603-615. *First clinical trial evaluating the combination of encorafenib and binimetinib in patients with BRAF-mutant melanoma.
9 Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib Plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 2017; 377:1813-1823.
10 Amaria RN, Menzies AM, Burton EM, et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol. 2019; 20(7):e378-e389. doi: 10.1016/S1470-2045(19)30332-8.
11 Long GV, Saw RPM, Lo S, et al. Neoadjuvant dabrafenib combined with MEK162 trametinib for resectable, stage IIIB-C, BRAF(V600)-mutation positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol. 2019; 20(8): 1083-1097. doi: 10.1016/S1470-2045(19)30274-8.
12 Ascierto PA, Ferrucci PF, Fisher R, et al. Dabrafenib, Trametinib and Pembrolizumab or Placebo in BRAF-mutant Melanoma. Nat Med. 2019; 25(6): 941-946. doi: 10.1038/s41591-019-0448-9.
13 US FDA. Braftovi™ (encorafenib) capsules: US prescribing information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf. Accessed 30 May 2020.
14 US FDA. Mektovi® (binimetinib) tablets: US prescribing information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf. Accessed 30 May 2020.
15 Delord JP, Robert C, Nyakas M, et al. Phase I dose-escalation and expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res 2017; 23: 5339–48.
16 Shirley M. Encorafenib and Binimetinib: First Global Approvals. Drugs. 2018; 78:1277-1284.
*This article provides relevant information and data regarding the combination of encorafenib and binimetinib.
17 European Medicine Agency. BRAFTOVI authorisation details; September 2018.
18 European Medicine Agency. MEKTOVI authorisation details; September 2018.
19 Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19 (10): 1315-1327.
20 Gogas HJ, Ascierto PA, Flaherty K, et al. Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600-mutant melanoma. J Clin Oncol 38: 2020 (suppl; abstr 10012). doi: 10.1200/JCO.2020.38.15_suppl.10012. *This work represents the latest update on the efficacy results of the combination of encorafenib and binimetinib in the COLUMBUS trial.
21 Dummer R, Ascierto PA, Gogas HJ, et al. Results of COLUMBUS Part 2: a phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus ENCO in BRAF-mutant melanoma. Ann Oncol. 2017;28(Suppl 5):v429–30.
22 Ascierto PA, Dummer R, Gogas HJ, et al. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer. 2020; 126:33-44. *This article provides significant data on the safety of combination treatment with encorafenib and binimetinib.
23 Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435-445. doi:10.1016/S1470-2045(17)30180-8
24 Solit DB, Garraway LA, Pratilas CA, et al: BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006; 439: 358-362.
25 Gogas HJ et al. Poster presented at the 13th Annual Congress of the European Society for Medical Oncology (ESMO); Madrid, Spain, 8-12 September 2017.