Trametinib in the treatment of patients with metastatic lung adenocarcinoma harboring NF1 mutation: a case series and literature review

Floryane Kim^*Maxime BorgeaudClaudio De VitoPetros TsantoulisAlfredo Addeo

• University Hospitals of Geneva, Geneva, Switzerland

Word count: 254 Background:The neurofibromin 1 (NF1) protein regulates the downstream RAS/RAF/MEK/ERK pathway and functions as a tumor suppressor. Somatic pathogenic mutations in NF1 are found in approximately 4.7–10% of NSCLC, with a higher frequency in lung adenocarcinomas, reaching up to 15% in certain cohorts.Trametinib, a MEK inhibitor, has demonstrated activity in tumors with NF1 alteration in preclinical models, and clinical activity in low-grade glioma and plexiform neurofibromas in neurofibromatosis type 1. Trametinib had only limited clinical efficacy in other tumor types with NF1 mutations in the NCI-Match trial. However, the sole Non small Cell Lung Cancer (NSCLC) patient that was evaluable for response in the NCI-Match trial benefited from a deep partial response. More data for the activity of MEK inhibitors in NF1 altered NSCLC are needed.Cases presentation:We report here a series of 4 NSCLC patients with NF1 pathogenic mutations treated with trametinib. All patients underwent extensive molecular testing with Next Generation Sequencing (custom 462-gene panel), copy number variation analysis and were deemed to have potential NF1-loss driven tumors after case discussion in multidisciplinary molecular tumorboard. Two patients exhibited homozygous NF1 Loss-OfFunction (LOF) alterations, while two patients had heterozygous loss of function alterations. All patients were treated with oral trametinib 2mg once daily, after failure of standard therapies. Trametinib was administered for a maximum duration of nine weeks. The best response observed was a stable disease in one patient. All patients died within three months of treatment initiation. No side effects warranted treatment cessation.Conclusion: In this small case series, NSCLC patients with NF1 alterations did not derive clinical benefit from trametinib. While these data do not support trametinib as a standard option for NF1-mutated NSCLC, larger studies are required to draw firm conclusions.