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European Journal of Hospital Pharmacy logoLink to European Journal of Hospital Pharmacy
. 2020 Sep 3;28(4):182–189. doi: 10.1136/ejhpharm-2020-002347

The incidence and risk of cutaneous toxicities associated with dabrafenib in melanoma patients: a systematic review and meta-analysis

Chen Peng 1,✉, Lei Jie-Xin 2
PMCID: PMC8239268  PMID: 32883694

Abstract

Objective

Dabrafenib, an inhibitor of mutated BRAF, has significant clinical activity in melanoma patients but is linked to a spectrum of cutaneous toxicities. Thus, our meta-analysis was conducted to evaluate the type, incidence and risks of dermatological toxicities from dabrafenib.

Methods

Systematic searches were performed using electronic databases such as Embase and PubMed and conference abstracts published by the American Society of Clinical Oncology. Eligible studies were limited to prospective phase I, II and III clinical trials and expanded-access (ie, outside clinical trials) programmes of melanoma patients receiving dabrafenib monotherapy (150 mg, twice daily) or combination therapy of dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily). The outcomes were mainly the incidence rate and risk of all-grade cutaneous toxicities associated with dabrafenib in melanoma patients.

Results

Twenty trials comprising a total of 3359 patients were included in the meta-analysis. The meta-analysis showed that the overall incidence of all-grade rash for melanoma patients assigned dabrafenib was 30.00% (95% CI 0.07 to 0.71), cutaneous squamous-cell carcinoma (cSCC) 16.00% (95% CI 0.11 to 0.24), alopecia 21% (95% CI 0.11 to 0.37), keratoacanthoma (KA) 20.00% (95% CI 0.12 to 0.31), hyperkeratosis (HK) 14.00% (95% CI 0.09 to 0.22) and pruritus 8.00% (95% CI 0.05 to 0.12). All-grade rash occurred in 19.00% (95% CI 0.15 to 0.25), cSCC in 10.00% (95% CI 0.04 to 0.22), alopecia in 6.00% (95% CI 0.03 to 0.12), KA in 6.00% (95% CI 0.04 to 0.09) and pruritus in 2/1265 patients assigned dabrafenib plus trametinib. The summary risk ratio (RR) showed that the combination of dabrafenib with trametinib versus dabrafenib was associated with a significantly increased risk of all-grade rash (RR 1.35, 95% CI 1.01 to 1.80) and a decreased risk of cSCC (RR 0.40, 95% CI 0.18 to 0.89), alopecia (RR 0.19, 95% CI 0.12 to 0.30) and HK (RR 0.25, 95% CI 0.10 to 0.62).

Conclusion

In summary, the most frequent cutaneous adverse reactions from dabrafenib were rash, cSCC, alopecia, KA, HK and pruritus. There was a significantly decreased risk of cSCC, alopecia and HK with the combination of dabrafenib with trametinib versus dabrafenib alone. Clinicians should be aware of these risks and perform regular clinical monitoring.

Keywords: adverse effects, drug administration (others), risk management, side effects of drugs, cancer pain

Introduction

Melanoma is the most lethal type of skin cancer, with approximately 65 000 people dying from the malignancy worldwide every year. Although metastatic melanoma has a poor prognosis, with an overall 5 year survival rate of 86.5%, new therapeutics have been developed to prolong progression-free survival time in recent years.1 Molecular treatment approaches play an important role in the mitogen-activated protein kinase (MAPK) signalling transmission pathway and have been identified as an attractive target for cancer treatments, such that mutation-selective (V600E) BRAF inhibitors have become the mainstay of treatment for metastatic melanoma, and the prognosis of patients has significantly improved in clinical practice.2

Activating oncogenic mutations of BRAF occur in 7% of human malignancies and approximately 50% of metastatic melanoma patients.3 Dabrafenib (GSK2118436) is a new targeted therapy—a reversible, potent ATP-competitive inhibitor with high potency and selectivity against RAF kinases in melanoma harbouring either BRAFV600 alterations or mutant N- and KRAS-driven signalling.4 Numerous clinical trials have clearly shown significant benefits with dabrafenib for melanoma patients and demonstrated that dabrafenib could be of benefit in prolonging overall survival and progression-free survival in melanoma patients. Dabrafenib is now a standard of care for patients with high tumour burden metastatic melanoma harbouring the BRAF K601E mutation.5 6 The results of recent studies in previously treated patients with other types of cancers, including non-small cell lung cancers, thyroid cancer and cholangiocarcinoma, also show that dabrafenib induces anti-tumour responses when administered as monotherapy.7 8 Furthermore, dabrafenib is applied as a single agent or in combination with trametinib.

However, dabrafenib is not devoid of undesirable side effects. It has been linked to some cutaneous toxicity profiles, including evidence of increased risk of rash, cutaneous squamous-cell carcinoma (cSCC), alopecia, keratoacanthoma (KA), hyperkeratosis (HK) and pruritus with its wider use.9 These frequent adverse reactions caused by dabrafenib can directly influence the outcome of treatment by interfering with patient acceptance of and adherence to therapy. Thus, careful observations and monitoring are necessary for the management of patients to ensure maximum treatment benefit and to avoid unnecessary treatment discontinuation.10 Additionally, there is considerable evidence that the severity of dermatological toxicities correlates with the drug’s therapeutic effect. Thus, there is a need to master the prevalence and characteristics of cutaneous toxicities to provide adequate prevention and early intervention. To address this issue, we performed a meta-analysis to evaluate the true effect of dabrafenib alone or in combination with trametinib on cutaneous toxicities in melanoma patients, and to provide insight into the prevention and therapeutic management of symptoms.

Methods

Search strategy

The search for relevant studies was performed in electronic databases, including the Excerpta Medical Database (Embase), the Cochrane Library, PubMed, the Web of Science (WOS), the China National Knowledge Infrastructure database (CNKI), the Wanfang Data Knowledge Service Platform (WKSP), the Chinese Scientific Journals Full Text Database (CSJFT) and the Chinese Biomedical Literature Service System (CBMdisc), from January 2000 to June 2019. The key words used in the search programme were “BRAF inhibitors”, “MEK inhibitors”, “dabrafenib”, “trametinib”, and “melanoma” as well as “clinical trials”. In addition, abstracts containing the term “dabrafenib in patients with melanoma” were also searched from the European Society for Medical Oncology (ESMO) and major meetings from the American Society of Clinical Oncology (ASCO). Finally, the reference lists of original articles and review articles from the WOS database were also scanned to ensure that no potentially important studies were missed.

Study selection and inclusion criteria

Studies were included according to the following criteria: (1) phase I, II and III trials, expanded-access (ie, outside clinical trials) programmes, and prospective clinical trials of patients with melanoma; (2) studies of dabrafenib monotherapy (150 mg, twice daily) and the combination of dabrafenib (150 mg, twice daily) plus trametinib (2 mg, once daily) treatment; and (3) studies in which cutaneous toxicities were recorded. The exclusion criteria were as follows: (1) repeat studies, abstracts, letters, reviews, editorial, or comment; and (2) published studies not meeting the inclusion criteria.

Data extraction

The two review authors (CP, JXL) extracted the data from the included studies on an Excel sheet. The following data were collected to better understand the baseline data of the included studies: the first author, year of publication, sample size, and therapeutic dose of the participants. The following outcomes were regarded as clinical endpoints in our analysis according to the presence/absence of dermatological adverse events (AEs) associated with dabrafenib in melanoma patients: rash, cSCC, alopecia, KA, HK and pruritus.

Quality assessment

To evaluate the methodological quality of the included literature, we assessed the quality of each included study using a modified version of the Jadad scale. A score of 4–8 is indicative of a high-quality study, whereas a score from 0–3 represents low-quality studies. The quality of each study was assessed for non-randomised studies (NRDS) and quantified using the Newcastle-Ottawa Scale (NOS). NRDS were graded as providing good (score 7–10), moderate (score 4–6) or low quality of evidence (score 0–3). Any disagreements between them were resolved by discussion with the third review author.

Definition of main outcomes

The severity of all toxicities was graded using the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. All grades of severity of dermatological AEs included high-grade and all-grade AEs. High-grade AEs were defined as events whose severity was prominent and graded as 3 or above. All-grade AEs included high-grade AEs and all others of lower severity; thus, all-grade cutaneous AEs of rash, cSCC, alopecia, KA, HK and pruritus were defined as these conditions graded 1–5.

Statistical analysis

Statistical analyses were conducted to calculate the overall incidences of all-grade skin toxicities and their 95% confidence intervals (95% CI). The pooled relative risk (RR) along with the 95% CI were estimated to make comparisons of pooled risk for adverse effects between the combined therapy and the monotherapy. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I 2 statistic). When homogeneity was considered significant (I 2 <50%, P heterogeneity >0.1), a fixed-effects model was used; otherwise, a random-effects model was used (I 2 >50%, P heterogeneity <0.1). All statistical analyses were carried out using R version 2.13.2 software (R Foundation for Statistical Computing) and Review Manager (RevMan) version 5.3 (The Cochrane Collaboration, Oxford, UK) for Windows at 64 bits. Any p value less than 0.05 (p<0.05) and 0.01 (p<0.01) was considered significant.

Results

Search results and study characteristics

For the systematic literature search for trials on dabrafenib in melanoma patients, based on the criteria mentioned above, 116 potentially relevant references were initially identified. Of these, 96 studies were excluded after screening by title, abstract or full text. Finally, a total of 20 studies11–30 were retained for the final analysis. The process of study selection according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines is shown in figure 1. The 20 selected studies comprised a total of 3359 patients, and the period of inclusion ranged from 2012 to 2018. In all studies, the starting dose and schedule of dabrafenib and trametinib were according to the recommendations of the US Food and Drug Administration: dabrafenib, 150 mg twice daily; trametinib, 2 mg once daily. The summary of the included studies, including the baseline characteristics of patients, varied among the trials, as shown in table 1.

Figure 1.

Figure 1

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Flow diagram of the study selection process.

Table 1.

Summary of the characteristics of the studies included in the meta-analysis

Author, year Trial Size, n Age, years Region Treatment region Quality scores
Falchook et al, 201511 Single-arm, phase II 46 (D) 54.5 (26–81) USA D (150 mg, twice daily) 4
Gorka et al, 201812 Single-centre controlled retrospective 30 (D) 59.2 (21.8–75.1) USA D (150 mg, twice daily) 4
Lau et al, 201413 Single-centre 31 (D) 55.3 (26.4–78.3) Australia D (150 mg, twice daily) 3
Ascierto et al, 201314 Single-arm, phase II 92 (D) 55.5 (22–83) USA D (150 mg, twice daily) 3
Long et al, 201215 Multicentre, open-label, phase II 172 (D) 52 (43–63) Australia D (150 mg, twice daily) 3
Momtaz et al, 201716 General clinical trial 23 (D) 54 (18–76) USA D (150 mg, twice daily) 4
Trefzer et al, 201117 Single-arm, phase IIA 92 (D) 56 (22–80) USA D (150 mg, twice daily) 4
Fujiwara et al, 201718 General clinical trial 12 (D) 51 (17–80) NS D (150 mg, twice daily) 4
Falchook et al, 201419 Single-arm, phase I 184 (D) 53.5 (20.4–82) USA D (150 mg, twice daily) 4
Anforth et al, 201220 General clinical trial 43 (D) 54 (18-82) USA D (150 mg, twice daily) 4
Grob et al, 201421 Phase III (RCT) 187 (D)/(63) DTIC 55.5 (22–83) NS D (150 mg, twice daily) 5
Hauschild et al, 201222 Multicentre, open-label, phase III 100 (D)/(26) DTIC 53 (22–93) NS D (150 mg, twice daily) 5
Long et al, 201523 Phase III (RCT) 211 (D+T)/212 (D) 56.5 (22–86) USA D (150 mg, twice daily) + T (2 mg, once daily) vs D (150 mg, twice daily) 6
Douglas et al, 201424 Phase I/II (RCT) 26 (D+T)/45 (D) 51.0 (18–82) USA D (150 mg, twice daily) + T (2 mg, once daily) vs D (150 mg, twice daily) 6
Keith et al, 201225 Phase I/II (RCT) 108 (D+T)/53 (D) 58 (27–79) USA D (150 mg, twice daily) + T (2 mg, once daily) vs D (150 mg, twice daily) 6
Martín et al, 201726 Retrospective 87 (D+T)/49 (D) 56.8 (26.2–84.3) NS D (150 mg, twice daily) + T (2 mg, once daily) vs D (150 mg, twice daily) 6
Long et al, 201727 Phase III (RCT) 435 (D+T)/placebo (432) 50 (18–89) Australia D (150 mg, twice daily) + T (2 mg, once daily) vs placebo 6
Schreuer et al, 201728 Single-arm, phase II 25 (D+T) 54.7 (29–72) NS D (150 mg, twice daily) + T (2 mg, once daily) 5
Davies et al, 201729 Single-arm, phase II 76 (D+T) 52 (23–84) NS D (150 mg, twice daily) + T (2 mg, once daily) 4
Yamazaki et al, 201830 Phase I/II (RCT) 12 (D+T) 52.5 (21–76) NS D (150 mg, twice daily) + T (2 mg, once daily)
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D, dabrafenib; DTIC, dacarbazin; NS, not stated; RCT, randomized controlled trial; T, trametinib.

Overall incidence of all-grade relevant dermatological toxicities with dabrafenib

Rash

Four trials (271 patients)11 12 15 16 included in this meta-analysis were evaluated for the overall incidence of all-grade rash associated with dabrafenib. Obvious heterogeneity (Q=85.56; p<0.0001; I 2=94.9%) was present among the included studies. As shown in figure 2A, the incidence of all-grade rash associated with dabrafenib through the random-effects model was 30.00% (95% CI 0.07 to 0.71). An analysis of the overall incidence of all-grade rash associated with dabrafenib plus trametinib was performed in six trials (966 patients).23–25 27–29 The incidence of all-grade events ranged from 15% to 26% (figure 3A). The overall incidence of all-grade rash associated with dabrafenib and trametinib was 19.00% (95% CI 0.15 to 0.25) by the random-effects model meta-analysis (Q=94.38; p=0.0076; I 2=65.7%).

Figure 2.

Figure 2

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Forest plot analysis of the incidence of all-grade cutaneous toxicities associated with dabrafenib in melanoma patients. (A) Rash. (B) Cutaneous squamous-cell carcinoma. (C) Alopecia. (D) Keratoacanthoma. (E) Hyperkeratosis. (F) Pruritus.

Figure 3.

Figure 3

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Forest plot analysis of the incidence of all-grade cutaneous toxicities associated with the combination of dabrafenib and trametinib in melanoma patients. (A) Rash. (B) Cutaneous squamous-cell carcinoma. (C) Alopecia. (D) Keratoacanthoma.

Cutaneous squamous-cell carcinoma

All-grade cSCC associated with dabrafenib occurred in 140 of 759 participants in eight trials.11 12 14 15 17 19 20 22 The overall prevalence of all-grade cSCC was 16.00% (95% CI 0.11 to 0.24) in patients assigned to dabrafenib using a random-effects model (Q=123.88; p<0.0001; I 2=81.2%) (figure 2B). A meta-analysis of the overall incidence of all-grade cSCC associated with the combination of dabrafenib and trametinib was performed in three studies (343 patients).23–25 The meta-analysis results revealed that the included studies were highly heterogeneous (Q=94.38; p=0.0049; I 2=81.2%). Thus, a random-effects model was used, and the overall incidence of all-grade cSCC was 10.00% (95% CI 0.04 to 0.22) (figure 3B).

Alopecia

Four trials14–16 18 reported all-grade alopecia, which occurred in 49 of 299 total events with an incidence ranging from 11–37%. The result of testing for interstudy heterogeneity showed that Q=52.67, p=0.0042, and I 2=77.3%; therefore, a random-effects model for meta-analysis was used. The meta-analysis results showed that the overall incidence of all-grade alopecia in patients with dabrafenib was 21% (95% CI 0.11 to 0.37) (figure 2C). The random-effects model was used in the analysis of the overall incidence of all-grade alopecia because of the heterogeneity (Q=38.01; p=0.0759; I 2=56.4%). The results showed that the mean rate of occurrence of all-grade alopecia in patients assigned dabrafenib and trametinib was 6.00% (95% CI 0.03 to 0.12) (figure 3C).

Hyperkeratosis

Seven trials11–13 15 17 20 22 included in this meta-analysis were evaluated for the incidence of all-grade HK. The data showed that the overall incidence of all-grade HK after therapy with dabrafenib was 20.00% (95% CI 0.12 to 0.31), with significant interstudy heterogeneity (Q=38.01; p<0.0001; I 2=79.9%) (figure 2D). With regard to the analysis of all-grade events with dabrafenib plus trametinib, five studies (456 patients)23–25 28 29 provided information on the analysis of all-grade HK, the incidence of which ranged from 4–9%. The fixed-effects model (Q=38.01; p=0.5992; I 2=0%) meta-analysis results showed that the overall incidence of all-grade HK in patients receiving a combination of dabrafenib and trametinib was 6.00% (95% CI 0.04 to 0.09) (figure 3D).

Keratoacanthoma

In total, seven studies12–15 18 20 22 reported a total of 651 melanoma patients with the incidence of all-grade KA associated with dabrafenib. The incidence of all-grade KA ranged from 9–22% in patients assigned dabrafenib. As determined by the random-effects model (Q=383.39; p<0.0001; I 2=78.5), the overall incidence of all-grade KA in patients with dabrafenib therapy was 14.00% (95% CI 0.09 to 0.22) (figure 2E). There were no data available on the incidence of all-grade KA for combination therapy with dabrafenib and trametinib.

Pruritus

Three trials14 16 21 reported all-grade pruritus, which occurred in 24 of 302 total events. No significant interstudy heterogeneity was observed from the meta-analysis results (Q=123.88; p=0.6497; I 2=0%); therefore, a fixed-effects model was used in this study. The data showed that the overall incidence of all-grade pruritus associated with dabrafenib in patients was 8.00% (95% CI 0.05 to 0.12) (figure 2F). With regard to the analysis of all-grade pruritus in melanoma patients associated with the combination of dabrafenib and trametinib, there were only 18 cases among the 209 patients enrolled from a study reported by Long et al. 23

RR of all-grade dermatological toxicities with the combination of dabrafenib and trametinib versus dabrafenib alone

Rash

The meta-analysis of the RR of all-grade rash associated with combined dabrafenib with trametinib versus dabrafenib was calculated based on three of the four randomized controlled trials (RCTs) (788 patients).23–26 The meta-analysis results showed that the RR of all-grade rash in melanoma patients with combination therapy was significantly higher than that observed in dabrafenib-alone groups (RR 1.35, 95% CI 1.01 to 1.80) (figure 4A). The results of the meta-analysis showed that the included studies were highly heterogeneous (χ2=10.21, df=3 (p=0.02), I 2=71%).

Figure 4.

Figure 4

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Forest plot analysis of the risk of all-grade cutaneous toxicities associated with the combination of dabrafenib and trametinib versus dabrafenib in melanoma patients. (A) Rash. (B) Cutaneous squamous-cell carcinoma. (C) Alopecia. (D) Hyperkeratosis.

Cutaneous squamous-cell carcinoma

Three studies23–25 reported the RR of all-grade cSCC associated with the combination of dabrafenib with trametinib versus dabrafenib alone for a total of 652 melanoma patients. According to the results of heterogeneity tests, statistically significant heterogeneity was detected among the included studies (χ2=6.04, df=2 (p=0.05), I 2=67%). The estimated RR of combination therapy versus dabrafenib alone by the fixed-effects model was 0.40 (95% CI 0.18 to 0.89) (figure 4B).

Alopecia

Three studies23 25 26 provided information on the RR of all-grade alopecia. As shown in figure 4C for a fixed-effects model (χ2=0.32, df=2 (p=0.85), I 2=0%) meta-analysis, there was a significant increase in the RR of all-grade alopecia in melanoma patients for combination therapy of dabrafenib with trametinib versus dabrafenib alone (RR 0.19, 95% CI 0.12 to 0.30; p<0.00001).

Hyperkeratosis

A meta-analysis of four included RCTs23–26 was performed to measure the RR of all-grade hyperkeratosis. Figure 4D shows the comparison of the RR of all-grade hyperkeratosis in patients between the combined dabrafenib and trametinib group and the dabrafenib monotherapy group, and an obvious decrease was observed (RR 0.25, 95% CI 0.10 to 0.62; p=0.003). The application of the I 2 statistic showed that significant heterogeneity existed among studies (χ2=10.66, df=3 (p=0.01), I 2=72%), and a random-effects model was applied.

Publication bias

The assessment of publication bias in the included studies was performed using Egger’s funnel plot and Egger’s test. There was no evidence of publication bias with Begg’s test for the incidence of all-grade cutaneous toxicities (p=0.32). The funnel plot and Egger’s funnel plot displayed in figure 5A and B revealed evidence of symmetry, but the symmetry was not marked, suggesting possible publication bias in our study. However, the number of studies included was small, and the funnel plot may not be convincing.

Figure 5.

Figure 5

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The funnel plot of publication bias (A) and Egger’s funnel plot of publication bias (B).

Discussion

Recently, an increasing number of authors have reported that cutaneous side effects are associated with dabrafenib in melanoma patients. This prompted us to perform this meta-analysis to evaluate the incidence and risk of cutaneous toxicities associated with dabrafenib in patients with melanoma. From this meta-analysis, we found that dabrafenib was associated with a high incidence and risk of all-grade cutaneous AEs, such as rash, cSCC, alopecia, KA, HK and pruritus. We also observed that dabrafenib and trametinib combination therapy may carry a lower risk of all-grade cSCC, alopecia and HK than therapy with dabrafenib alone.

Secondary cancers such as cSCC and HK are considered to be the characteristic AEs of BRAF inhibitor monotherapy and occur in approximately 14–26% of patients.31 The main reason for skin tumour development is the paradoxical activation of the MAPK pathway in KA with upstream activation of signalling by pre-existing RAS mutations.32 The mechanism underlying this interaction has been described in a mouse model of SCC, but it remains to be further determined what preceding mutations or signalling deviations may be required to induce this peculiar side effect of BRAF inhibitors.33 Our meta-analysis demonstrated that the combination of dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor), compared with dabrafenib monotherapy, significantly decreased the incidence of secondary cancers.

From the results of the meta-analysis, the most common cutaneous AE was rash, with an overall prevalence of 30.00% (95% CI 7.00% to 71.00%). There was an increased risk of all-grade rash with combined dabrafenib and trametinib treatment compared with dabrafenib alone in melanoma patients. Grade 1–2 dermatological toxicities are mild or moderate in severity, and these symptoms can be resolved with appropriate management.34 35 Interestingly, a systematic review by Zhou and co-workers has shown that the overall incidence of rash associated with dabrafenib (grade 3–4) is 12.00%, which is a prominent datapoint representing a common cutaneous side effect.36 Rash presents as an erythematous eruption and the desquamation of involved areas on the face, scalp and trunk.25 26 Although the mechanism of rash associated with combined BRAF and MEK inhibition is still unknown, some authors have suggested that MAPK-dependent resistance to BRAF inhibitors may be involved in it.

It has been reported that alopecia and pruritus belong to a wide spectrum of cutaneous AEs and their severity is proportional to the dose and drug exposure of dabrafenib or trametinib.37 In the current study, all-grade alopecia induced by dabrafenib therapy occurred in approximately 21% (95% CI 11.00% to 37.00%) of patients in the included trials. Alopecia usually presents as mild thinning or patchy hair and slow beard growth that does not lead to dose reduction or treatment interruption. Reactions generally occurred between 2 and 16 weeks after treatment.18 19 We have previously shown that most dabrafenib- and trametinib-related pruritus occurs early in the course of treatment (within the first 28 days for grade 1–2 or worse AEs) and is mild or moderate, monitorable and manageable by dose modification and supportive care.38 In our study, pruritus was also observed with a rate of 8.00% (95% CI 5.00% to 12.00%) in the dabrafenib group, and the incidence calculated by the meta-analysis indicated that pruritus is closely associated with dabrafenib.

KA is a relatively common low-grade skin cancer in the pilosebaceous glands and closely resembles SCC. In our study, KA was present in 14.00% (95% CI 9.00% to 22.00%) of melanoma patients assigned to dabrafenib treatment. The clinical/pathological features in dabrafenib-treated patients have been reported in the literature, but the pathological mechanism of KA is still unclear.39 In addition, as described above, the paradoxical activation of MAPK signalling in RAS-upregulated cell lines leads to increased signalling and, thus, can induce the evolution of KA in patients on BRAF inhibitor monotherapy.20–23 The addition of a MEK inhibitor, in turn, reduced the rate of KA, which is consistent with our results (RR of 0.25 with 95% CI 0.10 to 0.62 in dabrafenib + trametinib vs dabrafenib monotherapy).

It has been suggested that a higher risk of cutaneous toxicities related to some anticancer agents has been shown to be associated with some pharmacogenetic factors. However, similar factors have not yet been discovered with BRAF/MEK inhibition, and this should be considered a focus of research with these agents.11–13 Moreover, a cutaneous reaction has been linked to superior response rates and long-term survival outcomes with epidermal growth factor receptor (EGFR) inhibitors (which work on almost the same pathway as BRAF/MEK inhibitors), and whether the dermatological toxicities of BRAF/MEK inhibitors predict a higher response rate has yet to be determined.40 Ongoing studies will help define how to maximise the use of novel therapies in melanoma and will also provide important toxicity data so patients can receive the most efficacious regimens safely, but recent times have provided much needed hope in this aggressive disease.22–25

Although the majority of cutaneous side effects of BRAF/MEK inhibitors are mild and can be managed with supportive treatment, special management strategies including non-pharmacological and pharmacological administration may be required according to the severity and types of AEs.35 In general, for patients with grade 1–2 AEs, it is not recommended that patients modify the dose according to the protocol. For most unsolicited AEs of grade 3 or higher, the dose in either a combination of dabrafenib plus trametinib daily or dabrafenib alone is interrupted depending on the nature of the events.27 The dose can be resumed at the same or a lower amount when grade 2 toxicity occurs for the first time. We do not suggest low doses of dabrafenib and trametinib less than 75 mg and 1 mg a day, respectively, if a dose reduction is indicated according to the protocol.29 30 Finally, the overall benefit of the enormous healthcare expenditure associated with the use of these drugs has been questioned; additionally, the cost burden of associated toxicities cannot be ignored.

Limitations of the meta-analysis

This meta-analysis had some potential limitations that should be considered. First, 20 studies were included in our study, and some of these trials had relatively small sample sizes; thus, our conclusions should be interpreted with caution because smaller trials are more likely to result in an overestimation of the toxicity effect than larger trials. Second, the clinical heterogeneity among studies is increased due to the difference in treatment schedules in the meta-analysis. Third, the diagnosis of skin toxicity in clinical trials is mostly based on personal experience and is too subjective, with different researchers making different judgements about the same symptoms. Fourth, as most of the included studies came from the West, due to the lack of data collected from some Asian countries, selection bias was inevitable. Finally, publication bias might have occurred, although the evidence of publication bias was not strong based on the funnel plot. Therefore, further large-scale trials are needed to verify our findings.

Conclusion

As a BRAF inhibitor, dabrafenib is associated with a high risk of all-grade rash, cSCC, alopecia, KA, HK and pruritus in patients with melanoma. The addition of trametinib (a MEK inhibitor) leads to a reduced RR of all-grade cSCC, alopecia and HK and thus to an improved quality of life compared with dabrafenib alone. Clinicians should be aware of these risks and perform regular follow-up for such toxicities. A higher risk of dermatological toxicities associated with some anticancer agents has been linked to some pharmacogenetic factors. However, similar factors have not yet been discovered with combined dabrafenib and trametinib treatment in melanoma patients, and this should be considered a research priority with these agents. Moreover, a skin reaction has been linked to a higher response and better overall survival with combined dabrafenib and trametinib therapy than with dabrafenib monotherapy. Whether the dermatological toxicities of combined dabrafenib and trametinib treatment predict a lower response rate has yet to be determined.

Footnotes

Contributors: Draft the protocol: CP and JXL. Develop and run the search strategy: CP and JXL. Obtain copies of studies: CP. Select which studies to include: CP and JXL. Extract data from studies: CP and JXL. Carry out the analysis: CP and JXL. Draft the final review: CP.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Not required.

References

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Data Availability Statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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