The use of an investigational topical BRAF-inhibiting gel appeared to be effective in treating acneiform rash in patients with advanced colorectal cancer who were treated with an epidermal growth factor receptor (EGFR)-targeted drug, a randomized phase II trial showed.

The 39 patients randomly assigned to receive a high-dose 0.1% formulation of LUT014 gel were twice as likely to experience treatment success than the 39 patients on placebo (69% vs 33%, P=0.0015), reported Anisha Patel, MD, of the University of Texas MD Anderson Cancer Center in Houston, at the American Association for Cancer Research annual meeting in Chicago.

For 40 patients who received the low-dose 0.03% LUT014 formulation, the treatment success rate was also higher (47.5%) than that with placebo, but failed to reach statistical significance (P=0.12).

“LUT014 0.1% gel provides statistically significant benefit over placebo gel for the treatment of acneiform rash associated with cetuximab (Erbitux) or panitumumab (Vectibix) therapy for patients with advanced colorectal cancer,” Patel said.

Seventeen patients in the placebo arm were able to cross over to receive 0.03% LUT014 in an open-label extension study, with 53% of those patients achieving treatment success.

“This also showed clinical benefit for patients who failed placebo,” Patel observed. “So this was almost like an internal control for patients who did not respond in the placebo arm, but then had a response to the low-dose LUT014 compound.”

One of the consequences of developing acneiform rash is treatment discontinuation or delay of EGFR-targeted therapies. In this study, Patel and her team found that treatment interruptions of anti-EGFR therapy due to acneiform rash occurred in 11 patients in the placebo group, four in the high-dose LUT014 group (P=0.04), and five in the low-dose LUT014 group (P=0.09).

“You can see there is statistical significance for the high-dose group, and a trend towards that in the low-dose group, where they were able to maintain their compliance with their anti-EGFR therapy,” said Patel.

Invited discussant Miguel Villalona-Calero, MD, of the Chao Family Comprehensive Cancer Center at the University of California Irvine, noted that “an approach that interferes with the downstream effect on normal skin of these [EGFR inhibitors] is a welcome approach as long as it does not interfere with the desirable antitumor effect of these agents.”

“Topical LUT014 at the concentrations tested appears to have minimal systemic exposure and demonstrated in the data presented today a significant amelioration of symptoms in a patient population with moderate to severe symptoms,” he added.

Study Rationale and Design

Anti-EGFR therapies are associated with the development of papulopustular acneiform rash in up to 90% of patients, leading to impaired quality of life and suboptimal adherence to treatment.

Standard-of-care management is with corticosteroids, topical or oral antibiotics, and oral retinoids, “but none of these have been approved by regulatory bodies,” Patel said. “So there is still an unmet need for advanced management and regulatory approval.”

As explained by Patel, systemic EGFR-targeted therapies block EGFR activity and downstream signaling in multiple organs — including the skin — which can lead to subsequent dysregulation of skin cells and can induce an inflammatory response leading to acneiform rash.

Paradoxically, inhibiting the BRAF protein is known to reactivate downstream EGFR signaling, she said, which suggests that inhibiting BRAF locally with the gel at sites of acneiform rash could reverse the effects of EGFR inhibition in the skin and reduce the severity of the rash.

This study included 118 patients with metastatic colorectal cancer treated with cetuximab or panitumumab, who had grade 2 or non-infection grade 3 acneiform lesions at baseline. Across the three treatment groups, median age was 47-54, 62-73% were men, and 72-73% were white.

Patients who were on systemic antibiotics at the time of the study could remain on them as long as they had a stable dose for 28 days and continued on that stable dose until completion of LUT014 treatment. Patients not on systemic antibiotics were not permitted to initiate them during LUT014 treatment.

Patients applied the gel to the rash each day for 28 days, and treatment success was defined as a 1-grade or greater reduction in rash severity and/or improvement in at least five skin-specific, health-related quality-of-life criteria by the end of the 28-day period.

Treatment-related adverse events (TRAEs) included itchiness, burning sensation, skin redness, and stinging at the application site for patients treated with LUT014 — similar to TRAEs occurring in patients treated with placebo. Most of the adverse events in patients who received the LUT014 gel were grade 1, with one patient in the 0.1% LUT014 arm and three in the placebo arm experiencing grade 3 adverse events.

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