Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare alteration in non-small-cell lung cancer (NSCLC), occurring in about 3%-4% of cases. Here we report disease and patient characteristics, and efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS. Clinical-pathological and molecular data, and treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry. From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years, and most patients were male (52%), with an Eastern Cooperative Oncology Group performance status < 2 (72%) and adenocarcinoma subtype (83%). One hundred and twenty-five out of 146 (86%) patients received at least one line of systemic anticancer therapy. Fifty-six (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in the first and second line, respectively. In the cohort of patients treated with MET inhibitors, the response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow-up of 10.8 months, progression-free survival was 6.6 months [95% confidence interval (CI) 4.3-8.3 months] and overall survival was 10.7 months (95% CI 7.2-19.3 months). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases, respectively. Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the management of patients with METex14.

Purpose: First-line treatment options for MET exon 14 skipping–mutant metastatic non–small cell lung cancer vary because of differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI) ± chemotherapy. Experimental Design: Clinicopathologic data were collected from patients with metastatic MET exon 14 skipping–mutant non–small cell lung cancer treated with first-line MET TKI or ICI ± chemotherapy at five centers. Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS) to first-line MET TKI versus ICI ± chemotherapy. Subgroup analyses by clinical and tumor characteristics were performed. Results: Among 158 patients, 80 received MET TKI and 78 received ICI ± chemotherapy as first-line treatment. Baseline clinicopathologic features were balanced except for a higher proportion of patients with a history of smoking in the ICI ± chemotherapy group (P = 0.03). With a median follow-up of 37.9 months, no difference was observed in rwPFS (HR, 0.85; P = 0.4) or OS (HR, 0.97; P = 0.9) with first-line MET TKI versus ICI ± chemotherapy. In subgroup analyses, first-line ICI ± chemotherapy improved rwPFS in PD-L1 ≥80% (HR, 0.50; P = 0.03), whereas MET TKI improved rwPFS (HR, 0.40; P = 0.005) and OS (HR, 0.49; P = 0.03) in PD-L1 <50%, as well as rwPFS (HR, 0.39; P = 0.02) and OS (HR, 0.36; P = 0.03) in brain metastases and rwPFS (HR, 0.55; P = 0.01) in bone metastases. No significant differences were observed in the incidence of high-grade toxicity (P = 0.9) or rates of permanent treatment discontinuation (P = 0.2) between first-line MET TKI and ICI ± chemotherapy. Conclusions: First-line MET TKI improved outcomes in PD-L1 <50% and brain/bone metastases, whereas ICI ± chemotherapy prolonged PFS only in PD-L1 ≥80%, emphasizing the need for personalized treatment selection.

In recent years, the therapeutic landscape of non-small cell lung cancer (NSCLC) has been transformed by immune checkpoint inhibitors (ICIs), which have led - in some patients - to unprecedented survival expectancy. Nevertheless, identifying patients most likely to benefit from ICI remains a major challenge. While PD-L1 expression and tumor mutation burden (TMB) represent established predictive biomarkers, their predictive ability still needs to be improved, which underscores the need for identifying additional (bio)markers for treatment selection. Recent research has highlighted multiple emerging biomarkers, including genomic alterations (eg, KEAP1, STK11, SMARCA4), markers of metabolic pathway dysregulation (IDO, adenosine axis), tumor-infiltrating lymphocytes, and blood-based biomarkers (eg soluble markers of inflammation, germline HLA diversity, and circulating tumor DNA). Host-related determinants, such as the history of tobacco exposure and the body mass index, further contribute to immunotherapy outcomes. In addition, artificial intelligence (AI) and machine learning (ML) approaches are enabling integration of multidimensional data, leading to predictive scoring systems which have outperformed conventional biomarkers in certain settings. This review synthesizes current evidence on established and emerging predictive biomarkers in NSCLC, highlighting the potential of combining biological, host, and computational features to inform precision immunotherapy strategies.

In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood–brain barrier.