Molecular characteristics and overall survival of STK11-mutant NSCLC according to KRAS mutation status. In this study, researchers compared clinical and molecular differences between STK11-mutant/KRAS-mutant non-small cell lung cancer (NSCLC) and STK11-mutant/KRAS-wildtype NSCLC. Data from 2022 to 2024 were included for analysis. Among 808 patients with STK11-mutant NSCLC, 453 (56.1%) harbored a KRAS mutation as well. In the KRAS-mutant group, frameshift mutation was the most common mutation type, present in 30.2% of patients versus 25.6% of KRAS-wildtype patients (Fisher’s exact test p=0.157). The most common mutation type in the KRAS-wildtype group was missense mutation, observed in 45.6% of patients versus 27.6% of KRAS-mutant patients (p<0.001). Nonsense mutations were significantly more prevalent in the KRAS-mutant group versus the KRAS-wildtype group (25.6% vs. 13.5%, p<0.001). A similar proportion of KRAS-mutant and KRAS-wildtype patients had in-frame insertions/ deletions (5.1% and 2.5%, respectively; p=0.071). In both groups, STK11 mutations were most frequently within the kinase domain (KRAS-mutant: 88.2%; KRAS-wildtype: 81.4%), with fewer mutations in the N-terminal region (KRAS-mutant: 7.4%; KRAS-wildtype: 9.3%) and C-terminal region (KRAS-mutant: 4.5%; KRAS-wildtype: 9.3%). Analyzing data from 445 patients with stage IV disease, researchers found no significant difference in overall survival (OS) based on KRAS mutation status; median OS was 14.2 months (95% confidence interval [CI]: 6.8–21.7 months) in the KRAS-mutant group and 17.4 months (95% CI: 9.6–25.2 months) in the KRAS-wildtype group (log-rank p=0.318).
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RAS-precision medicine (RAS-PM) transatlantic partnership: focus on the characteristics and outcomes of advanced KRAS G12D non-small cell lung cancer patients. Currently, research on the impact of KRAS G12D mutation on survival in immunotherapy-treated patients with advanced NSCLC is limited. As such, researchers conducted a multicenter retrospective study to assess treatment outcomes among this patient population. Data from 2008 to 2023 were included for analysis. Of 686 patients with RAS mutations, 102 patients with KRAS G12D mutations and complete survival data were identified. Twenty-five percent of patients were never smokers, which was a significantly higher frequency than for other alleles (p<0.001). Median programmed death-ligand 1 (PD-L1) expression was 0% in the KRAS G12D group compared to 40% in the KRAS G12C group (p=0.01), and PD-L1 of 50% or greater was observed in 13% of never smokers. Any-line immunotherapy was associated with improved OS compared to chemotherapy (hazard ratio [HR]: 0.45, 95% CI: 0.28–0.74), with median OS of 21 and 8 months, respectively (p=0.001). In patients treated with immunotherapy (either alone or with chemotherapy), factors associated with improved progression-free survival (PFS) and OS were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 through 1 (HR: 0.05, 95% CI: 0–0.41, p=0.05) and TP53 comutation (HR: 0.03, 95% CI: 0–0.38, p=0.05).
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Combinatory genomic and transcriptomic sequencing of Chinese KRAS-mutant non-small cell lung cancer revealed KRASmSTK11mTP53m tumors were highly immune cold with a worse survival outcome. Here, researchers evaluated cellular and molecular characteristics of KRAS-mutant NSCLC tumor samples to further understand this disease state. Tumor specimens from 162 patients underwent histological evaluation as well as genomic and transcriptomic profiling. Most patients were male (n=141), had adenocarcinoma histology (n=140), and had a history of smoking (n=121). The most common KRAS mutation was KRAS G12C (n=68), followed by KRAS G12D (n=33) and KRAS G12V (n=32). Frequently comutated genes included TP53, STK11, LRP1B, and KEAP1. Patients were stratified into four groups based on comutation status: KRAS mutation only, KRAS/TP53 comutation, KRAS/STK11 comutation, and KRAS/TP53/STK11 comutation; between these four groups, OS (p=0.034), tumor mutation burden (p=1.54×10–6), and immune score as measured by ESTIMATE (p=0.0264) significantly differed. Furthermore, ribonucleic acid (RNA) expression profiles were significantly different between groups, with area under the curve (AUC) ranging from 0.83 to 0.90 across eight models. Median OS was shortest in the KRAS/TP53/STK11 comutation group, at 217 days, and longest in the KRAS mutation–only group, at 577 days. The KRAS/TP53/STK11 comutation group exhibited a low median immune score of 423.7, and the KRAS/TP53 comutation group had the highest immune score (median: 1,326.8). Median tumor mutation burden was lowest in the KRAS mutation–only group (5.5) and highest in the KRAS/TP53 comutation group (12.7).
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Impact of smoking status on the efficacy of first-line immune checkpoint inhibitors in stage IV oncogene-addicted lung cancer. In this study, researchers assessed the treatment benefit of first-line immune checkpoint inhibitors (ICIs) with or without chemotherapy in oncogene-driven NSCLC, as well as the impact of smoking status on outcomes. Data from the Epidemiological Strategy and Medical Economics (ESME) lung cancer database were analyzed. In total, 3,182 patients with were included for analysis. Median age was 64 years (range: 32–92 years). Most patients were former (50.6%) or current (40.8%) smokers, and 8.6% were never smokers. The majority of patients harbored KRAS mutations (74.8%), followed by BRAF (9.7%) and MET (7.6%). The most common first-line treatment was chemotherapy plus ICI (45.1%), followed by chemotherapy alone (38.1%) and ICI monotherapy (16.8%). ICI treatment was associated with improved PFS (adjusted HR [aHR]: 0.77) and OS (aHR: 0.75) upon multivariable analysis, and these results were similar between KRAS-mutant and KRAS-wildtype patients. Smoking status did not impact ICI treatment efficacy (interaction test, aHR: 0.96).
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Testing patterns and outcomes in unresected stage III non-small cell lung cancer (NSCLC): insights from a nationwide French real-world cohort. The aim of this real-world study was to describe molecular testing and treatment outcomes among patients with unresected, stage III NSCLC. Data from 875 patients in the ESCAP-2020 study were analyzed. Mean age was 68.1 years, 56.8% of patients were current smokers and 36.2% were former smokers. Stage IIIA, IIIB, and IIIC disease were reported in 35.7%, 45.0%, and 19.3% of patients, respectively. PD-L1 of 1% or greater was reported in 60.6% of patients, and 44.1% had squamous histology. Molecular testing for at least one biomarker was conducted in 51.0% of patients, and the most common reason for testing omission was histology (75.8%). KRAS mutations were identified in 32.0% (92/282) of patients, and 16.6% (42/282) harbored KRAS G12C mutations. Other frequent mutations included EGFR mutations (7.7%, 28/360) and BRAF mutations (7.7%, 21/270). Chemotherapy was the most common treatment modality (78.2%), followed by thoracic radiotherapy (52.6%), immunotherapy (35.5%), and chemo-immunotherapy (30.2%). The three-year OS rate was 33.9% (95% CI: 29.0–39.6%) for stage IIIA patients, 32.4% (95% CI: 28.0–37.4) for stage IIIB patients, and 26.2% (95% CI: 20.3–33.8%) for stage IIIC patients. In patients with KRAS-mutant NSCLC, three-year OS rate was 41.3% (95% CI: 32.4–53.7%), with a higher rate observed in patients with PD-L1 over 50% (52.0% [95% CI: 35.7–75.8%]) compared to patients with PD-L1 less then 1% (37.5% [95% CI: 22.4–62.9%])
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