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A novel topical formulation of a BRAF inhibitor significantly reduced acneiform rash associated with anti–epidermal growth factor receptor (EGFR) therapies in patients with colorectal cancer, a new study found.

This gel could improve treatment adherence, said Anisha B. Patel, MD, lead author of the phase 2 clinical trial, during her presentation of the results at the American Association for Cancer Research (AACR) Annual Meeting 2025.

The study found that LUT014 gel at 0.1% concentration demonstrated statistically significant improvement over placebo in reducing the severity of acneiform rash, a common side effect that often leads to interruption or discontinuation of life-extending cancer therapies.

“Up to 90% of patients treated with anti-EGFR therapies experience papulopustular acneiform eruption, leading to impaired quality of life and suboptimal adherence to the anti-EGFR therapies,” explained Patel during her presentation. In an earlier study, 75% of patients who were on monoclonal antibody EGFR inhibitors had a rash. “Of those patients with the rash, two thirds had a dose impact on their cancer therapy because of the rash alone.”

Mechanism of Action

During her talk, Patel, who is a dermatologist at MD Anderson Cancer Center, Houston, explained the scientific rationale behind investigating the use of LUT014 to mitigate skin rash caused by anti-EGFR therapies.

“What makes this inhibitor so unique is the mechanism of action as opposed to most of the therapies we have for EGFR inhibitor–induced acneiform eruption, which are symptom-directed. This formulation actually works on the mechanism of the rash,” Patel said.

During an interview with Medscape Medical News, Patel explained that EGFR inhibition in the skin leads to acneiform eruption.

“With topical BRAF inhibition, there is a paradoxical upregulation of the downstream MAP kinase pathway,” she said. “This reverses the effects of the EGFR inhibition in the skin only. Phase 1 trials showed no systemic absorption of the BRAF inhibitor.”

Previous dose-escalation phase 1 testing of LUT014, conducted in 10 patients with colorectal cancer experiencing grades 1-2 acneiform rash from EGFR inhibitors, showed no systemic absorption of the topical LUT014. LUT014 was well tolerated, with no dose-limiting toxicities.

Study Design

The double-blind, placebo-controlled trial enrolled 118 patients with metastatic colorectal cancer who were receiving cetuximab or panitumumab and had developed grade 2 or noninfected grade 3 acneiform lesions. Participants were randomly assigned 1:1:1 to receive either LUT014 0.1% gel, LUT014 0.03% gel, or placebo gel for 4 weeks.

The primary endpoint was treatment success, defined as either one Common Terminology Criteria for Adverse Events grade improvement in skin toxicity (investigator-assessed) or a 5-point improvement in patient-reported outcomes using the first 13 skin-directed questions of the FACT-EGFRI-18 health-related quality-of-life questionnaire.

Significant Clinical Benefit

In the intent-to-treat analysis, the high-dose LUT014 (0.1%) demonstrated a 74% success rate compared with 28% in the placebo group (P = .0001). The lower-dose formulation (0.03%) showed a 56% success rate (P = .021 vs placebo).

Similar results were observed in the per-protocol analysis, which excluded patients who dropped out for reasons other than rash. The high-dose formulation achieved an 85% success rate vs 32% for placebo (P = .0001), while the low-dose formulation showed a 69% success rate (P = .009).

The study included an open-label extension for patients in the placebo group whose rash persisted. Seventeen patients crossed over to receive the low-dose LUT014 formulation, which also showed clinical benefit. “This group of patients was almost like an internal control for patients who did not respond to the placebo arm but then had a response to the low-dose LUT014,” Patel said.

Patel shared before-and-after photos of patients during her presentation, highlighting improvements even in typically difficult-to-treat areas such as the perioral region. “Patients who had seborrheic dermatitis-acneiform eruption overlap also had a response,” she noted.

Impact on Cancer Treatment

The investigators conducted an exploratory analysis to assess the impact of topical BRAF inhibition on cancer treatment adherence. The analysis showed that patients receiving LUT014 had lower rates of anti-EGFR therapy interruption due to skin toxicity.

Miguel Villalona-Calero, MD, of UCI Health, Orange, California, who discussed the findings of this phase 2 trial during the session, emphasized the importance of this exploratory analysis: “When you add them all together, 9 out of 54 patients, that’s 16% of patients, interrupted the treatment while receiving either the high dose or the low dose, and 11 patients out of the 29, which is 26%, interrupted the treatment who were in the placebo group.”

“The only patients who were included in this exploratory analysis had EGFR interruption because of their acneiform rash,” Patel explained during her talk. “There was statistical significance for the high-dose group and a trend toward that in the low-dose group, where they were able to maintain compliance with their anti-EGFR therapy.”

In her interview, Patel expanded on the clinical implications of this finding from an oncologic perspective. “Patients who had good rash response also had good EGFRI therapy compliance, which could potentially lead to better tumor response,” she said.

Safety Profile

The adverse events related to LUT014 were predominantly mild, with most patients reporting pruritus or skin irritation. Interestingly, there were more grade 2-3 adverse events in the placebo group than in the treatment arms.

“We think this is because patients had untreated flaring acneiform eruption, and they were also applying a placebo gel that had no active ingredient that could be potentially irritating to their skin when inflamed,” Patel explained.

When asked about managing application site reactions from LUT014 gel, Patel said: “We observed that most of the site reactions would decrease with time as patients’ rashes continued to improve. But for those first couple of weeks when it may be uncomfortable, washing the gel off a couple of hours after application helped with the reactions and did not appear to affect the efficacy.”

Clinical Implications and Future Directions

Standard care for EGFR inhibitor–induced acneiform eruption typically includes oral tetracyclines, topical steroids, and oral retinoids. However, Patel pointed out, “None of these have been approved by regulatory bodies, so there is still an unmet need for advanced management and regulatory approval.”

In an interview with Medscape Medical News, Villalona-Calero noted that despite current guidelines for the management and mitigation of EGFR inhibitor–induced rash, this manifestation is still an issue, resulting in instances of withholding and discontinuation of treatment. “An approach that interferes with the downstream effect on normal skin of these agents is a welcome approach, as long as it does not interfere with the desirable antitumor effect of these agents,” he said.

“Topical LUT014 at the concentrations tested appears to have minimal systemic exposure and demonstrated a significant amelioration of symptoms in a patient population with moderate to severe symptoms,” Villalona-Calero added during the interview.

However, he raised an important question about its potential use as a preventive measure: “It is less clear if its utilization as a rash preventive tool would add value over current guidelines or would interfere with the reported ‘on target’ tumor effect predictive value of the skin symptomatology.”

This question arises because skin toxicity has been associated with better tumor response in some studies of EGFR inhibitors, raising theoretical concerns about whether reducing rash might affect treatment efficacy, he explained.

When asked which populations with cancer beyond colorectal cancer might benefit from this approach, Patel suggested broad applicability: “Potentially any patient on a MAP kinase pathway inhibitor with acneiform eruption could benefit from this drug.”

Patel is hopeful that having an effective topical treatment for acneiform rash will change how clinicians approach EGFR inhibitor dosing. “Hopefully, managing the acneiform rash in a timely and safe manner will allow patients to remain on full doses of their EGFR inhibitors without interruption,” she said in the interview.

Patel reported financial relationships with the University of Texas MD Anderson Cancer Center (employment); Asymmetric, Erasca, Janssen Pharmaceuticals, Lutris, and SynOx (consultation fees); and Lutris Pharma, Hoth Therapeutics, and Melanoma Research Foundation (grant or research support). Villalona-Calero reported financial relationships with the University of California, Irvine (employment); Guidepoint, Eli Lilly and Company, National Cancer Institute, Amgen, and Winn/AACR Clinical Trials Workshop (consultation fees).

Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.