Of the four patients with advanced NF1-mutant lung adenocarcinoma in poor performance status, only one achieved disease stability after third-line trametinib treatment, which may be related to an allele mutation. Further expanded MAPK gene screening is needed. – Sohu.com

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Neurofibromatosis protein 1 (NF1) regulates the downstream RAS/RAF/MEK/ERK pathways, acting as a tumor suppressor. In non-small cell lung cancer (NSCLC), approximately 4.7%–10% of patients have somatic pathogenic mutations in NF1, with a higher frequency in lung adenocarcinoma, reaching up to 15% in some cohorts. Trametinib, a MEK inhibitor, has shown activity against NF1-mutant tumors in preclinical models and has demonstrated clinical activity in low-grade gliomas and plexiform neurofibromas associated with neurofibromatosis type 1. However, in the NCI-Match trial, trametinib showed limited clinical efficacy against other tumor types with NF1 mutations. Nevertheless, the only evaluable NSCLC patient in this trial benefited from a deep partial response. Further data on the activity of MEK inhibitors in NF1-mutant NSCLC are needed. This article reports a series of four NSCLC patients with NF1 pathogenic mutations who received trametinib. All patients underwent molecular testing and copy number variation analysis and were identified as potentially NF1-inactivation-driven tumors following case discussions by a multidisciplinary molecular oncology committee. Two patients presented with homozygous loss-of-function NF1 variants, and two others with heterozygous loss-of-function variants. All patients received oral trametinib 2 mg once daily after failure of standard therapy. The longest duration of trametinib administration was 9 weeks. The best observed response was disease stabilization in one patient. All patients died within 3 months of treatment initiation. No side effects requiring discontinuation occurred. In this small case series, patients with NF1-mutant NSCLC did not derive clinical benefit from trametinib treatment. While these data do not support trametinib as a treatment option for NF1-mutant NSCLC, larger-scale studies are needed to draw definitive conclusions. Neurofibromatosis protein 1 (NF1) encodes a small GTPase activator protein that binds to the RAS protein family and functions as a tumor suppressor gene. NF1 binds to KRAS, HRAS, and NRAS, placing them in an inactivated GDP-binding state, thereby regulating cell growth and differentiation. Germline NF1 mutations are associated with neurofibromatosis type 1, characterized by the development of neurofibromas. Individuals with this syndrome also face an increased risk of various cancers, including malignant peripheral nerve sheath tumors (MPNST), leukemia, gliomas, and breast cancer. Acquired somatic mutations in the NF1 gene have been found in various malignancies unrelated to neurofibromatosis type 1. Notably, Approximately 8% of non-small cell lung cancer (NSCLC) carries pathogenic NF1 mutations, although most studies do not report the proportion of patients with complete inactivation of both alleles, and this proportion is likely even lower. A deeper understanding of tumor biology and the detection of driver genes in NSCLC have driven the development of targeted therapies that have revolutionized patient care and improved prognosis. Trametinib, a mitogen-activated protein kinase (MEK) inhibitor targeting the key components of the MAPK/ERK pathway, MEK1 and MEK2, has emerged as a potential treatment for NF1-mutant tumors. It has shown encouraging results in patients with unresectable plexiform neurofibromas and low-grade gliomas associated with neurofibromatosis type 1. However, trametinib appears to have limited efficacy in other tumors carrying NF1 mutations. In the NCI-Match trial, which enrolled patients with NF1, GNAQ, or GNA11-mutant tumors, three patients with NF1-mutant NSCLC were initially enrolled, but only one was evaluable for efficacy, showing near-complete response. The other two patients were not evaluable due to rapid disease progression or early withdrawal. Researchers are unaware of other studies or case reports detailing the response of NF1-mutant non-small cell lung cancer to MEK inhibitors. Therefore, it remains unclear whether patients in this situation can derive a clinically meaningful benefit from MEK inhibitors. This article reports a series of cases of four patients with NF1-mutant metastatic lung adenocarcinoma treated with trametinib at the University Hospital of Geneva, Switzerland, and provides a comprehensive literature review. All four patients underwent the same extensive molecular testing, including next-generation sequencing and copy number variation analysis. The NGS panel was larger than 1 Mb. Variant interpretation and classification were performed using Cancer Gene Census, COSMIC (Catalogue of Somatic Tumor Mutations), CIVIC (Clinical Interpretation of Cancer Variants), and OncoKb. For NF1 splicing variants, pathogenicity was determined based on the SpliceAI and Pangolin algorithms. Clinical characteristics and treatment outcomes are summarized in Figure 1. Descriptions of the different genomic alterations found in each patient are shown in Table 1 and Figure 2. Following discussions by the Molecular Oncology Committee, based on preclinical theoretical evidence (suggesting the potential effectiveness of MEK inhibitors in NF1-deficient tumors) and drawing on evidence from other NF1-mutant cancers, trametinib treatment regimens were proposed for each patient. The off-label use of trametinib and the nature of its clinical trials were clearly discussed with each patient individually. The patient was a 62-year-old female with a history of smoking, diagnosed with PD-L1-negative lung adenocarcinoma in September 2020. The patient was diagnosed with stage IIIB according to the 8th edition of the TNM staging system. He received concurrent chemoradiotherapy (carboplatin and paclitaxel), followed by durvalumab maintenance therapy for one year. Two months after discontinuing immunotherapy, the patient experienced a biopsy-confirmed peritoneal metastatic recurrence. First-line chemotherapy with carboplatin and pemetrexed achieved disease stabilization, followed by pemetrexed maintenance therapy until new metastatic progression occurred in November 2022. Two pathogenic NF1 mutations were detected (Table 1). Based on recommendations, the patient began trametinib treatment in March 2023. At the start of treatment, the patient's ECOG score was 2 and Charlson score was 7. During treatment, a grade 3 skin rash developed, requiring topical corticosteroids and oral doxycycline. The first CT scan was performed at week 7 of treatment, showing disease progression with a 70% increase in lesion size according to RECIST criteria (Figure 3). Treatment was discontinued, and the patient died rapidly. The patient was an 80-year-old male with a 65-pack-year smoking history. In January 2022, he was diagnosed with PD-L1-negative metastatic lung adenocarcinoma. Initial treatment consisted of 4 cycles of carboplatin-pemetrexed-pembrolizumab. Due to disease stability, maintenance therapy with pemetrexed-pembrolizumab was initiated, but discontinued after one cycle due to grade 3 treatment-related fatigue. The patient's condition remained relatively stable until November 2022, when a CT scan showed progression in the pleura and lungs. Second-line therapy was initiated with paclitaxel in combination with bevacizumab. The patient exhibited poor clinical tolerance to chemotherapy, experiencing grade 3 fatigue, grade 4 thrombocytopenia, and grade 3 leukopenia. Further molecular analysis revealed a stop codon mutation in the NF1 gene and an increased NF1 gene copy number (4 copies). No RASA1 gene alterations were found. Based on the mutation abundance, the mutation is likely located on the obtained alleles (Table 1). Following discussion, and considering the patient's poor tolerance to chemotherapy, ECOG PS score of 2, and Charlson score of 15, trametinib treatment was initiated in February 2023. The patient tolerated trametinib adequately, presenting with cough, and developed grade 2 creatinine elevation, grade 2 thrombocytopenia, and grade 1 anemia. All side effects, except cough, were considered treatment-related. None of these side effects required discontinuation of treatment or dose adjustment. Six weeks after trametinib treatment, a CT scan showed stable disease (according to RECIST criteria, Figure 3). The clinical course subsequently complicated by an accidental fall and hip fracture, followed by heart failure with acute pulmonary edema. Trametinib treatment was immediately discontinued, and the patient died two weeks later. The patient was female. A 70-year-old patient was diagnosed with unresectable stage IIIC lung adenocarcinoma in the right upper lobe, with PD-L1 expression at 10%. The patient received first-line chemoimmunotherapy, including four cycles of carboplatin, pemetrexed, and pembrolizumab. After initial partial remission, the patient experienced disease progression during pemetrexed-pembrolizumab maintenance therapy. Second-line treatment consisted of paclitaxel in combination with bevacizumab for three cycles until January 2022. Molecular analysis revealed a mutation in the conserved splice donor sequence of the NF1 gene;

based on variation abundance, this mutated allele was amplified, potentially leading to partial NF1 inactivation (Table 1). No activating co-mutations of the RAS/MAPK pathway were found, particularly no alterations in the RASA1 gene. Subsequently, trametinib 2 mg was initiated in February 2023. The patient's ECOG score was 2, and the Charlson Comorbidity Index was 9. The patient developed grade 1 skin rash and diarrhea. Eight weeks after treatment, a CT scan showed progression in the chest and central nervous system (Figure 3). Trametinib was discontinued, and due to rapid deterioration, the patient was transferred to best supportive care and died in April 2023. A 62-year-old male patient was diagnosed with metastatic lung adenocarcinoma with PD-L1 expression of 10%. He received first-line therapy with carboplatin, pemetrexed, and pembrolizumab, achieving partial remission. One year later, disease progression occurred, and he received second-line therapy with carboplatin and gemcitabine for 3 months, after which further metastatic progression occurred. Molecular analysis revealed a pathogenic mutation in the NF1 gene and deletion of another allele (Table 1). No co-mutation with RASA1 was found. The patient's ECOG score was 2, and his Charlson comorbidity index was 7. Trametinib treatment was initiated, but the patient's general condition deteriorated rapidly, and he died one week later. The clinical deterioration was due to disease progression, not trametinib toxicity. NF1 mutations have been reported in both lung adenocarcinoma and squamous cell carcinoma, with incidences of 8.3% and 12%, respectively, but a lower prevalence in Asian populations. NF1 is a large gene, consisting of 60 exons (>280 kb), and can carry a variety of alterations—including nonsense mutations, missense mutations, frameshift mutations, splice site variations, insertions/deletions, and large deletions—making comprehensive analysis technically challenging. This may be one reason why research on NF1-mutant tumors is relatively limited compared to other oncogenic driver genes. It has been observed that most cases of non-small cell lung cancer carrying NF1 mutations do not have co-mutations. In a large genomic cohort analyzed by Bowman et al. , in the Caucasian population, KRAS mutations were the most common co-alteration (16.5%), followed by EGFR (6.8%) and BRAF (3.9%) alterations. These KRAS mutations were primarily located at G12 and G13 sites. Tlemsani et al. also described similar co-mutation patterns and their association with smoking. In a previous observational study, most patients with NF1 mutations were current or former smokers (88%). In Asian populations, the number of NF1 co-mutations with known oncogenic mutations was significantly higher, primarily involving EGFR mutations, which are known to be more prevalent in this population. Whether NF1 mutations have a prognostic role in NSCLC is unclear and appears to depend on the specific context. The prognosis of patients with tumors carrying NF1 inactivation mutations appears to be comparable to that of patients carrying KRAS codon 12 or 13 mutations, but worse than that of patients with EGFR mutations. Interestingly, in the Chinese population, NF1 mutations appear to be associated with better prognosis in patients with EGFR mutations/TP53 wild-type. In patients with EGFR mutations, the co-occurrence of TP53 mutations with alterations in tumor suppressor genes such as NF1 appears to be a worse prognosis. In a study by Liu et al. , NF1 mutations were associated with improved survival in patients receiving immunotherapy, but patients with EGFR-mutated or ALK-rearranged NSCLC had poorer prognoses with targeted therapy. Other co-occurring mutations with NF1 are also noteworthy, such as RASA1 (a Ras-GTPase activator protein), as RASA1/NF1 co-mutations appear to be mutually exclusive with other driver mutations and are more sensitive to MEK inhibition in preclinical models. The literature on trametinib for NF1-mutant tumors is almost nonexistent. The NCI-MATCH trial evaluated the efficacy of trametinib in patients with advanced tumors harboring NF1 mutations in one of its sub-regimes. Eligible patients were those with advanced solid tumors, lymphomas, or multiple myeloma that had progressed after at least one line of systemic therapy. Initially, three patients diagnosed with lung cancer were enrolled in the study;

however, only one patient was evaluable for efficacy, showing near-complete remission with a median progression-free survival of 6.4 months. Notably, no co-mutations were found in this case, particularly no KRAS alterations. Although both NF1 deletion and KRAS activating mutations can lead to MAPK pathway activation and sensitivity to MEK inhibition in vitro, MEK inhibitors have failed to show efficacy in KRAS-mutant non-small cell lung cancer patients. This may be due to the existence of multiple mechanisms that bypass MAPK pathway inhibition, such as enhanced AKT signaling in KRAS-mutant tumors. In the National Lung Matrix trial (an umbrella study), In a study of 14 patients with NF1 deficiency treated with the MEK inhibitor selmetinib in combination with docetaxel, the objective response rate was 31%, and the median progression-free survival (PFS) was 5.3 months. Eligible patients had either received prior anticancer therapy or refused first-line standard treatment. Unfortunately, the efficacy of selmetinib monotherapy in this study is unclear, and the results may have been driven by docetaxel. The NCT03232892 trial aimed to investigate the efficacy of trametinib in patients diagnosed with non-small cell lung cancer carrying NF1 mutations. Unfortunately, this trial was terminated early due to insufficient participant recruitment. Therefore, the four cases described in this article represent the largest reported case series to date on the use of the MEK inhibitor trametinib in patients with metastatic lung adenocarcinoma carrying NF1 alterations. All patients had poor performance status (ECOG score 1–2) at the start of treatment, and trametinib was used as third-line therapy. Although some patients experienced serious side effects, such as grade 3 skin rash and hematologic toxicity, these side effects were effectively managed without discontinuation or dose reduction. This indicates that trametinib is well-tolerated in this multi-line therapy population with close monitoring (including regular clinical assessments, complete blood counts, liver and kidney function tests, and consideration of dose adjustment or temporary treatment interruption for ≥ grade 2 adverse events). However, close monitoring remains crucial. Treatment was generally well-tolerated, but no adverse events warranted discontinuation. Two of the three patients experienced rapid disease progression according to RECIST criteria at the initial CT scan. The third patient achieved disease stability but unfortunately died in the early stages of treatment due to an accidental fall. The fourth patient died only one week after receiving trametinib treatment and could not be formally evaluated. In summary, one of the three patients may have received some radiographic benefit from trametinib, but no deep response was observed. In the cases presented in this study, several factors may have contributed to the lack of response to trametinib. First and foremost, two of the four patients had only one pathogenic mutation, accompanied by NF1 gene amplification—likely a mutant allele amplification—suggesting that the other wild-type allele may still be functional. In these cases, a single allele alteration in NF1 may not be sufficient to activate the MAPK pathway alone, leading to treatment resistance. Secondly, no co-occurrence alterations of the MAPK/ERK pathway were found in any of the patients. While some mutations (such as KRAS) appear to confer resistance to MEK inhibitors in this context, other alterations, such as RASA1 deletion, have been shown to significantly enhance the sensitivity of NF1-deficient cell lines to MEK inhibition, perhaps highlighting the need to consider not only NF1 mutations. The importance of the overall genetic background also needs to be considered. In case 3, it remains uncertain whether MAP3K13 amplification might promote bypass survival by upregulating the JNK signaling axis. From this perspective, future research exploring combination therapies to address compensatory pathways or resistance mechanisms limiting MEK inhibition efficacy in this situation may be valuable. Finally, all patients received third-line therapy and had poor performance status and short expected survival. In summary, this article reports four cases of metastatic lung adenocarcinoma with complete or partial NF1 inactivation, all of whom received trametinib monotherapy as third-line therapy. None of them achieved clinically meaningful benefit. The findings of this study raise questions about the use of trametinib in this population, especially in cases with only one allele mutation, despite the small patient population, high molecular heterogeneity, and the significant limitations of initiating treatment as third-line therapy. Future comprehensive studies including more patients and a full analysis of all MAPK genes are needed to deepen our understanding of this patient subgroup. Solid tumor 1299 gene testing, solid tumor 272 gene testing PLUS, and lung cancer 126 gene testing all cover the entire coding region of the NF1 gene, assisting in precise clinical diagnosis and treatment. Kim F, Borgeaud M, De Vito C, Tsantoulis P and Addeo A (2025) Case Report: Trametinib in the treatment of patients with metastatic lung adenocarcinoma harboring NF1 mutation: a case series and literature review. Front. Oncol. 15: 1481284. doi: 10.3389/fonc. 2025.1481284