Study shows EGFR inhibitors may be effective in melanoma that does not respond to standard treatments

A newly published study from NYU Langone Health and the Perlmutter Cancer Center suggests a promising avenue of treatment for patients with advanced melanoma harbouring mutations in the neurofibromin 1 (NF1) gene—particularly those whose tumours have proven resistant to immune checkpoint inhibitor therapy. The research, published in Cancer Research, points to the efficacy of epidermal growth factor receptor (EGFR) inhibitors in limiting tumour growth in this challenging subgroup of skin cancer patients.

Immunotherapy has revolutionized melanoma care, but its benefits are not universally realized. In the study, investigators found that more than 40% of tumours from melanoma patients unresponsive to immunotherapy harboured NF1 mutations. These samples were drawn from NYU Langone’s repository spanning more than 6,000 melanoma cases.

Molecular analysis revealed that the EGFR pathway was markedly hyperactive in NF1 mutant melanoma cells compared to other gene mutation subtypes. Prior research has linked increased EGFR activity to rapid tumour proliferation and inferior survival outcomes in several different cancers.

Lead investigator Milad Ibrahim, PhD, summarized the study’s goal in a press release:

“There is a pressing need for new drug therapies for melanoma patients with neurofibromin 1 mutations that do not respond to the latest immunotherapy, and for which there are no subsequent effective treatment options.” Co-senior investigator Dr. Iman Osman noted, “Our study results reveal a unique vulnerability in melanoma patients with neurofibromin 1 mutations, that an overexpression of the epidermal growth factor receptor pathway is essential for their survival and growth.”

To evaluate potential therapeutic strategies, researchers tested the U.S. FDA-approved EGFR inhibitors cetuximab and afatinib—already used in head and neck, lung, and colorectal cancers—in cell cultures and patient-derived xenograft models. These drugs selectively suppressed cell proliferation and tumour growth in NF1 mutant samples, while showing no effect on wild-type or other mutation subtypes.

“While further tests are needed, our results support a novel approach of deploying EGFR inhibitors either alone or in combination with other immunotherapies for treatment of melanoma patients whose tumours harbour NF1 mutation,” added co-senior investigator Markus Schober, PhD.

Metastatic melanoma remains a formidable challenge in oncology. The present study provides a rationale for clinical trials, with the goal of translating these findings into treatment options for this patient population.

Researchers are now developing prospective clinical trials to confirm these laboratory observations, to determine if EGFR inhibitors could become a new standard for the treatment of patients with NF1 mutant, treatment-resistant melanoma.