BRAF inhibitors for the treatment of papulopustular eruptions from MAPK pathway inhibitors

Abstract

Inhibitors of the mitogen-activated protein kinase (MAPK) pathway are commonly used in clinical oncology. However, with the exception of BRAF inhibitors (BRAFi), MAPK pathway inhibitors such as EGFR inhibitors (EGFRi) or MEK inhibitors (MEKi) are associated with dose-limiting papulopustular eruptions. Interestingly, patients treated with a combination of systemic BRAFi and MEKi experience less skin toxicities than patients on monotherapy BRAFi or MEKi. The reduction in cutaneous adverse events with combination therapy is thought to be due to a paradoxical activation of the MAPK pathway by BRAFi in keratinocytes carrying wildtype BRAF. Although treatment options for EGFRi- or MEKi-induced papulopustular eruptions exist, many patients still experience dose reduction, interruption, or discontinuation of EGFRi or MEKi. With the goal of activating MAPK signaling in the skin via BRAFi while minimizing systemic risks, we propose topical BRAFi therapy for the treatment and prevention of papulopustular eruptions due to MAPK pathway inhibitors. If effective, patients will be able to tolerate higher doses of MAPK pathway inhibitors, stay on treatment longer, and achieve better therapeutic outcomes overall.

1. Introduction

The mitogen-activated protein kinase (MAPK) cellular signaling pathway is typically activated by a transmembrane receptor tyrosine kinase, such as epidermal growth factor receptor (EGFR), and is critical for cellular regulation[1]. The pathway comprises a series of sequentially-activated protein kinases (RAS/RAF/MEK/ERK) and modulates gene expression to regulate cell survival, proliferation, migration, and death. Dysregulation of MAPK signaling is implicated in many cancers, and inhibition of this pathway, either directly (e.g. MEK inhibitors) or via upstream mediators (e.g. EGFR inhibitors), is widely used to treat solid tumors [Fig. 1]. With the notable exception of BRAF inhibitors (BRAFi), inhibitors of the MAPK pathway are associated with dose-limiting papulopustular eruptions. Interestingly, patients treated with a systemic combination of BRAFi and MEK inhibitors (MEKi) experience reduced severity and incidence of skin toxicities[2, 3]. In this manuscript, we review the pathophysiology and treatment of papulopustular eruptions associated with MAPK inhibitors and discuss the potential utility of topical BRAFi to manage these eruptions.

Fig. 1. Schematic of MAPK pathway, inhibitors, and associated cutaneous adverse events.

Inhibitors of the MAPK pathway (left) and their associated adverse events (right). Double green arrows represent the paradoxical activation in WT BRAF cells caused by BRAF inhibitors. cSCC, cutaneous squamous cell carcinoma; KA, keratoacanthoma; MAPK, mitogen-activated protein kinase; WT, wildtype

2. Papulopustular eruptions from MAPK pathway inhibitors

EGFR inhibitors (EGFRi) include tyrosine kinase inhibitors, such as erlotinib or gefitinib, and anti-receptor monoclonal antibodies, such as cetuximab, necitumumab, or panitumumab[4]. EGFRi are commonly used to treat advanced lung, colorectal, breast, and head and neck cancers. MEKi such as trametinib, cobimetinib, binimetinib, and selumetinib are also used against many cancers, including melanoma, colorectal, non-small cell lung, pancreatic, and hepatocellular cancer[3]. Typically, MEKi are used in combination with BRAFi for the treatment of cancers driven by V600 mutant BRAF oncoproteins. However, selumetinib was recently approved for monotherapy treatment of inoperable plexiform neurofibromas in children with neurofibromatosis type 1[5, 6]. Currently, multiple clinical trials are testing MEKi as monotherapy or in combination with agents other than BRAFi for a variety of indications.

Despite their clinical utility, EGFRi and MEKi are associated with significant skin toxicities, of which papulopustular eruptions are among the most prevalent[3, 4]. These papulopustular eruptions have also been referred to as acneiform eruptions, acneiform dermatitis, or acneiform hypersensitivity drug reaction in the literature[7]. EGFRi- or MEKi-induced papulopustular eruptions usually occur early in treatment, often within the first weeks of therapy[4], and in a dose-dependent manner. These eruptions present with inflammatory papules and pustules in seborrheic areas such as the face, scalp, and upper trunk[4, 8]. Rupture of pustules can result in crusting and other secondary changes[4]. Histological analysis typically reveals folliculitis with neutrophilic infiltration[2]. Although these eruptions can superficially resemble acne, unlike acne vulgaris EGFRi- or MEKi-induced papulopustular eruptions are monomorphic, lack comedones or cysts, and are often associated with pruritus. Additionally, these eruptions can occur in locations atypical of acne vulgaris, such as the scalp, abdomen, extremities, or lower back[9]. Overall, EGFRi- or MEKi-induced papulopustular eruptions are thought to be distinct from acne vulgaris and are managed differently[4]. Importantly, studies have demonstrated that the incidence and severity of EGFRi-related papulopustular eruptions can correlate with favorable tumor responses[10–12]. Other cutaneous adverse events (AEs) from EGFRi are xerosis, hair and nail changes, paronychia, and mucositis[4, 9]. For MEKi, additional skin toxicities include morbilliform eruption, xerosis, paronychia, alopecia, and hyperpigmentation[3]. More recently, inhibition of the MAPK pathway with ERK inhibitors (ERKi) has also been shown to cause papulopustular eruptions in clinical trials[13]. Other cutaneous AEs associated with ERKi include rash and alopecia.

3. Pathophysiology

To date, the exact molecular mechanism behind papulopustular eruptions in patients on monotherapy EGFRi or MEKi is poorly understood. It has been proposed that the eruptions are due to the role of EGFR/MAPK signaling in hair follicle homeostasis, with inhibition of EGFR in mouse models leading to follicle changes and skin inflammation[8]. One study found that the epidermis in EGFR-deficient mice was more permissible to commensal microbiota invading into the hair follicle, resulting in chronic folliculitis[14]. Another study found that EGFRi and commensal skin bacterium Cutibacterium acnes (C. acnes) act synergistically on keratinocytes to induce IL-36γ, a pro-inflammatory cytokine, and IL-8, a neutrophil chemoattractant, leading to skin inflammation and papulopustular eruptions[2]. Thus, reduced MAPK signaling may produce skin changes that promote bacterial dysbiosis and inflammatory signaling, resulting in formation of papules and pustules.

Combining a BRAFi with a MEKi reduces cutaneous AEs related to MEKi monotherapy, including papulopustular eruptions[3, 7]. A retrospective analysis[7] of papulopustular eruptions in patients on monotherapy MEKi (trametinib) versus combination BRAFi/MEKi (dabrafenib/trametinib) found that 77% of patients receiving trametinib experienced the eruption, whereas only 10% of dabrafenib/trametinib patients were affected. Moreover, the time to onset for papulopustular eruptions in the trametinib group versus dabrafenib/trametinib was 12.5 days and 307 days, respectively. Thus, the addition of a BRAFi to MEKi therapy notably reduces the incidence and delays the onset of papulopustular eruptions. A reduction in the incidence of papulopustular eruptions was also noted in early clinical trials combining BRAFi and MEKi[15].

BRAFi (e.g. vemurafenib, dabrafenib, and encorafenib) target V600 mutant BRAF oncoproteins and are associated with their own AEs including keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). Remarkably, the cutaneous AEs associated with BRAFi monotherapy are also decreased with combination BRAFi/MEKi therapy[3]. This reciprocal reduction in AEs is thought to be due to a paradoxical activation of the MAPK pathway by BRAFi in keratinocytes carrying wildtype BRAF[16–19], with MEKi counteracting this activation[3, 7]. In cells with wildtype BRAF, BRAFi can activate CRAF via formation of RAF dimeric complexes. This consequently activates the MEK-ERK pathway, leading to potentiated ERK signaling in normal tissue, such as the skin [Fig. 1]. However, with the addition of a MEKi, which blocks ERK signaling in both normal tissue and tumor, the paradoxical MAPK activation by BRAFi is attenuated. The opposing effects of BRAFi and MEKi on MAPK signaling is also presumably why combining BRAFi with MEKi reduces the cutaneous AEs associated with MEKi monotherapy – the increased MEK activation by BRAFi in the skin offsets the pathway inhibition caused by the MEKi. Consistent with this mechanism, when human keratinocytes are treated with a BRAFi in combination with a MEKi and C. acnes, reduced levels of IL-36γ mRNA are produced[2]. Whereas most studies support this hypothesis, at least one mouse study reported a BRAFi reducing the MEKi papulopustular eruption without measurably restoring MAPK signaling in the epidermis, suggesting that the diminished skin toxicities seen with combination therapy may be due to off-target effects rather than equilibration of MAPK signaling[20].

Regardless of the specific mechanism, the increased incidence of papulopustular eruptions associated with MEKi monotherapy relative to combination BRAFi/MEKi therapy makes it evident that adding a BRAFi reduces the papulopustular eruptions associated with inhibitors of MAPK signaling[7, 15, 20].

Recent studies have also demonstrated that combination BRAFi/EGFRi reduces the incidence of papulopustular eruptions. The safety results from the phase III BEACON Colorectal Cancer (CRC) trial studying binimetinib (MEKi), encorafenib (BRAFi), and cetuximab (EGFRi) in patients with BRAF V600E-mutated metastatic colorectal cancer showed that fewer patients experienced grade 3 or 4 skin toxicities than patients on monotherapy cetuximab[21]. Moreover, when comparing patients treated with the doublet regimen (encorafenib and cetuximab) and a control group (cetuximab plus chemotherapy), fewer patients on the doublet regimen experienced a papulopustular rash as compared to the control group (29% vs. 39%, respectively)[22]. These results suggest that BRAF inhibition can reduce EGFRi-associated cutaneous eruptions. Combination BRAFi/EGFRi also seemingly reduces BRAFi-associated cutaneous AEs. The incidence of KAs/cSCCs among patients who received monotherapy encorafenib was 8%, whereas in the BEACON CRC trial studying encorafenib and cetuximab, the incidence was only 1.4%[23]. An independent pilot study combining BRAFi and EGFRi also reported a reduction in both BRAFi- and EGFRi-associated AEs, particularly BRAFi-induced KAs/cSCCs[24]. EGFRi may reduce the BRAFi-induced KA/cSCC by reducing overall levels of MAPK signaling in the skin. Further investigation is required to elucidate the mechanisms behind the reduced cutaneous toxicities with combination BRAFi/EGFRi therapy.

4. Treatment options and proposal of topical BRAFi for papulopustular eruptions

Current treatment options for EGFRi- or MEKi-induced papulopustular eruptions include topical low-potency steroids, antiseptic washes, topical antibiotics (clindamycin), systemic antibiotics (tetracyclines), or isotretinoin[3, 4]. Preventative measures include topical low-potency steroids and sunscreen. Prophylactic tetracyclines may also be considered for prevention. Despite these measures, patients often require reduction, interruption, or discontinuation of EGFRi or MEKi therapy.

Although systemic combination therapy with BRAFi can prevent EGFRi- and MEKi-induced papulopustular eruptions, systemic BRAFi are contraindicated in BRAF wildtype cancers due to the potential for paradoxical MAPK activation. Additionally, systemic BRAFi/MEKi combination therapy has its own unique AE profile as compared to monotherapy, notably pyrexia and gastrointestinal disturbances[25]. An alternative therapeutic option recently proposed for EGFRi-induced papulopustular eruptions is recombinant fibroblast growth factor 7 (FGF7). The receptor for FGF7 is expressed on keratinocytes and injection of FGF7 can restore epidermal ERK signaling and prevent pustules in mice with disrupted EGFR signaling[14]. However, the potential adverse consequences of combining FGF7 treatment with EGFRi in patients with cancer have not been explored. Overall, despite recent advances, novel efficacious therapies are still needed for papulopustular eruptions associated with MAPK inhibition.

With the goal of using BRAFi to activate MAPK signaling in the skin while minimizing systemic risks, we propose topical BRAFi therapy for the treatment and prevention of papulopustular eruptions due to MAPK pathway inhibitors. Topical application is feasible as the papulopustular rash is generally limited to the face, scalp, and upper trunk, and patients are already advised to apply emollients and sunscreen for prevention. Some studies have investigated the effects of topical BRAFi. In mouse models, topical BRAFi have been shown to accelerate wound healing through paradoxical MAPK activation[26]. In humans, a small phase I trial is currently investigating the use of a topical BRAFi, LUT014, for EGFRi-induced acneiform lesions in patients with metastatic colorectal cancer (NCT03876106). The safety of topical BRAFi will need to be evaluated, especially in light of the KAs/cSCCs associated with systemic monotherapy BRAFi. Fortunately, not all patients develop KAs/cSCCs with systemic BRAFi – a meta-analysis of 6,445 patients estimated the incidence of all-grade cSCCs from BRAFi to be 12.5%[27]. However, as discussed above, concomitant EGFRi or MEKi should reduce the risk of KA/cSCC formation associated with topical BRAFi. Moreover, with topical BRAFi, only the treated skin should be at risk, further reducing the overall incidence of KAs/cSCCs. Fortunately, should these AEs occur, they can be addressed by simply discontinuing the topical therapy at the site where they arise. Future clinical trials can investigate the safety and efficacy of topical BRAFi in EGFRi-, MEKi-, or ERKi-induced skin toxicities.

5. Conclusion

Physicians should be aware of cutaneous AEs associated with MAPK inhibition, particularly papulopustular eruptions. Dermatologists play an important role in managing these skin toxicities, which can be dose-limiting, cause significant morbidity, and negatively impact a patient’s quality of life. The use of topical BRAFi holds promise in managing the papulopustular eruptions associated with EGFRi, MEKi, and ERKi. If effective, patients will be able to tolerate higher doses of MAPK inhibitors, stay on treatment longer, and achieve better therapeutic outcomes overall.

Key points.

• Inhibitors of the MAPK pathway can cause significant papulopustular eruptions.

• Topical BRAF inhibitors may diminish the incidence and severity of papulopustular eruptions from MAPK pathway inhibitors.