Advancing Treatment for EGFR Inhibitor-Associated Dermal Toxicities

The application of a genetically modified Staphylococcus epidermidis bacteria-based ointment may reduce EGFR inhibitor-associated dermal toxicities, according to Jonathan Leventhal, MD.

The application of a genetically modified Staphylococcus epidermidis bacteria-based ointment may reduce EGFR inhibitor-associated dermal toxicities, according to Jonathan Leventhal, MD.

Leventhal, an associate professor of Dermatology, director of the Dermatology Residency Program, and director of the Onco-Dermatology Clinic at Smilow Cancer Hospital of Yale School of Medicine, spoke with CancerNetwork® about ATR04-484, a live biotherapeutic product in development for managing EGFR inhibitor-associated skin rash.

He began by outlining the design for an upcoming phase 1/2 trial (NCT06830863), which will compare the Staphylococcus epidermidis bacteria-based ointment with a placebo ointment only containing the vehicle component. He further described that patients will apply the ointment daily to afflicted skin for 28 days. According to Leventhal, end points will include rash severity based on Common Terminology Criteria for Adverse Events (CTCAE); pruritus, pain, and quality of life metrics; and biomarker assessments.

Outlining preclinical trials presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Leventhal explained that the drug showed inhibition of both methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA, MRSA), which are associated with severe rash. He further remarked that the biotherapeutic reduced interleukin 36 (IL-36) inflammation; IL-36 cytokine is increased in the skin following EGFR inhibition.

Leventhal further outlined current treatment strategies for skin toxicities, which include topical antibiotics, topical steroids, and oral antibiotics for acneiform rash. Overall, these treatments are associated with severe limitations by way of adverse effects; Leventhal highlighted a need for more pathogenesis-driven treatments for these toxicities. He concluded by expressing excitement that companies are interested in pursuing clinical trials aimed at treated cutaneous toxicities.

CancerNetwork®: ATR04-484 will be evaluated in patients experiencing EGFR inhibitor-associated dermal toxicities in a phase 1/2 trial (NCT06830863). Can you describe the trial design?

Leventhal: This is a randomized, controlled study that will recruit patients from multiple cancer centers. We are going to evaluate the efficacy, safety, and tolerability of a topical ointment made of genetically modified Staphylococcus epidermidis bacteria, and we are going to compare it to a cohort of patients receiving placebo ointment only containing the vehicle component. The patients will be [randomly assigned] to either receive the treatment ointment or the placebo vehicle, and they will apply it once daily to affected skin, including the face, neck, chest, and back for 28 days.

We are looking to see if the ointment, [ATR04-484], helps to reduce the skin toxicities that we see from the EGFR-targeted cancer therapies. Specifically, the end points we [will be] looking for include the disease severity scores of the rashes, which will be based primarily on CTCAE [on a 0 to 4] scale, as well as a few other end points, including pruritus, pain, and quality of life metrics.

Interestingly, we are also going to look at biomarkers, including changes in the skin microbiome, to see how the Staphylococcus epidermidis ointment impacts skin dysbiosis. The theory here is that the Staphylococcus epidermidis, or the good bacteria, will reduce the Staphylococcus aureus, MSSA, and MRSA, which are the bacteria that we know are associated with severe rash.

[We will] also look at inflammatory markers such as IL-36, which is a marker known to be associated with rash. The hypothesis is that the topical Staphylococcus epidermidis ointment will reduce the Staphylococcus aureus [bacteria] and will reduce IL-36 inflammation, which will help combat the EGFR inhibitor-[associated] skin toxicities.

Can you outline the preclinical findings for the live biotherapeutic presented at ASCO 2025?

Leventhal: [Developers] found that [after] genetically engineering ATR04-484—which is a naturally derived Staphylococcus epidermidis bacterial strain, to make it safe by deleting a gene needed for its growth––they showed on reconstructed human skin and pig skin that it inhibited Staphylococcus aureus bacteria, both MSSA and MRSA. It also showed that the EGFR inhibitors increased IL-36 cytokine in the skin, and that this genetically modified bacterial strain reduces the IL-36 inflammation. This gives us the scientific foundation supporting the clinical trial, and the results are exciting.

What do current strategies look like for mitigating EGFR inhibitor-related toxicities, and what are some strengths and limitations associated with these strategies?

Leventhal: As someone who sees [many] patients with cancer who are on these targeted cancer therapies, I can tell you that rash is very prevalent. It happens in over 90% of patients on EGFR inhibitors. First, in background, it causes acneiform rash, known as papulopustular or acneiform eruption, paronychia, nail infections, dry eczematous skin, pruritus, hirsutism, hair loss on the scalp, trichomegaly of the eyelashes––a lot of cutaneous toxicities that impact quality of life. We need better treatments.

Current strategies that we employ in clinical practice include topical antibiotics, topical steroids, and oral antibiotics for the acneiform rash. [Those are] the mainstay treatments, and in severe presentations of the rash, we will have a drug holiday where the patient holds their dose of cancer treatment. Occasionally, in very severe presentations, we will use systemic steroids, and in recalcitrant cases, a medicine called oral isotretinoin [Accutane]. There [are many] limitations in that these treatments are nonspecific. They are often putting a bandage [on] or chasing these dermatologic toxicities, as opposed to actually preventing them or treating them in a more targeted manner.

There are [adverse] effects and limitations of the treatments. For instance, the oral antibiotics, which is the mainstay treatment, can cause an upset stomach. You can change the bacterial flora of the gastrointestinal tract, [as well as] photosensitivity. Systemic steroids, which can be helpful in the short term, have a lot of long-term [adverse] effects. We cannot use them in the long term because they can cause hyperglycemia, weight gain, cataracts, bone weakness; you name it. Isotretinoin can be helpful, but there is a limitation of using it in that it often causes a lot of cirrhosis and dryness, and these patients on EGFR inhibitors already are at major increased risk of eczema [or] cirrhotic skin, so they often can tolerate higher therapeutic doses of isotretinoin.

The bottom line is we need more pathogenesis-directed treatment approaches that are targeting the pathways that lead to the rash or that propagate and worsen the rash. What I like about the [phase 1/2] trial is that it targets the skin microflora while looking to reduce Staphylococcus aureus bacteria and IL-36 inflammation, both of which are integral in rash development and severity. I am hopeful that it is going to be effective and safe, potentially changing the approach [for] these patients [towards] a more pathogenesis-directed treatment.

What other developments in treatment for patients with EGFR inhibitor-induced dermal toxicities or similar toxicities have the potential to change clinical practice?

Historically, there have not been [many] major breakthroughs. One specific to the EGFR inhibitor class is our trials that have showed that using oral antibiotics, topical steroids, and sun protection at the onset of treatment can reduce the severity of the acneiform rash. Clearly, it does not prevent the rash, but it does reduce the severity to an extent. The problem is a lot of the newer treatments, such as amivantamab-vmjw [Rybrevant] for patients [with lung cancer], pose new challenges. The incidence of the rash is so high, exceeding 90%, and the rash severity is high as well.

We need new treatment approaches, and the future of the field is going to [include] treatments that are pathogenesis-directed or target the pathways that either disrupt bacterial dysbiosis, like this study…or even future medicines that target the EGFR pathway itself to restore normal EGFR activity in the skin. I think that is going to be the future of how we treat these rashes.

Is there anything else that you would like to highlight?

As an oncodermatologist who sees patients [with cancer] daily who are struggling with cutaneous toxicities of their treatments and quality of life, and, in some cases, the skin toxicities are so severe that patients want to stop their treatment or oncologists look for alternative treatments, it’s exciting and inspiring to see companies…want to pursue clinical trials looking for new approaches to manage and prevent cutaneous toxicities. It is great, and I hope to see other cancer centers continue to collaborate and participate in these types of trials.

Reference

Spellman MC, Whitfill TC. Epidermal growth factor receptor (EGFR) inhibitor-induced dermal toxicity treated with topical application of a novel Staphylococcus epidermidis compound. J Clin Oncol. 2025;43(suppl 16):TPS12149. doi:10.1200/JCO.2025.43.16_suppl.TPS12149