FormalPara Key Summary Points

The BRAF plus MEK inhibitor combination of encorafenib plus binimetinib is indicated for the treatment of BRAF V600E-mutant metastatic non-small cell lung cancer.

Adverse reactions experienced with encorafenib plus binimetinib in clinical trials were well managed with dose modifications.

There is a need for resources detailing management of adverse reactions with encorafenib plus binimetinib in a clinical setting.

We describe approaches for managing select adverse reactions as determined by published clinical trial data as well as opinion of an expert panel of oncologists with years of experience treating patients with metastatic non-small cell lung cancer receiving targeted therapy.

The goal of adverse reaction management is minimizing treatment discontinuations.

Introduction

Approximately 85% of patients with lung cancer are diagnosed with non-small cell lung cancer (NSCLC), and most NSCLCs have an adenocarcinoma histology [1,2,3]. To date, multiple actionable biomarkers with approved therapies have been identified, including oncogenic alterations in ALK, BRAF V600E, EGFR, HER2, KRAS, MET, NTRK, RET, ROS1, and expression of programmed death ligand 1 [4,5,6,7]. BRAF mutations occur in various solid tumors, including melanoma (≈ 40%), thyroid (≈ 33%), colorectal (CRC; ≈ 9%), and NSCLC (≈ 2–4%) [3, 8]. The BRAF gene encodes a kinase involved in the mitogen-activated protein kinase (MAPK) signaling pathway, which regulates cellular processes, including growth, differentiation, proliferation, and survival [9, 10]. BRAF mutations are grouped into three classes based on dimerization status and kinase activity level [9, 11]. While class I mutations occur exclusively at codon 600, resulting in a constitutively active BRAF monomer, class II and III mutations occur at non-V600 codons, resulting in constitutively active and kinase-dead or kinase-impaired dimers, respectively [11]. Class I mutations account for the majority of BRAF mutations (≈ 77%) in melanoma, whereas NSCLC has a more even distribution, with class I, II, and III mutations accounting for 31–45%, 32–34%, and 23–31% of BRAF-mutant NSCLCs, respectively [8, 12]. The most common BRAF mutation in NSCLC, which accounts for approximately 2% of all NSCLCs, is a class I mutation that replaces the valine at codon 600 with glutamic acid (V600E), resulting in an approximately 500-fold increase in kinase activity [8, 11, 13]. When considering treatment options for NSCLC, identification of oncogenic alterations is critically important since targeted therapy has improved outcomes for many actionable mutations, including BRAF V600E-mutant NSCLC [3, 14,15,16]. Therefore, all patients with advanced or metastatic NSCLC should undergo broad-based molecular testing, as recommended by current guidelines [5, 7].

Available Treatments for BRAF V600E-Mutant Metastatic NSCLC

Clinical investigation of targeted therapy for BRAF V600E-mutant NSCLC began with BRAF inhibitor monotherapy (vemurafenib, dabrafenib) [17, 18]. However, clinical benefit of monotherapy was limited by acquired resistance, which reactivates the MAPK pathway [19]. The addition of a MEK inhibitor (trametinib, binimetinib) to a BRAF inhibitor provided dual inhibition of the MAPK pathway and prolonged antitumor activity with a tolerable safety profile [15, 20, 21]. Dabrafenib plus trametinib was approved as the first BRAF plus MEK inhibitor targeted therapy for patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC) in 2017 [22]. Encorafenib plus binimetinib was approved in October 2023 as the second BRAF and MEK inhibitor combination for this patient population [23]. Currently approved BRAF inhibitors inhibit monomers, and binding to one protomer in a dimer can cause paradoxical activation of the second protomer [9, 24]. Therefore, BRAF monomer inhibitors are not effective for inhibiting class II or III dimers [9, 25]. Novel drugs that inhibit dimers or disrupt dimerization are currently under investigation in preclinical and ongoing clinical trials and have even demonstrated initial efficacy against all three classes of BRAF mutations in preclinical models [25,26,27].

Guidelines for BRAF V600E-mutant NSCLC recommend BRAF and MEK inhibitors as the preferred first-line treatment and immunotherapy, chemotherapy, or a combination as alternative options [5, 7]. Although some clinicians prescribe immunotherapy with or without chemotherapy in the first-line setting, data from studies of immunotherapy or chemotherapy for patients with BRAF V600E-mutant NSCLC are limited with retrospective analyses, small population sizes, and conflicting results [12, 13, 28, 29]. Given the recent approval of encorafenib plus binimetinib for patients with BRAF V600E-mutant mNSCLC [23], we summarize the efficacy and safety profile of this combination therapy and address management of adverse reactions (ARs) in the clinical setting. These management approaches were determined by oncologists on the basis of their experience treating patients with mNSCLC receiving targeted therapy. This article is based on previously conducted studies and does not contain any new studies with human participants.

PHAROS Study: Efficacy and Safety

The phase 2 PHAROS (NCT03915951) study enrolled 59 treatment-naïve and 39 previously treated patients with BRAF V600E-mutant mNSCLC [15]. The key inclusion and exclusion criteria for the study are described in Supplementary Materials Table S1 [30]. Patients received orally administered encorafenib 450 mg once daily plus orally administered binimetinib 45 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. Tumor response was determined by independent radiology review (IRR, also called independent review committee) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [15, 31]. For treatment-naïve patients, objective response rate (ORR) by IRR was 75%, median duration of response (DOR) was not estimable (NE), and median time to response was 1.9 months (Table 1) [15]. Median duration of follow-up for progression-free survival (PFS) by IRR was 18.2 months, median PFS was NE, and median overall survival (OS) was NE. For previously treated patients, ORR by IRR was 46%, median DOR was 16.7 months, and median time to response was 1.7 months. Median duration of follow-up for PFS by IRR was 12.8 months, median PFS was 9.3 months, and median OS was NE.

Table 1 Summary of efficacy data from PHAROS [15]
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In the published primary analysis of PHAROS, safety data were reported as treatment-related adverse events and resulting dose modifications [15]. However, the US Food and Drug Administration (FDA) labels report all-causality ARs that occurred in ≥ 10% of patients in PHAROS and resulting dose modifications [31, 32]. Safety analysis of the 98 patients revealed that the most common ARs reported in ≥ 25% of patients included fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, dyspnea, rash, constipation, and cough (Table 2) [31, 32]. Pyrexia was reported in 22% of patients, with no grade 3 or 4 events. Serious ARs occurred in 38% of patients; ARs occurring in ≥ 2% of patients were hemorrhage (6%); diarrhea (4%); anemia, dyspnea, and pneumonia (3% each); and arrhythmia, device-related infection, edema, myocardial infarction, and pleural effusion (2% each). Dose modifications were generally related to gastrointestinal (GI) ARs. For encorafenib, ARs led to dose interruption in 59% of patients with diarrhea (17%) as the most common, dose reduction in 30% of patients with diarrhea and nausea (8% each) as the most common, and permanent discontinuation in 16% of patients with diarrhea and musculoskeletal pain (3% each) as the most common [31]. For binimetinib, ARs led to dose interruption in 62% of patients with diarrhea (17%) as the most common, dose reduction in 33% of patients with diarrhea (8%) as the most common, and permanent discontinuation in 17% of patients with diarrhea (3%) as the most common [32]. Treatment-related ARs led to dose interruption, dose reduction, and permanent discontinuations of both encorafenib plus binimetinib in 44%, 24%, and 15% of patients, respectively [15].

Table 2 ARs and laboratory abnormalities reported in ≥ 10% of patients in PHAROS [31, 32]
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Dabrafenib plus Trametinib for Patients with BRAF V600E-Mutant mNSCLC

In the updated analysis of the phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant mNSCLC, the ORR and median PFS were 64% and 10.8 months in treatment-naïve patients (n = 36) and 68% and 10.2 months in previously treated patients (n = 57) [14]. According to the US FDA label, the most common ARs in the overall population (n = 93) were pyrexia (55%), fatigue (51%), and nausea (45%) (Supplementary Materials Table S2) [33, 34]. While the incidence of cutaneous squamous cell carcinoma (SCC) was 12% with dabrafenib monotherapy in a previous trial, SCC was reported in 4% of patients receiving dabrafenib plus trametinib [18, 20]. The most common treatment-emergent laboratory abnormalities were hyperglycemia (71%), increased alkaline phosphatase (64%), and increased aspartate aminotransferase (AST; 61%) [33, 34]. For dabrafenib, ARs led to dose interruption in 62% of patients with pyrexia (27%) as the most common, dose reduction in 35% of patients with pyrexia (10%) as the most common, and permanent discontinuation in 18% of patients with pyrexia, decreased ejection fraction, and respiratory distress (2% each) as the most common [33]. For trametinib, ARs led to dose interruption in 57% of patients with pyrexia (16%) as the most common, dose reduction in 30% of patients with pyrexia (5%) as the most common, and permanent discontinuation in 19% of patients with pyrexia, decreased ejection fraction, and respiratory distress (2% each) as the most common [34]. Management strategies for ARs associated with dabrafenib plus trametinib have been summarized in previous publications, and the strategies generally focus on patient education, proactive evaluations, supportive care, and dose modifications [35, 36]. Pyrexia was the leading cause for dose modifications for patients treated with dabrafenib plus trametinib [33, 34]. Therefore, there is an emphasis on managing pyrexia for patients receiving dabrafenib plus trametinib [35, 36].

Encorafenib plus Binimetinib for Patients with Other Solid Tumors

In 2018, encorafenib plus binimetinib was approved by the US FDA for BRAF V600E/K-mutant unresectable or metastatic melanoma [37]. This approval was based on the phase 3 COLUMBUS study, which evaluated encorafenib (n = 194), encorafenib plus binimetinib (n = 192), and vemurafenib (n = 191) [37, 38]. According to the US FDA labels, the most common ARs were fatigue (43%), nausea (41%), and vomiting (30%) (Supplementary Materials Table S3) [31, 32]. The most common laboratory abnormalities were increased creatinine (93%), increased gamma glutamyl transferase (45%), and anemia (36%). For encorafenib, ARs led to dose interruption in 30% of patients with nausea and vomiting (7% each) as the most common, dose reduction in 14% of patients with arthralgia, fatigue, and nausea (2% each) as the most common, and permanent discontinuations in 5% of patients with hemorrhage (2%) as the most common [31]. For binimetinib, ARs led to dose interruption in 33% of patients with left ventricular dysfunction (6%) as the most common, dose reduction in 19% of patients with left ventricular dysfunction and serous retinopathy (3% each) as the most common, and permanent discontinuations in 5% of patients with hemorrhage (2%) as the most common [32].

The PHAROS study demonstrated that the safety profile and pharmacokinetic data (Table 3) for encorafenib plus binimetinib were generally consistent with those reported in previous melanoma studies [15, 39, 40]. Direct comparisons between the clinical trials cannot be made because of differences in trial designs, populations, and analyses; however, dose modification rates vary between melanoma and NSCLC [31, 32]. For patients with BRAF V600E-mutant mNSCLC, GI ARs were the most common reason for both encorafenib and binimetinib dose modifications. For patients with BRAF V600E/K-mutant melanoma, GI ARs, arthralgia, fatigue, and nausea were the most common reasons for encorafenib dose modifications and left ventricular dysfunction, serous retinopathy, and hemorrhage were the most common reasons for binimetinib dose modifications.

Table 3 Pharmacokinetic data
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Encorafenib, in combination with cetuximab, is approved for patients with previously treated BRAF V600E-mutant metastatic CRC [31]. This approval was based on the phase 3 BEACON study, which compared encorafenib plus cetuximab with or without binimetinib (n = 224 and n = 220, respectively) with investigator’s choice of chemotherapy plus cetuximab (n = 221) in patients with previously treated BRAF V600E-mutant CRC [41, 42]. Management strategies for ARs associated with this treatment combination were previously published [43].

Management of Encorafenib plus Binimetinib–Associated ARs in Clinical Practice Treating Patients with BRAF V600E-Mutant NSCLC

While clinical trials monitor and manage ARs [44], this publication outlines real-world strategies for healthcare providers. Providing healthcare providers with management strategies can potentially improve the patient’s experience on treatment, decrease incidence of permanent discontinuations, increase duration of treatment, and improve treatment outcomes [35, 44, 45]. While the NSCLC indication for encorafenib plus binimetinib was recently approved, this combination has been used to treat patients in standard of care with melanoma since 2018 [23, 37]. Therefore, clinicians have years of experience managing the associated ARs, and AR management strategies for patients with melanoma have been previously published [44, 45]. These AR management strategies for patients with BRAF V600E-mutant mNSCLC were developed on the basis of clinical data from the PHAROS trial and recommendations from oncologists experienced in treating patients for NSCLC with encorafenib plus binimetinib along with prior recommendations for treating patients with melanoma.

Prior to beginning treatment with encorafenib plus binimetinib, patients and caregivers should be educated on the potential ARs and what to do should they occur [44]. Special attention should be given to Gl ARs as these are common reasons for dose interruption and reduction [31, 32]. Patients should keep track of ARs between appointments to discuss with their healthcare providers. Baseline and recurring evaluations should be conducted for liver function, electrolytes, creatinine with creatine phosphokinase (CPK), echocardiogram or multiple gated acquisition (MUGA) scan, and dermatologic examinations [31, 32]. Ophthalmologic evaluations should be done at regular intervals and when assessing new or worsening symptoms. Patients with certain comorbidities (e.g., cardiovascular risks) should be closely monitored.

Some ARs can be managed with lifestyle changes or over-the-counter (OTC) medications (Table 4) [44]. However, dose modifications are typically recommended for higher grade or recurrent ARs, and recommendations for general ARs are summarized in Fig. 1 [31, 32]. Starting doses and dose modifications are similar for patients with NSCLC or melanoma; however, for patients with BRAF V600E/K-mutant melanoma, if there is moderate or severe hepatic impairment, the recommended starting dose for binimetinib is 30 mg instead of 45 mg [31, 32]. For BRAF V600E-mutant metastatic CRC, the recommended starting dose of encorafenib is 300 mg instead of 450 mg and the minimum dose is 150 mg instead of 225 mg [31]. ARs of hepatotoxicity, uveitis, dermatologic conditions, cardiomyopathy, new primary malignancy, corrected QT interval (QTc) prolongation, rhabdomyolysis, serous retinopathy, retinal vein occlusion, venous thromboembolism, and interstitial lung disease have specific dose modification recommendations (Fig. 2). Some ARs are associated with either encorafenib or binimetinib and necessitate dose modification of that agent alone (Fig. 2b, c). If encorafenib is permanently discontinued, binimetinib should be discontinued [32]. If binimetinib is withheld, encorafenib should be reduced to a maximum of 300 mg once daily [31]. The following sections describe ARs observed in PHAROS and corresponding management strategies.

Table 4 Clinical management of select adverse reactions
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Fig. 1
figure 1

Dose modifications for AR management [31, 32]. a Recommendations for general ARs. b Encorafenib and binimetinib dose reduction schema. AR adverse reaction, BID twice daily, QD once daily

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Fig. 2
figure 2

Dose modifications for specific ARs [31, 32]. a ARs that require encorafenib plus binimetinib dose modifications. b ARs that require encorafenib dose modifications. c ARs that require binimetinib dose modifications. ALT alanine aminotransferase, AR adverse reaction. AST aspartate aminotransferase, CPK creatine phosphokinase, DVT deep vein thrombosis, LLN lower limit of normal, LVEF left ventricular ejection fraction, PE pulmonary embolism, QTc corrected QT interval, QTcF Fridericia correction formula

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General Disorders

General disorders, comprising systemic instead of localized reactions, were the most common group of ARs, including fatigue (61%), edema (23%), and pyrexia (22%) (Table 2) [31, 32]. For fatigue, management strategies include resting when necessary [44] and exercising when tolerable (Table 4). The appropriate level of physical activity should be determined by several factors, including anemia, comorbidities, and safety (e.g., fall risk) [46]. Additionally, referral for rehabilitation (e.g., physical therapy, occupational therapy, physical medicine) or nutrition consultation should be considered. For edema, compression and elevation may help relieve swelling [45]. For pyrexia, all reported pyrexia events in PHAROS were grade ≤ 2 [31, 32]. For mild to moderate pyrexia (100.4–104.0 °F or 38.0–40.0 °C), management strategies include OTC medications (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) and fluids to maintain hydration [44, 47]. While severe to life-threatening pyrexia (grade ≥ 3 [104.0 °F or 40 °C]) was not reported in PHAROS, it was reported by 4% of patients receiving encorafenib plus binimetinib in previous melanoma trials [31, 32, 47]. Management strategies that can be considered for symptomatic, recurrent, refractory, or grade ≥ 3 pyrexia include treatment interruptions, antibiotics, antipyretics, or low-dose corticosteroids (e.g., prednisone) [44, 48]. Alternative causes for these ARs, such as infection, disease progression, or a hematologic abnormality (e.g., anemia), should also be considered and addressed accordingly. Although most general disorder ARs in PHAROS were grade ≤ 2, dose modifications were required by some patients [31, 32]. Dose modifications are recommended for ARs that are either recurrent grade 2 or any occurrence of grade ≥ 3 (Fig. 1).

Gastrointestinal ARs

GI ARs are class effects associated with BRAF plus MEK inhibitors and are typically mild or moderate [31, 32, 44, 45]. In PHAROS, GI effects included nausea (58%), diarrhea (52%), vomiting (37%), abdominal pain (32%), and constipation (27%) (Table 2) [31, 32]. Most GI ARs can be managed with non-pharmacological or pharmacological strategies on an outpatient basis [44]. Non-pharmacological management strategies include dietary changes, such as eating frequent, small meals and reducing fiber consumption (Table 4) [44]. Encorafenib and binimetinib can be taken with or without food [31, 32]. Eating a small meal with treatment may help with nausea. No data evaluating the impact of fasting on efficacy and tolerability of encorafenib plus binimetinib for patients from PHAROS are available. Hydration is critical given the potential for loss of fluids through vomiting and diarrhea to lead to dehydration, hypotension, or, in severe incidences, kidney failure [45]. Sports drinks are an option for remaining hydrated and replacing electrolytes.

OTC medications, antiemetics (e.g., dexamethasone, lorazepam, metoclopramide, olanzapine, prochlorperazine, 5-hydroxytryptamine-3 [5-HT3] receptor antagonists), and anti-diarrheal medications (e.g., loperamide, diphenoxylate/atropine, octreotide) can be used to relieve GI symptoms [44, 49]. When prescribing drugs for coadministration, healthcare providers should consider all current medications and be cautious of potential drug interactions. Encorafenib is associated with QTc prolongation, so when administered with other drugs that may prolong QT intervals (e.g., olanzapine, metoclopramide, 5-HT3 receptor antagonists), patients should be monitored by electrocardiogram [31, 49]. Dexamethasone is a CYP3A4 inducer and may lower encorafenib plasma concentration and subsequently efficacy [31, 50]. Other causes of GI effects, such as infections (e.g., Clostridium difficile) or progressive disease, should also be considered [45]. Although most GI ARs in PHAROS were grade ≤ 2, they were the most common reasons for dose interruptions, reductions, and permanent discontinuations for both encorafenib and binimetinib [31, 32]. Dose modifications are recommended for GI ARs that are either recurrent grade 2 or any occurrence of grade ≥ 3 (Fig. 1).

Musculoskeletal and Connective Tissue Disorders

Musculoskeletal pain, which included events such as back pain, arthralgia, myalgia, and non-cardiac chest pain, was reported by 48% of patients [31, 32]. Although not reported in PHAROS, arthritis occurred in 1% and 2% of patients receiving encorafenib with and without binimetinib, respectively, in a prior melanoma trial; polyarthritis occurred in 2% of patients receiving encorafenib, including grade 3 in 1% [38]. Medication (e.g., analgesics, NSAIDs, low-dose anti-inflammatory drugs, or steroids) [44], physical therapy, stretching, and hot and cold compresses may relieve pain and swelling of joints. Moderate- to high-dose steroids should be considered for severe ARs, including myositis or vasculitis [44, 45]. A rheumatologist consultation may be recommended for select cases, including if considering intra-articular or high-dose steroids. If a patient is refractory to steroids, leflunomide or methotrexate may be considered after a rheumatologist consultation. Recurring or severe musculoskeletal ARs should be managed with dose modifications (Fig. 1) [31, 32].

In addition to musculoskeletal pain, increased CPK was a laboratory abnormality observed in 41% of patients, including grade ≥ 3 in 3% of patients [31, 32]. Increased CPK may be a potential sign of rhabdomyolysis, which is the rapid breakdown of skeletal muscle and has been associated with encorafenib plus binimetinib treatment in previous trials with melanoma (0.1%) [32, 51]. CPK and creatinine levels should be measured prior to initiating treatment and periodically throughout treatment [32]. If a patient has asymptomatic grade 4 CPK elevation (> 10 × upper limit of normal) or any-grade symptomatic CPK elevation or renal impairment, binimetinib should be withheld ≤ 4 weeks (Fig. 2c) [32, 47]. If CPK levels have improved to grade ≤ 1 (≤ 2.5 × upper limit of normal), binimetinib can be resumed at a reduced dose. However, if there is no improvement, binimetinib should be permanently discontinued and the dose of encorafenib adjusted [31, 32, 47]. In clinical practice, if the patient has low-grade symptomatic CPK but is otherwise doing well, it would be considered reasonable to continue treatment under close observation.

Hepatotoxicity

Hepatotoxicity manifests as increased liver enzymes in laboratory tests, including alanine aminotransferase (ALT) and AST. ALT was increased in 34% of patients, with grade 3 or 4 in 9% [31, 32]. AST was increased in 31% of patients, with grade 3 or 4 in 10%. Patients should be aware of the possible signs of liver dysfunction, such as jaundice, dark or brown urine, nausea, vomiting, loss of appetite, fatigue, bruising, and bleeding [31, 32]. Liver function should be evaluated prior to treatment and monthly throughout treatment [31, 32]. Specific dose modification guidance for ALT and AST elevations is found in Fig. 2a. A differential diagnosis should be conducted, and alternative causes considered, such as liver injury or infection [45].

Ocular Disorders

Ocular disorders are class effects associated with BRAF and MEK inhibitors [35, 44]. Visual impairment was observed in 29% of patients, with grade ≥ 3 events in 2% of patients (Table 2) [31, 32]. Additionally, serous retinopathy without blindness (2%) and uveitis (1%) were reported in PHAROS. In previous clinical trials with encorafenib plus binimetinib for patients with melanoma, serous retinopathy without blindness (20%), uveitis (4%), and retinal vein occlusion (0.1%) were reported. Visual symptoms should be assessed at each visit, and ophthalmologic evaluations should be performed at regular intervals and as directed for new visual disturbances. Safety has not been determined for patients with a history of or risk factors for retinal vein occlusion [32]. In clinical practice, asymptomatic patients might not undergo ophthalmologic evaluations [31, 32]. However, this approach may differ, and it is best to use clinical judgment when determining when ophthalmologic examinations are necessary. Patients should be educated about the possibility of changes to their vision and be advised to inform their healthcare provider. For symptomatic relief, management strategies include topical NSAIDs or carbonic anhydrase inhibitors [44]. For some cases, an ophthalmologist may be consulted. Symptomatic serous retinopathy or retinal pigment epithelial detachments should be managed by withholding binimetinib for up to 10 days (Fig. 2c) [32]. If the condition improves and is asymptomatic, binimetinib should be resumed at a reduced dose. However, if the condition does not improve, binimetinib could be resumed at a reduced dose or discontinued.

Skin and Subcutaneous Tissue Disorders

Dermatologic ARs are considered a class effect of both BRAF and MEK inhibitors (Table 2, Supplementary Materials Table S3) [35, 44]. In PHAROS, dermatological ARs included rash (27%), pruritus (16%), dry skin (13%), and alopecia (12%) [31, 32]. It is important for patients to inform their healthcare provider about any skin changes immediately [31, 32]. Management strategies for mild rashes include creams, emollients, topical corticosteroids (e.g., hydrocortisone) [44], changes in clothing, or lotions. Moderate to severe cases may require additional medications, such as topical steroids (e.g., triamcinolone, clobetasol), prednisone, antihistamines, or referral to a dermatologist [44]. Photosensitivity was reported by 4% of patients in a previous trial of encorafenib plus binimetinib for melanoma [52]. Patients should proactively prevent photosensitive reactions by applying broad-spectrum sunscreen and lip balm, wearing ultraviolet-protective clothing, avoiding sun exposure [44], and avoiding alcohol-based fragrances or lotions. Dose modifications for general dermatologic ARs are summarized in Fig. 2a.

New skin cancers, including cutaneous SCC and basal cell carcinoma, are associated with encorafenib and other BRAF inhibitors [21, 31, 53]. In PHAROS, cutaneous SCC and skin papilloma each occurred in 2% of patients [31]. The incidence of SCC is decreased by the addition of MEK inhibitors [20, 53]. For instance, in previous trials with encorafenib monotherapy and encorafenib plus binimetinib for patients with melanoma, cutaneous SCC occurred in 8% and 3% of patients, respectively [31]. Proactive management is important as the median onset to first occurrence for cutaneous SCC with encorafenib plus binimetinib for patients with melanoma was 5.8 months. Patients should proactively check their skin for any changes (e.g., new wart, a sore that bleeds or does not heal, changes to a mole) and alert their healthcare provider. Healthcare providers should check the patient’s skin before treatment and every 2 months during treatment and up to 6 months after treatment. In clinical practice, ongoing dermatologic evaluations every 3 to 6 months are suggested. Dose modifications are not recommended for new primary cutaneous malignancies, but non-cutaneous malignancies can also occur. Patients should be monitored for symptoms of non-cutaneous malignancies, and encorafenib should be discontinued for RAS-mutant non-cutaneous malignancies (Fig. 2b).

Cardiac Disorders

In PHAROS, cardiomyopathy manifesting as left ventricular dysfunction was reported in 11% of patients, with grade 3 in 1% (Table 2) [31, 32]. In a previous melanoma trial, left ventricular dysfunction occurred in 7% of patients, with grade 3 in 2% and a median time to onset of 3.6 months. Cardiomyopathy resolved in 82% and 87% of patients in NSCLC and melanoma trials, respectively. Ejection fraction should be assessed by echocardiogram or MUGA scan before initiating treatment, 1 month after treatment initiation, and every 2 to 3 months during treatment. Safety of encorafenib plus binimetinib has not been evaluated in patients with baseline ejection fraction that is < 50% or below institutional lower limit of normal. In addition, dose-dependent QTc prolongation has been associated with encorafenib treatment, with an increase in QTcF to > 500 ms in 2.1% of patients in PHAROS [31]. Electrolytes should be evaluated, and abnormalities should be remedied. Close monitoring should be instituted for patients with cardiovascular risks, including current or risk for developing QTc prolongation [31, 32]. Patients who experience a decrease in left ventricular ejection fraction or prolongation in QTc need to be carefully assessed, and treatment should be withheld, dose reduced, or permanently discontinued on the basis of severity and recurrence as outlined in Fig. 2. Consultation with a cardiologist should also be considered [44].

Conclusion

In the PHAROS study, encorafenib plus binimetinib was an effective therapy option for patients with BRAF V600E-mutant mNSCLC and was generally well tolerated, with most ARs being grade ≤ 2 [15, 31, 32]. ARs were generally managed with dose interruptions or dose reductions, with ARs resulting in permanent discontinuation of encorafenib or binimetinib in only 16% and 17% of patients, respectively. The safety profile was generally consistent with that observed in patients with BRAF V600E- or V600K-mutant unresectable or metastatic melanoma. The 5-year updated analysis from that trial demonstrated continued tolerability with no new safety concerns [52]. Management of ARs associated with encorafenib plus binimetinib involves proactive communication, supportive care, and occasional dose modifications. Proactive AR management may prevent unnecessary treatment discontinuations and enable patients to remain on encorafenib and binimetinib while deriving clinical benefit.