Adverse Event Management in Patients with BRAF V600E‐Mutant Non‐Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

The review summarizes treatment guidelines, along with key insights obtained from previous clinical‐trial and real‐world experiences in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for non‐small cell lung cancer.

Abstract

Therapies for advanced non‐small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600‐mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression‐free survival of 10–11 months. BRAF mutations are a high‐frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical‐trial and real‐world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC.

Implications for Practice.

The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E‐mutant non‐small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.

Introduction

Lung cancer, which accounts for approximately 14% of all cancer diagnoses, is the deadliest type, having caused 25% of cancer deaths in the U.S. in 2017 [1]. Approximately 85% of lung cancers are of the non‐small cell (NSCLC) type [1], and recent investigations have begun to unravel the intricacies of NSCLC through the discovery of several activating molecular alterations that drive NSCLC oncogenesis [2]. Some known genomic alterations in NSCLC include those observed in EGFR, ALK, ROS1, RET, MET, and HER2 genes [3], [4], [5], [6], [7].

Chemotherapy was traditionally used to treat advanced‐stage NSCLC [1]; however, the treatment landscape now includes immune checkpoint inhibitors and targeted therapeutics, which directly inhibit aberrant signaling driven by specific molecular alterations [3], [4], [5], [6], [7]. Therapies targeting NSCLC with mutations in the BRAF gene, which encodes for a protein involved in the mitogen‐activated protein kinase (MAPK) signaling pathway, are the most recent to have received regulatory approval by the U.S. Food and Drug Administration (FDA) and European Commission. The combination of dabrafenib and trametinib is now approved by the FDA for use in patients with NSCLC with a valine‐to‐glutamic acid substitution at position 600 (V600E) in BRAF that drives constitutive activation of the protein and MAPK signaling [8].

The advent of novel therapies introduces the risk of new toxicities. In this review, we focus on toxicities associated with dabrafenib plus trametinib that may be unfamiliar to care providers in the thoracic and general oncology community. Furthermore, we summarize official treatment guidelines in addition to experience from clinical practice for the proper management of these events with the goal of enhancing patient benefit and quality of life.

BRAF Mutations in NSCLC

BRAF is a serine/threonine kinase downstream of RAS in the MAPK signaling pathway (Fig. 1) [2], [8]. Activating mutations in BRAF lead to constitutive activation and downstream MEK phosphorylation, enhancing cell growth, proliferation, and survival [2]. Somatic mutations in BRAF have been identified in cancers such as melanoma, papillary thyroid cancers, colorectal cancers, ovarian carcinomas, and lung cancers [2]. In melanoma, BRAF mutations are observed in approximately 50% of cases [9], [10], [11]. In lung cancer, the frequency of BRAF mutations is relatively low at 2%–4%. Nevertheless, based on the reported incidence of new metastatic melanoma and lung cancer cases in the U.S. [12] and the reported prevalence of BRAF mutations in the respective tumor types, the number of patients with newly diagnosed metastatic disease harboring BRAF mutations would be expected to be similar in melanoma and NSCLC (≈ 2,000 new metastatic cases annually in the U.S.). Most importantly, response to combined BRAF and MEK inhibition can be both effective and long lasting. About half of BRAF mutations in NSCLC are at V600E [2], [8], [10], [13].

Figure 1.

BRAF mutations in the context of mitogen‐activated protein kinase (MAPK) molecular alterations. (A): BRAF is an integral component of the intracellular MAPK pathway. (B): BRAF V600E mutations encode for a constitutively active BRAF protein, leading to overactive MAPK pathway signaling, aberrant proliferation, and cell growth, which can drive cancer initiation and progression. (C): In cells that do not harbor a BRAF mutation, BRAF inhibitors can lead to paradoxical hyperactivation of BRAF, leading to enhanced MAPK signaling and increased cellular proliferation. (D): However, mutant BRAF‐specific inhibitors, such as dabrafenib, provide antitumor activity in BRAF V600‐mutant tumors by mitigating hyperactive signaling.

Clinical Characteristics of Patients with BRAF‐Mutant NSCLC

The prognostic significance of BRAF mutations in NSCLC largely remains unclear. The heterogeneity of the disease, the rarity of the mutation, small patient numbers, and limited number of studies contribute to this lack of understanding [8]. In one retrospective series of patients with stage I–IV NSCLC, univariate (hazard ratio [HR], 2.97; p < .001) and multivariate (HR, 2.18; p = .014) analysis showed a significant association between BRAF V600E mutation and shorter overall survival (OS) [14]. However, other reports have suggested no association or a trend toward improved survival in patients with tumors harboring BRAF mutations [15], [16]. Overall, the limited number of patients included in these studies and the heterogeneous clinical characteristics of those patients makes interpretation of the prognostic significance of BRAF mutations difficult. Large‐scale analyses are warranted to fully address the impact of BRAF mutations on survival in NSCLC.

With regard to clinical characteristics, patients with BRAF‐mutant NSCLC appear more likely to have a history of smoking compared with patients with tumors harboring EGFR mutations or ALK rearrangements, which are more commonly observed in never smokers [13], [15], [17], [18]. A recent large‐scale analysis (n = 17,664 patients; 18,679 molecular analyses) revealed that the incidence of activating BRAF mutations was similar among patients with no smoking history, former smokers, and current smokers (2.3%, 1.6%, and 1.7%, respectively); this finding suggests that patients should be screened for BRAF mutations regardless of smoking history [16], [19]. Interestingly, some evidence suggests that V600E mutations may be more common in never smokers (≈ 5%) than current/former smokers (≈ 2%), whereas other BRAF mutations were found exclusively in current or former smokers [16], [19].

The frequency of BRAF mutations has shown an association with specific ethnicities in other tumor types [20], [21], [22]. In NSCLC, BRAF mutations have been reported at a lower frequency in Asian patients (≈ 0.8%–2.0%) compared with white patients (≈ 2%–4%), and the proportion of V600E mutations among those with BRAF mutations has been reported to be lower in Asian patients (30%–40% vs. ≈ 50%–70%) [2], [16], [19], [23], [24], [25], [26]. These data should be interpreted cautiously because of the rare nature of the mutation, the limited sample sizes of studies included, and the nature of comparisons across studies. No associations between other clinical characteristics, including age and sex, and BRAF mutations, have been established [13], [27]. Overall, further studies are needed for a better understanding of the pathological significance of BRAF‐mutant NSCLC.

Clinical Development of Dabrafenib plus Trametinib

Dabrafenib is an inhibitor of several mutated forms of BRAF kinases, and trametinib is a reversible inhibitor of MEK1 and MEK2 activation and kinase activity. Both compounds were initially investigated and approved to treat BRAF V600E‐mutant metastatic melanoma as single agents. Dabrafenib resulted in a significant increase in progression‐free survival (PFS) compared with dacarbazine (medians, 5.1 vs. 2.7 months; p < .0001) [28], and trametinib resulted in a significant PFS increase compared with chemotherapy (medians, 4.8 vs. 1.5 months; p < .0001) for BRAF V600E‐ or V600K‐mutant metastatic melanoma [29].

As dabrafenib and trametinib affect distinct targets within the MAPK pathway (Fig. 1), it follows that outcomes may be improved when combining treatments versus the respective monotherapies. This hypothesis was confirmed in two clinical trials in patients with unresectable or metastatic BRAF V600E/K‐mutant melanoma, in which dabrafenib plus trametinib resulted in substantial improvements in OS, PFS, and objective response rate compared with dabrafenib plus placebo [30] or vemurafenib monotherapy [31].

Because BRAF mutations are also found in patients with NSCLC, dabrafenib as monotherapy and in combination with trametinib was investigated to treat patients with BRAF V600E‐mutant metastatic NSCLC in the multicenter, phase II, nonrandomized, multicohort, open‐label BRF113928 trial [32], [33], [34]. Histologically confirmed stage IV BRAF V600E‐mutant NSCLC was required for enrollment. Patients were divided into three cohorts (A, B, and C). Cohort A enrolled previously treated patients (n = 78) to receive dabrafenib monotherapy 150 mg twice daily. Patients in cohort B (previously treated [n = 57]) and cohort C (treatment naive [n = 36]) received combination therapy with dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. The primary endpoint was investigator‐assessed overall response rate, and key secondary endpoints included investigator‐assessed PFS and OS as well as safety. Patients had a median age of 64–67 years (range, 28–85 years); most had a baseline Eastern Cooperative Oncology Group performance status of 0 (27%) or 1 (63%). Nearly all participants (96%) had adenocarcinoma, and 68% were current or former smokers (Table 1).

Table 1. Patient demographics and clinical activity in the BRF113928 trial [32], [33], [34], [35] .

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; PFS, progression‐free survival.

Results from cohort A (median follow‐up, 10.7 months) demonstrated the clinical activity of dabrafenib monotherapy, with a partial response (PR) reported in 33% of previously treated patients and a median duration of response of 9.6 months (95% confidence interval [CI], 5.4–15.2 months). The median PFS and OS were 5.5 months (95% CI, 3.4–7.3 months) and 12.7 months (95% CI, 7.3–16.9 months), respectively [32].

However, as has been observed in patients with melanoma, clinical activity in patients with NSCLC is enhanced with combination dabrafenib plus trametinib when indirectly compared with dabrafenib monotherapy. In cohort B, 66.7% (95% CI, 52.9%–78.6%) of patients with previously treated BRAF V600E‐mutant NSCLC treated with dabrafenib plus trametinib achieved a response, including 5% with complete response (CR) and 61% with PR. The median PFS was 10.2 months (95% CI, 6.9–16.7 months), and the median OS was 18.2 months (95% CI, 14.3 months to not estimable) [35]. Similar results were observed in treatment‐naive patients in cohort C; 64% of patients had a response (58% PR; 6% CR), with a median PFS of 10.9 months (95% CI, 7.0–16.6 months). At the time of the primary analysis for cohort C, the median OS was 24.6 months (95% CI, 12.3 months to not estimable), with a 2‐year OS of 51% (95% CI, 33%–67%; Table 1) [34]. Based on the data from this trial, the combination was approved by the FDA in June 2017.

Adverse Events and Management

The adverse event profile observed when treating NSCLC with older targeted agents is well characterized [36]. For instance, epidermal growth factor receptor inhibitors are associated with cutaneous events, diarrhea, mouth sores, and loss of appetite, whereas drugs targeting ALK rearrangements can cause nausea and vomiting, diarrhea, constipation, fatigue, and vision changes. The combination of dabrafenib plus trametinib has unique, and sometimes challenging, toxicity management requirements.

Among 93 patients with previously untreated (n = 36) or treated (n = 57) metastatic BRAF V600E‐positive NSCLC treated with dabrafenib plus trametinib in the BRF113928 trial [37], 53 (57%) were treated for >6 months and 27 (29%) were treated for ≥1 year. Pyrexia, fatigue, nausea, and dry skin were the most common events overall (Table 2), and pyrexia most frequently led to dose reductions, interruptions, or discontinuations (Table 3) [37]. Additional events included a range of cutaneous, ocular, and hemorrhagic conditions [37]. Notably, no treatment‐related deaths occurred on study.

Table 2. Summary of any adverse events occurring in ≥20% of patients during treatment with dabrafenib plus trametinib for BRAF V600E‐mutant non‐small cell lung cancer [19], [21], [26] .

In each cohort, adverse events were reported only if occurring at grade 1/2 in ≥10% of patients.

^aPreviously treated patients were defined as having documented tumor progression after ≥1 prior platinum‐based chemotherapy but ≤3 previous systemic anticancer therapies.

Abbreviation: NR, not reported.

Table 3. Summary of adverse events leading to dosing changes during treatment with dabrafenib plus trametinib for BRAF V600E‐mutant non‐small cell lung cancer [19], [21], [26] .

Clinical experience with dabrafenib plus trametinib in melanoma has yielded substantial information about adverse‐event management, demonstrating that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation [38]. Guidance on the management of specific events during dabrafenib plus trametinib therapy for NSCLC is summarized in Figure 2 and detailed subsequently, with insights from clinical and regulatory guidelines and clinical experience across indications [37], [39], [40], [41], [42].

Figure 2.

Guidance for adverse event management.

Abbreviation: NA, not applicable.

Figure 3.

Photographs of typical cutaneous adverse events experienced by patients treated with dabrafenib and trametinib [49], [50]. (A): Patient who developed acneiform skin rash typical of MEK inhibitor therapy. Patients treated with a BRAF inhibitor who developed keratoacanthoma (B) and plantar hyperkeratosis (C).

Note: Image A reprinted with permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Moreno Garcia V, et al. Br J Cancer 2012;107:1797–800, copyright 2012. Images B and C reprinted from Rinderknecht JD, et al. PLoS One 2013;8:e58721. Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Pyrexia (Fever)

Across all indications, pyrexia is consistently the most common adverse reaction with dabrafenib plus trametinib and led to dose reduction (10%), interruption (27%), or discontinuation (2.2%) more frequently than any other event in patients with NSCLC [37]. Pyrexia is specifically related to dabrafenib treatment and is defined as a body temperature ≥38.5°C in the absence of infection [43]. Associated reactions can include influenza‐like illness, cytokine release syndrome, and systemic inflammatory response syndrome. Serious noninfectious febrile events may occur, defined as a serious event of pyrexia complicated by hypotension, dehydration (with or without the need for intravenous fluids), severe rigor or chills, or renal failure in the absence of another identifiable etiology. The underlying mechanism by which dabrafenib causes pyrexia is not fully understood but has been hypothesized to be related to a dabrafenib metabolite [43], [44], [45].

Experience from melanoma studies suggests that initial onset of pyrexia occurs during the first 3–4 weeks of treatment, although it can occur as early as the first day of treatment and up to many months after treatment [45]. On average, fevers last approximately 9 days. Generally, half of patients who experience pyrexia have recurrent events that typically last 4–5 days [44], [45].

It is important to note that pyrexia does not correlate with treatment response or clinical outcome and that no baseline characteristics predict the development of the condition [43], [45].

Management.

Prior to initiating dabrafenib plus trametinib, it is recommended that patients be informed of the possibility of developing fever and alerted to associated effects such as chills or shaking chills, dehydration, hypotension, dizziness, or kidney problems [37], [39]. Patients should also be encouraged to immediately report fever or related symptoms while undergoing dabrafenib plus trametinib treatment [46]. If pyrexia does occur, the recommended course of action is to rule out infection [37], [39], although an infectious workup (i.e., complete blood count, comprehensive metabolic panel, and blood and urine cultures) is not recommended if pyrexia is uncomplicated, with no evidence of localizing symptoms [44], [45]. If pyrexia is severe, serum creatinine should be monitored.

Guidelines generally recommend withholding medication based on the degree of fever [47]. If the patient's temperature is 38.5°C–40°C, dabrafenib can be withheld until fever resolves then resumed at the same or lower dose level, while trametinib dosing may be continued as usual [37], [39]. If the fever exceeds 40°C or is complicated by rigors, hypotension, dehydration, or renal failure, both drugs should be withheld until fever resolves, after which they may be resumed at a lower dose level or permanently discontinued if deemed necessary [37], [39]. In addition to official guidelines, clinical experience treating patients with melanoma suggests that the most effective treatment for pyrexia is prompt interruption of dabrafenib and trametinib at the first symptom [45]. Acetaminophen or nonsteroidal anti‐inflammatory drugs can be used for symptom control.

When resuming treatment after a dose interruption for pyrexia, antipyretics may be used as secondary prophylaxis if the patient had a prior episode of severe febrile reaction or fever associated with complications. Corticosteroids (e.g., prednisone 10 mg daily) can be administered for at least 5 days for a second or subsequent pyrexia event if temperature does not return to baseline within 3 days, or for pyrexia associated with complications but no active infection [37], [39]. Corticosteroids are considered more effective than dose reduction or antipyretics as secondary prophylaxis for recurrent pyrexia [43].

Cutaneous Events

Dermatologic events are considered a class effect of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) [40], [42], [48]. Cutaneous toxicities are especially common with BRAFi because of paradoxical activation of the MAPK pathway in BRAF wild‐type cells (Fig. 1) [40]. Events commonly observed in patients treated with BRAFi and/or MEKi include rashes and other skin irritations and hyperproliferative skin disorders (rash was reported in 19% of patients with NSCLC treated with the combination in BRF113928; Fig. 2) [40], [42]. Although the time to onset of cutaneous adverse events in patients with NSCLC treated with dabrafenib plus trametinib has not been reported, the time to onset of rash (median, ≈ 2 weeks) and cutaneous squamous cell carcinoma (median, ≈ 7 weeks) in patients with melanoma receiving BRAF inhibitor therapy was often rapid [49].

Events and Management.

A proactive approach is recommended to effectively manage cutaneous toxicities. This approach includes dermatologic evaluations prior to initiating dabrafenib plus trametinib, followed by checkups every 2 months during therapy and for up to 6 months following discontinuation [37], [39]. Patients should be educated about rash and other possible skin reactions and should be encouraged to promptly report skin irritation symptoms, such as a persistent, bothersome rash, acne, redness, swelling, peeling, or tenderness of hands or feet. Additionally, patients should be made aware that dabrafenib monotherapy or dabrafenib plus trametinib may increase risk of developing new skin cancers, including cutaneous squamous cell carcinoma, keratoacanthoma, and basal cell carcinoma. Encourage patients to maintain vigilance and immediately report skin changes, including a new wart, skin sore or reddish bump that bleeds or does not heal, or changes in the size or color of a mole.

Dermatitis acneiform, an eruption of papules and pustules typically on the face, scalp, upper chest, and back, is the most common and most dose‐limiting toxic effect of trametinib monotherapy, but its incidence is decreased when dabrafenib is used in combination with trametinib [29], [50], [51], [52]. A less specific maculopapular rash can also occur, causing symptoms of itching, burning, and tightness of the skin [53].

Rash can be managed based on toxicity. For grade 1 rash, topical care such as cold compresses, moisturizing creams, potassium permanganate/oatmeal baths, sulfo‐salicylic cream, topical steroid, or antibiotic creams can be used. Additionally, oral antihistamines may be effective. If the rash is more serious (e.g., grade 2 or 3), oral corticosteroids or low‐dose acitretin can be used [40].

Although squamous cell cancers can occur, they may be asymptomatic. Because these events are associated with paradoxical activation of BRAF in nontumor cells, they are less frequently observed when dabrafenib is combined with downstream MEK inhibitors. Patients should be referred for prompt removal of any suspicious lesions; typically, squamous cell carcinomas present as fast‐growing, firm, round nodules that are flesh‐toned to red in color.

Ultimately, if intolerable grade 2 or grade 3/4 skin toxicities occur and the measures outlined above are ineffective, the recommended course of action is to withhold dabrafenib plus trametinib for ≤3 weeks. If symptoms improve, treatment may be resumed at a lower dose level; however, if there is no improvement, permanently discontinue dabrafenib plus trametinib [37], [39].

Ocular Toxicities

Visual disturbances and ocular toxicities, including blurred vision, retinal detachment, retinal vein occlusion, and chorioretinopathy, have been reported with MEKi [54], and uveitis and iritis have been reported with BRAFi [37], [54]. Retinopathy, retinal vein occlusion, and retinal detachment may be asymptomatic or result in mild visual disturbances, blurry or decreased vision, or visual field defects [53]. Uveitis is characterized by inflammation in the uvea of the eye and can be asymptomatic or result in eye redness, vison loss, light sensitivity, eye pain, floaters, or headache [53], [55], [56].

Management.

Patients should undergo thorough ophthalmologic examinations both before and after initiating treatment with dabrafenib plus trametinib [54]. A baseline ophthalmologic assessment provides an important reference for subsequent evaluations any time a patient reports visual disturbances. It is also important to educate patients on the possibility of developing eye problems, including those that may lead to blindness, and the importance of promptly reporting any symptoms, such as vision changes or loss, seeing colored dots or halo (blurred outline around objects), eye pain, swelling, or redness [37], [39].

No validated treatment options are currently available for ocular toxicities, highlighting the importance of rapid diagnosis and close monitoring [54]. If ocular conditions occur, treatment changes are recommended. For retinal pigment epithelium detachment, trametinib should be withheld for ≤3 weeks, then can be resumed at the same or lower dose level if improved, or resumed at a lower dose or discontinued if there is no improvement. For retinal vein occlusion, trametinib should be permanently discontinued. Mild or moderate uveitis (including iritis and iridocyclitis) resistant to ocular therapy, or severe uveitis, should be addressed by withholding dabrafenib for ≤6 weeks and treating as clinically indicated [55]. If improvement to grade 0–1 uveitis is observed, treatment may be resumed at the same or a lower dose level. However, if the condition does not improve, and/or persistent grade ≥2 uveitis lasts longer than 6 weeks, dabrafenib should be permanently discontinued. For patients experiencing iritis, ocular therapy can be administered without dose modification of dabrafenib or trametinib.

Cardiac‐Related Events

Cardiac‐related adverse events have been observed with both BRAFi and MEKi therapies [38], [57], [58], although they appear to be more strongly associated with MEKi. Initial studies with trametinib reported left ventricular ejection fraction (LVEF) dysfunction in 8% of patients compared with 5% of patients using combination therapy in the COMBI‐d trial in patients with BRAF V600‐mutant metastatic melanoma. In the METRIC trial evaluating trametinib monotherapy, changes in LVEF were noted to be asymptomatic and reversible [29].

Management.

Prior to initiating dabrafenib plus trametinib, patients should be educated on the possibility of developing heart problems, and to remain vigilant and immediately report any signs and symptoms. Additionally, patients should undergo an echocardiogram or multigated acquisition scan to assess LVEF prior to initiation of dabrafenib plus trametinib. Follow‐up assessments are recommended 1 month after initiation and at 2‐ to 3‐month intervals during treatment [37], [39].

If asymptomatic LVEF occurs (absolute decrease ≥10% from baseline and below institutional lower limits of normal from pretreatment value), withhold trametinib for ≤4 weeks, then assess for improvement. If normal values are restored, treatment may be resumed at a lower dose level. If LVEF does not improve, then trametinib should be permanently discontinued. If LVEF manifests as symptomatic congestive heart failure or a ≥20% decrease from baseline that is below the lower limit of normal, permanently discontinue trametinib and withhold dabrafenib until improvement is observed, then resume dabrafenib at the same dose.

Hemorrhages

Major hemorrhagic events can occur with dabrafenib plus trametinib, as revealed in the COMBI‐d study in patients with melanoma, in which 19% of patients experienced hemorrhagic events with dabrafenib plus trametinib [37]. The rate of hemorrhagic events was also relatively high in NSCLC, occurring in 23% of patients receiving combination therapy, including two fatalities due to these events [37].

Management.

Effective management of hemorrhage begins with educating patients on the possibility of developing bleeding problems and their potential severity, with instructions to immediately report any unusual signs of bleeding. If grade 3 hemorrhage occurs, both dabrafenib and trametinib should be withheld, then resumed at a lower dose level if improvement is observed. If there is no improvement, or if grade 4 hemorrhage occurs, both drugs should be permanently discontinued [37], [39].

Other Serious Adverse Events/Abnormalities

In addition to the events described above, several additional rare but serious events may occur. Thromboembolic events were observed in 4.3% of patients receiving combination therapy for NSCLC [39]. Patients should be educated about possible symptoms. Trametinib should be withheld if the condition is uncomplicated, and both agents should be discontinued permanently if the condition appears life threatening [37], [39].

Interstitial lung disease/pneumonitis occurred in 2.2% of patients treated with dabrafenib plus trametinib for NSCLC [39]. Should this event occur, the recommended course of action is permanent discontinuation of trametinib. Moreover, if patients demonstrate new or progressive pulmonary symptoms and findings, including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, trametinib should be withheld pending clinical investigations.

Several treatment‐emergent laboratory abnormalities were also observed among patients treated with combination therapy for NSCLC. These included abnormal findings on hematological parameters (neutropenia, anemia, lymphopenia, and thrombocytopenia), liver function tests (increased aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase), and chemistry parameters (hyperglycemia, hypoalbuminemia, hypophosphatemia, and hyponatremia), ranging in frequency between 32% and 71% of patients [37], [39]. Although there is no specific guidance for the management of these abnormalities, periodic monitoring is recommended.

Differential Interruption/Discontinuation

It is important to note that, as described above and summarized in Figure 2, recommendations vary by event and may include dose modifications of dabrafenib or trametinib individually, as opposed to both simultaneously [37], [39]. When either drug is reduced or interrupted, it is important to remain alert because the adverse event profile may shift to become more characteristic of the ongoing monotherapy. Common events associated with trametinib monotherapy include rash, diarrhea, and lymphedema [39], whereas events associated with dabrafenib monotherapy include hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar‐plantar erythrodysesthesia syndrome [37]. Hyperproliferative skin conditions are of particular concern if discontinuing trametinib and continuing with dabrafenib. In the BRF113928 trial, cutaneous squamous cell carcinoma occurred in 12% of patients treated with dabrafenib monotherapy compared with 4% treated with dabrafenib plus trametinib [32], [33]. Because treatment guidance recommends reducing or discontinuing trametinib and continuing dabrafenib during events such as retinal vein occlusion, pigment epithelium detachment, deep vein thrombosis, and pulmonary embolism, the onset of hyperproliferative skin conditions should be monitored closely when trametinib is reduced to address these or other events.

Conclusion

The management of key adverse reactions associated with dabrafenib plus trametinib in patients with BRAF V600E‐mutant NSCLC owes a great deal to the lessons learned in patients with BRAF V600‐mutant metastatic melanoma. Based on the diversity of potential adverse events during treatment with dabrafenib plus trametinib, it is important that effective communication occurs between care providers and their patients, and across the entire clinical team, to ensure that these events are reported early and managed effectively. Proper management includes remaining vigilant for new events that may occur when reducing or discontinuing either drug in the combination, especially hyperproliferative skin conditions, which are associated with dabrafenib monotherapy. Although dabrafenib plus trametinib treatment is associated with adverse events that may be uncommon in the thoracic and general oncology community, vast experience with the combination in melanoma has demonstrated that the events are generally low grade and can be effectively managed to improve patient experience on treatment and ultimately treatment outcomes.

Author Contributions

Conception/design: Anna Chalmers, Laura Cannon, Wallace Akerley

Collection and/or assembly of data: Anna Chalmers, Wallace Akerley

Data analysis and interpretation: Anna Chalmers, Laura Cannon, Wallace Akerley

Manuscript writing: Anna Chalmers, Laura Cannon, Wallace Akerley

Final approval of manuscript: Anna Chalmers, Laura Cannon, Wallace Akerley

Disclosures

The authors indicated no financial relationships.