FDA Grants Orphan Drug Designation to LUT014 for EGFR Inhibitor–Induced Rash


The FDA granted an orphan drug designation to LUT014 for the treatment of EGFR inhibitor–induced acneiform rash.

Noa Shelach, PhD

Noa Shelach, PhD

The FDA granted an orphan drug designation to the novel topically applied BRAF inhibitor LUT014 for the treatment of EGFR inhibitor–induced acneiform rash, according to a press release from Lutris Pharma. Notably, there are currently no FDA-approved drugs or treatments for the prevention or treatment of EGFR inhibitor–induced acneiform lesions.1

The decision was supported by data from a phase 1, multicenter study (NCT03876106) evaluating the safety, tolerability, and preliminary efficacy of LUT014 in patients with metastatic colorectal cancer (mCRC) with EGFR inhibitor–induced acneiform lesions. In this investigation, 10 patients with mCRC who had developed acneiform rash during treatment with an EGFR inhibitor were enrolled and received LUT014, which was found to be well tolerated.2 Notably, there were no dose-limiting toxicities.

Acneiform rash improved with LUT014 treatment in the 6 patients who started with grade 2 rash in the low and intermediate cohorts, leading investigators to note that LUT014 is safe and efficacious in improving rash induced by EGFR inhibitors.2

“Receipt of orphan drug designation for LUT014 is strategically important for Lutris, as it reflects the significant unmet need for patients treated with EGFR inhibitors, approximately 75% of whom develop some grade of acneiform rash, and allows for an expedited FDA regulatory pathway for LUT014,” Noa Shelach, PhD, chief executive officer of Lutris Pharma, stated in the press release.1

EGFR plays a role in regulating cell growth, survival, proliferation, and differentiation through its signaling pathway. Overactivation of EGFR has been observed in various cancers, including colorectal, lung, head and neck, urinary bladder, pancreatic, and breast, leading to downstream phosphorylation and activation of the MAPK pathway. EGFR inhibitors thereby work by blocking the EGFR signal responsible for cell growth and have therapeutic use for patients who have not responded to prior chemotherapy.1

Although EGFR inhibitors are effective at shrinking tumors, these agents are associated with adverse effects (AEs). Notably, a significant proportion of patients treated with EGFR inhibitors develop dermatological AEs, commonly presenting as a papulopustular skin rash, also referred to as acneiform lesions. These AEs can significantly impact quality of life (QOL) and adherence to therapy.1

LUT014 is a novel BRAF inhibitor that is being investigated to combat these AEs and is administered topically to the skin. In cases where the BRAF protein is mutated, inhibiting this pathway induces cell apoptosis and reduces tumor size. Conversely, blocking the same pathway in normal, non-mutated cells activates the MAPK pathway, promoting cell growth. This is known as the paradoxical effect of BRAF Inhibitors, which LUT014 utilizes to increase cell proliferation and maintain a balance between cell destruction, which is characteristic of radiation dermatitis.1

In the phase 1 study, treatment with LUT014 was investigated in 3 cohorts, which received the agent at dose levels 1, 2, and 3. LUT014 was topically applied to the face, neck, and upper portion of the anterior and posterior chest once a day for 4 weeks.3 Notably, the trial investigated the safety, tolerability, and maximum tolerated dose of LUT014 applied topically once daily for 4 weeks in patients with mCRC who presented with EGFR inhibitor–induced acneiform lesions.3

Furthermore, the safety of LUT014 was also investigated in a phase 1/2 study (NCT04261387) in women with breast cancer who presented with radiotherapy-associated dermatitis.4 In part 1 of this investigation, LUT014 was found to be tolerable and efficacious in the treatment of grade 2 radiation dermatitis, and 75% of patients experienced complete resolution of their radiation dermatitis.

Part 1 of the investigation was an open-label trial, and part 2 was a double-blind, placebo-controlled study. The trial evaluated patients who were treated with either a conventional fractionation or hypofractionated approach and had both grade 2 dermatitis and a Dermatology Life Quality Index (DLQI) score of greater than 6 at screening and baseline.5

All 8 women who received LUT014 achieved treatment success, per the 5-point DLQI reduction at day 14, compared with 73% success for patients on the placebo arm in part 2 of the study (P = .591).5 All patients receiving the investigational treatment derived QOL benefit by day 28, with 7 of 8 patients experiencing no or small effect of dermatitis on their respective QOL outcomes following the treatment course.4 Notably, the time to complete recovery was shorter in the treatment arm.

Evaluable patients were randomly assigned 1:1 to receive topical LUT014 gel or placebo at 0.3 mg/g daily for 28 days following their final round of radiotherapy, followed by a 2-month follow-up period.4,5 Although the gel was administered on day 0 under supervision, it was thereafter applied by the participant at home.

In part 1 of the study, the primary end point was to evaluate the safety and tolerability of LUT014, and in part 2, the primary end point was to determine whether a therapeutic signal was evident.5

On day 7, 75% of patients in the intervention group experienced improved rash, with rash grades decreasing from grade 2 to grade 1, compared with 55% of patients in the control group. By day 21, 50% of women in the treatment arm achieved full recovery, compared with 27% of those in the placebo arm (P = .3765). Overall, complete recovery was seen in 50% of patients in the LUT014 gel group and 36% of those in the placebo group by the day 28 of the study (P = 0.6577).

In part 1 of the trial, a total of 33 nonserious AEs were reported, with 28 unrelated to LUT014 gel and 5 classified as mild adverse drug reactions among 3 patients.5 These reactions included transient mild skin burning in 2 patients, mild breast pain resolving within a week, and pruritis in 1 patient. No serious AEs were reported.

During part 2, 46 AEs were reported in 15 patients: 21 in the LUT014 gel group and 25 in the placebo group. Only 5 AEs (in 4 patients) were related to LUT014 gel, including 2 cases of mild skin burning, 1 case of mild pruritus, and 1 case of moderate skin burning. No serious AEs were observed. One patient discontinued treatment before the day 7 visit due to an AE unrelated to the study drug.

Rhe efficacy and safety of 2 dosage strengths of LUT014 applied topically once a day for 4 weeks will be evaluated in comparison with placebo in patients with mCRC who have developed grade 2 or noninfected grade 3 EGFR inhibitor–induced acneiform lesions in a phase 2, randomized, double-blind, placebo-controlled study (NCT04759664).6


  1. Lutris Pharma receives FDA orphan drug designation for LUT014 for the treatment of EGFRI-induced acneiform rash. News release. Lutris Pharma. February 28, 2024. Accessed February 28, 2024. https://www.prnewswire.com/il/news-releases/lutris-pharma-receives-fda-orphan-drug-designation-for-lut014-for-the-treatment-of-egfri-induced-acneiform-rash-302073519.html
  2. Lacouture ME, Wainberg ZA, Patel AB, et al. Reducing skin toxicities from EGFR inhibitors with topical BRAF inhibitor therapy. Cancer Discov. 2021;11(9): 2158-2167. doi:10.1158/2159-8290.CD-20-1847
  3. A study of LUT014 in patients with metastatic colorectal cancer with EGFR inhibitor induced acneiform lesions. ClinicalTrials.gov. Updated April 6, 2022. Accessed February 28, 2024. https://clinicaltrials.gov/study/NCT03876106
  4. Lutris Pharma announces publication of positive data from its phase 1/2 trial of LUT014 to treat radiation dermatitis in patients with breast cancer. News release. Lutris Pharma. February 21, 2024. Accessed February 28, 2024. https://www.prnewswire.com/il/news-releases/lutris-pharma-announces-publication-of-positive-data-from-its-phase-12-trial-of-lut014-to-treat-radiation-dermatitis-in-patients-with-breast-cancer-302066543.html
  5. Katz S, Ciuba D, Ribas A, et al. A topical BRAF inhibitor (LUT-014) for treatment of radiodermatitis among women with breast cancer. JAAD Int. 2023;15:62-68. doi:10.1016/j.jdin.2023.11.009
  6. LUT014 for the reduction of dose-limiting acneiform lesions associated with EGFRI treatment of mCRC. ClinicalTrials.gov. Updated October 6, 2023. Accessed February 28, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04759664
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