Patients with non–small cell lung cancer (NSCLC) who harbor epidermal growth factor receptor (EGFR) mutations represent a unique subgroup [1]. Women, nonsmokers, and patients with adenocarcinoma are more likely to carry EGFR mutations, with an incidence of 30% to 35% in East Asian populations [2]. In the Chinese NSCLC population, the prevalence of EGFR mutations is 28.2%, rising to 50.2% in those with lung adenocarcinoma [3]. EGFR tyrosine kinase inhibitors (EGFR-TKIs) selectively block the EGFR signaling pathway, thereby improving survival in patients with NSCLC carrying EGFR mutations [4]. It is categorically endorsed as a grade IA recommendation for the postoperative, locally advanced, and advanced first-line treatment of EGFR-positive NSCLC [5]. However, as EGFR is also expressed in skin keratinocytes, sebaceous glands, hair follicles, and perinuclear tissues [6], inhibiting EGFR activity can trigger a cascade of intracellular signaling pathways. The integrity of the human epidermis is compromised, the proliferation of epidermal cells is perturbed, the sebaceous gland lipid secretion is disrupted, and the skin’s hydration retention function is impaired, culminating in the manifestation of adverse cutaneous reactions [7].

According to phase 3 clinical trials approved by the US Food and Drug Administration, the incidence of skin rash associated with gefitinib use was 66% in patients from East Asia, whereas 3.1% experienced grade 3 rashes. Erlotinib use resulted in a 73% rash incidence, with 32% being grade 3; afatinib use led to rashes in 80.8% of patients, with 14.6% experiencing grade 3 rashes. In China, icotinib use caused rashes in 15.5% of patients, with 14.9% experiencing grade 3 rashes [8]. Results from the FLAURA2 trial found that the incidence of grade 3 adverse effects was higher in the combination therapy group than in the monotherapy group (ranging from 11% to 54%), with serious adverse effects increasing from 5% to 19%. Osimertinib, another EGFR-TKI, was associated with skin toxicity in approximately 24% of patients [9].

The most common and earliest cutaneous side effects of anti-EGFR therapies are papules and pustules distributed in seborrheic areas such as the face, scalp, and upper trunk, sometimes extending to the limbs, palms, and soles. These reactions typically occur within 1 to 2 weeks of starting targeted therapy and are dose dependent. It is noteworthy that this issue is encountered in a minimum of 75% of the patient population [10]. The severity of the rash is often positively correlated with the response to treatment of the patients [11]. Approximately 35% of patients initially manifest dry, pruritic dermatitis affecting the extremities [12,13]. The onset of sebum deficiency in eczema is typically concurrent with the exacerbation of the condition, culminating in a pustular rash secondary to either Staphylococcus aureus or herpes simplex infection [14], which may or may not be accompanied by hyperpigmentation and telangiectasia [15]. Unlike acne vulgaris [16], these skin reactions are characterized by erythematous papules and pustules without acne or cysts. Other associated symptoms include dry skin, burning sensations, itching, pain, and changes to the hair and nails (eg, paronychia) [17]. To manage these side effects, patients should avoid contact with irritants, particularly in areas prone to rashes. Daily skin care should include the use of moisturizers and sun protection and the avoidance of extreme temperatures. Wearing comfortable clothing and shoes and using nonirritating bath products is also recommended [18]. It is imperative to mitigate the adverse cutaneous reactions that are elicited.

At present, the assessment of targeted drug–induced cutaneous toxicities is conducted in accordance with the 2017 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Various guidelines, including those from the Multinational Association of Supportive Care in Cancer skin toxicity study group, the National Comprehensive Cancer Network, and the European Society for Medical Oncology, offer different expert opinions and consensuses on managing skin toxicity [11,19-21]. However, these guidelines lack comprehensive, evidence-based recommendations [8,10]. As patients often experience dry, itchy skin that compromises their skin barrier, most treatment strategies focus on symptom relief, and there are discrepancies in clinical practice regarding medication use [8,10].

The dermatological adverse effects associated with EGFR inhibitors are transient and tend to diminish with extended treatment duration. Resolution of the rash is typically complete upon cessation of therapy, and it is seldom constrained by the dosage or duration of treatment. Xerosis and pruritus are commonly attributable to a compromised skin barrier function. The predominant therapeutic modalities used for the management of grade 1 or 2 cutaneous toxicity encompass topical treatments such as 2.5% hydrocortisone cream, topical antibiotics (including erythromycin cream, clindamycin emulsion, metronidazole cream, and tacrolimus cream), and moisturizers (such as urea cream and fusidic acid cream). For more severe cases, oral medications may be considered, such as doxycycline (100 mg twice daily) or minocycline (50‐100 mg twice daily). Oral antihistamines, including levocetirizine (5 mg daily), desloratadine (5 mg daily), diphenhydramine (25‐50 mg 3 times daily), hydroxyzine (25 mg 3 times daily), or fexofenadine (60 mg 3 times daily), can help manage pruritus. For grade 3 rashes, oral tretinoic acid (0.3‐0.5 mg per kilogram) or prednisone (0.5 mg per kilogram) may be prescribed. Gamma-aminobutyric acid receptor agonists such as gabapentin (300 mg every 8 hours) or pregabalin (50‐75 mg every 8 hours) can also be considered for symptom relief. In severe cases, the dosage of targeted drugs should be reduced according to clinical guidelines, and for grade 4 rashes, oral steroid use may be escalated, and targeted therapy should be discontinued as soon as possible. Additionally, other studies have explored alternative treatments. For example, a study by Nagase et al [22] found that rapid desensitization therapy was effective in treating severe rashes caused by molecularly targeted drugs in patients with NSCLC. Furthermore, vitamin K₁ has shown potential in preventing rashes associated with EGFR inhibitors, possibly reducing both the incidence and severity of acne-like rashes [18,21].

Retinoic acid drugs are commonly used in clinical practice, but higher doses can exacerbate skin and mucosal dryness. Additionally, due to their photosensitivity, patients need to avoid radiation exposure as these factors can worsen rashes [23]. Doxycycline has been found to reduce the severity of rashes induced by EGFR-TKIs [18]. However, in clinical practice, doxycycline and minocycline are not frequently used for treatment; instead, they are primarily used in preventive studies [18,24-26]. The findings of Deplanque et al [25] also confirmed that, while doxycycline may not lower the incidence of erlotinib-induced folliculitis, it does reduce the severity of the rash. It is important to note the potential side effects of tetracycline antibiotics, which include anorexia, nausea, vomiting, diarrhea, esophagitis, and esophageal ulcers [27]. Systemic steroid hormones are usually not the first line of treatment for EGFR inhibitor–associated rashes due to their own side effects [19], such as endocrine disorders, osteoporosis, and weakened immunity, which can have serious consequences [28].

Due to the complex nature of infections and the standardized use of antibiotics, it is important to remain vigilant about antibiotic resistance. Glucocorticoids, while potent in treating skin toxicity, should only be considered when other treatment options are ineffective, making both antibiotic therapy and glucocorticoid therapy less ideal for routine clinical use. Patients receiving molecular-targeted therapies are often highly sensitive to irritants and allergens, complicating clinical treatment decisions. Most of the patients with lung cancer and EGFR mutations who experience cutaneous adverse reactions to EGFR-TKIs do not seek treatment due to a lack of awareness of or confidence in existing treatment options. Research reveals that EGFR-TKI skin toxicity stems from a compromised skin barrier linked to abnormal keratinocyte differentiation, apoptosis, and inflammatory infiltration [29]. To guarantee the rational deployment and therapeutic efficacy of clinical pharmacotherapy, it is advisable to use mild emollients, which incorporate active constituents such as urea, ceramide, plant sterols, and linolenic acid, among others, for the purpose of local hydration; moisturization; anti-inflammatory action; antipruritic effects; and amelioration of cutaneous symptoms such as dryness, itching, and pain [29]. Consequently, the identification of novel and well-tolerated therapeutic modalities to address drug-induced dermatotoxicity continues to pose a significant challenge for the oncological community.

Traditional Chinese medicine (TCM) active ingredients and preparations are increasingly used in skin disease treatment as modern pharmacology and clinical trials advance [30]. Jiedu xiaozhen (JDXZ) granules, a blend of Astragalus membranaceus, Isatis indigotica Fort, and Concha margaritifera, show promise in managing EGFR-TKI–induced skin toxicity. Author LL, with 40 years’ experience in TCM, has shown JDXZ granules’ efficacy and safety for treating EGFR-TKI–related skin toxicity. The oral JDXZ granules in their single-arm trial [31] effectively alleviated systemic symptoms, sustaining rash improvement and reducing posttargeting recurrence with minimal side effects. In clinical observation, targeted drug–related skin toxicity showed sustained improvement with an effectiveness rate of 80.77% and was well tolerated by patients. This exploratory randomized controlled trial (RCT) will preliminarily evaluate the efficacy and safety of JDXZ granules to explore a potential management strategy for skin toxicity induced by EGFR-TKIs.

This study is currently underway. As of December 1, 2025, a total of 81 eligible participants had been enrolled, all of whom were assigned to groups following the randomization principle. Among them, 42 participants were allocated to the JDXZ group (with an additional 2 participants pending enrollment), and 39 to the control group. Based on the current progress, the estimated trial completion date has been extended to January 31, 2026.

Currently, the investigation into skin-related toxicities caused by EGFR-TKIs remains in the exploratory phase, with its findings yet to be fully substantiated, thereby necessitating further comprehensive research. EGFR-TKIs have the potential to elicit the aggregation of inflammatory cells within the context of normal skin. A study by Satoh et al [34] showed EGFR-TKIs’ synergy with skin Bacillus acnes to boost interleukin (IL)-36γ in keratinocytes. EGFR-TKIs suppressed EGFR signaling and upregulated KLF4, whereas Bacillus acnes triggered the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). KLF4 and NF-κB collaborate to upregulate IL-36γ promoter activity, thereby inducing neutrophil recruitment via IL-8 and worsening skin inflammation. EGFR-TKIs not only suppress the proliferative activity of basal keratinocytes but also facilitate their transition toward terminal differentiation, ultimately leading to xerosis of the skin. Erlotinib, as demonstrated by Ikarashi et al [35], markedly lowered aquaporin-3 expression in keratinocytes via the extracellular signal–regulated kinase pathway. Aquaporin-3 is crucial for skin hydration; reduced expression may impair this function. EGFR-TKIs have the potential to disrupt the intimate associations between basal keratinocytes, consequently impairing the epidermal barrier’s functionality. Gefitinib impairs the epidermal barrier by reducing claudin-1 and claudin-4 expression and increasing claudin-2 levels, as discovered by Fang et al [36].

Astragaloside IV, the main active compound of Astragalus, can inhibit the production of pro-inflammatory cytokines and the expression of TLR4 and its downstream signaling molecules, NF-κB, iNOS (inducible nitric oxide synthase), and COX-2 (cyclooxygenase-2) proteins [30]. Astragalus polysacharin, a monomeric Astragalus extract, curbs inflammatory cytokine (tumor necrosis factor, IL-6, and monocyte chemoattractant protein 1) production in lipopolysaccharide-activated RAW264.7 macrophages through NF-κB and mitogen-activated protein kinase (extracellular signal–regulated kinase and c-Jun N-terminal kinase) pathways [37]. Compounds 4 (3H) -quinazolinone (I) and 2,4 (1H, 3H) -quinazolindione (II) from purified I indigotica Fort effectively eliminate S aureus, Escherichia coli, Bacillus subtilis, and Salmonella [38]. Min et al [39] found that I indigotica Fort extract eases atopic dermatitis–like inflammation by suppressing NF-κB pathway–induced cytokine and chemokine production. Chymotrypsin severs desmosome links in skin keratinocytes, speeding cell shedding and boosting epithelial metabolism [40]. C margaritifera’s bioactives boost chymotrypsin, stimulate skin cell growth, and enhance collagen synthesis for skin regeneration and elasticity [40]. Reports confirm the synergistic effects of A membranaceus, I indigotica Fort, and C margaritifera, deeming JDXZ granules safe and effective for inflammation, antibacterial protection, and skin protection.

In the treatment of NSCLC with EGFR-TKIs, the presence of a rash has been shown to significantly predict the effectiveness of the treatment, particularly in patients with unknown EGFR mutation status [17]. As a result, clinicians must closely monitor skin toxicity throughout the entire course of treatment and manage it appropriately to prevent treatment discontinuation or dose reduction of EGFR-TKIs. Building on the clinical promise of JDXZ granules for EGFR-TKI-induced skin toxicity demonstrated in this RCT, a follow-up RCT is warranted to rigorously assess the treatment’s efficacy and safety, with the goals of reducing skin toxicity and enhancing patient quality of life. In this study, the severity of the rash will be graded according to the NCI-CTCAE 5.0 criteria. Assessment tools such as the itch numerical rating scale, the Dermatology Life Quality Index, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 will be used. Additionally, serum levels of fibroblast growth factor 7 [41] and hepatocyte growth factor [42] will be incorporated as biomarkers, with WoMo [43,44] scores and dermatopathological findings serving as secondary end points. This approach provides a more comprehensive and updated perspective on EGFR-TKI–associated cutaneous toxicities.

However, this nonblinded study has limitations, first, in its level of evidence, with potential issues such as unevenly designed control groups and subjective bias in patient-reported outcomes (eg, itching and pain). Furthermore, the collection of long-term medication safety data remains insufficient. Should this study show promising signs, a more rigorously designed multicenter, large-sample, randomized, double-blind, double-dummy, active- or placebo-controlled clinical trial will be necessary for further validation. Such a step is critical to elevate the findings to a higher evidence level and support their potential inclusion in clinical guidelines. Future research should also focus on identifying predominant responders to JDXZ granules based on specific TCM syndrome types or biomarkers, enabling more precise application. Additionally, exploring synergistic effects with conventional Western treatments (such as topical corticosteroids or oral antibiotics) may help reduce the dosage and duration of antibiotic or corticosteroid use, thereby minimizing potential side effects.