The following non-small cell lung cancer studies were presented at the ESMO 2025 Congress, held October 17–21, 2025.
STK11-Mutant NSCLC: KRAS Mutation Status and Overall Survival
Researchers analyzed molecular and clinical differences between STK11-mutant NSCLC patients who also harbored a KRAS mutation and those who did not, assessing whether KRAS mutation status influenced overall survival in stage IV disease.
Study Snapshot
- Study: Retrospective molecular analysis
- Population: Patients with STK11-mutant non-small cell lung cancer
- Sample size: 808 patients (453 KRAS-mutant; 355 KRAS-wildtype)
- Data years: 2022–2024
- Focus: Clinical and molecular differences between STK11-mutant/KRAS-mutant and STK11-mutant/KRAS-wildtype NSCLC
Study Background
Researchers compared clinical and molecular differences between STK11-mutant/KRAS-mutant 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.
Key Results
- In the KRAS-mutant group, frameshift mutation was the most common mutation type (30.2% vs 25.6% in KRAS-wildtype; p=0.157)
- Missense mutation was the most common type in the KRAS-wildtype group (45.6% vs 27.6% in KRAS-mutant; p<0.001)
- Nonsense mutations were significantly more prevalent in the KRAS-mutant group (25.6% vs 13.5%; p<0.001)
- In-frame insertions/deletions were similar between groups (5.1% KRAS-mutant vs 2.5% KRAS-wildtype; p=0.071)
- In both groups, STK11 mutations were most frequently within the kinase domain (KRAS-mutant: 88.2%; KRAS-wildtype: 81.4%)
- Among 445 patients with stage IV disease, no significant difference in OS by KRAS mutation status was observed: KRAS-mutant median OS 14.2 months (95% CI: 6.8–21.7) vs KRAS-wildtype 17.4 months (95% CI: 9.6–25.2); log-rank p=0.318
Clinical Takeaway
STK11-mutant/KRAS-mutant and STK11-mutant/KRAS-wildtype NSCLC differ in molecular mutation patterns, but KRAS mutation status alone did not significantly impact overall survival in patients with stage IV disease.
Link to Abstract
KRAS G12D NSCLC: Outcomes With Immunotherapy
This multicenter retrospective study examined treatment outcomes in patients with advanced KRAS G12D-mutant NSCLC, a population with notably low PD-L1 expression and a higher proportion of never smokers than other KRAS alleles.
Study Snapshot
- Study: RAS-precision medicine (RAS-PM) transatlantic partnership — multicenter retrospective study
- Population: Patients with advanced KRAS G12D-mutant NSCLC treated with immunotherapy
- Sample size: 102 patients with KRAS G12D mutations and complete survival data (from 686 RAS-mutant patients)
- Data years: 2008–2023
- Focus: Treatment outcomes in KRAS G12D-mutant advanced NSCLC
Study Background
Research on the impact of KRAS G12D mutation on survival in immunotherapy-treated patients with advanced NSCLC is currently limited. Researchers conducted a multicenter retrospective study to assess treatment outcomes among this patient population. 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, a significantly higher frequency than for other alleles (p<0.001).
Key Results
- 25% of patients were never smokers — significantly higher than for other alleles (p<0.001)
- Median PD-L1 expression: 0% in the KRAS G12D group vs 40% in the KRAS G12C group (p=0.01); PD-L1 ≥50% was observed in only 13% of never smokers
- Any-line immunotherapy was associated with improved OS vs chemotherapy: HR 0.45 (95% CI: 0.28–0.74); median OS 21 months vs 8 months (p=0.001)
- Among immunotherapy-treated patients, ECOG PS 0–1 was associated with improved PFS and OS: HR 0.05 (95% CI: 0–0.41; p=0.05)
- TP53 comutation was also associated with improved PFS and OS in immunotherapy-treated patients: HR 0.03 (95% CI: 0–0.38; p=0.05)
Clinical Takeaway
In patients with advanced KRAS G12D-mutant NSCLC, immunotherapy was associated with significantly improved overall survival compared to chemotherapy. Good performance status and TP53 comutation were associated with better outcomes among immunotherapy-treated patients.
Link to Abstract
KRAS-Mutant NSCLC: Genomic and Transcriptomic Profiling in Chinese Patients
Using combined genomic and transcriptomic sequencing, researchers investigated how comutation status, particularly the presence of TP53 and STK11 mutations alongside KRAS, shaped the immune landscape and survival outcomes in Chinese patients with KRAS-mutant NSCLC.
Study Snapshot
- Study: Combinatory genomic and transcriptomic sequencing analysis
- Population: Chinese patients with KRAS-mutant NSCLC
- Sample size: 162 patients
- Focus: Cellular and molecular characteristics stratified by comutation status
Study Background
Researchers evaluated cellular and molecular characteristics of KRAS-mutant NSCLC tumor samples. 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, KRAS/STK11, and KRAS/TP53/STK11.
Key Results
- OS (p=0.034), tumor mutation burden (p=1.54×10⁻⁶), and immune score by ESTIMATE (p=0.0264) significantly differed between the four comutation groups
- RNA expression profiles were significantly different between groups, with AUC ranging from 0.83 to 0.90 across eight models
- Median OS was shortest in the KRAS/TP53/STK11 group (217 days) and longest in the KRAS mutation–only group (577 days)
- The KRAS/TP53/STK11 group had the lowest median immune score (423.7); the KRAS/TP53 group had the highest (1,326.8)
- Tumor mutation burden was lowest in the KRAS mutation–only group (median 5.5) and highest in the KRAS/TP53 group (median 12.7)
Clinical Takeaway
KRAS/TP53/STK11 comutated NSCLC tumors were highly immune cold and associated with the worst survival outcomes, while KRAS mutation alone carried the most favorable prognosis. Comutation profiling may help stratify prognosis and guide treatment strategies in KRAS-mutant NSCLC.
Link to Abstract
Smoking Status and ICI Efficacy in Oncogene-Driven NSCLC
This large real-world analysis investigated whether smoking history affected the benefit of immune checkpoint inhibitor therapy in patients with oncogene-driven stage IV NSCLC, a question with direct implications for treatment decision-making.
Study Snapshot
- Study: Real-world analysis from the ESME lung cancer database
- Population: Patients with stage IV oncogene-addicted NSCLC
- Sample size: 3,182 patients
- Focus: Impact of smoking status on first-line immune checkpoint inhibitor efficacy
Study Background
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. 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 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%).
Key Results
- ICI treatment was associated with improved PFS (adjusted HR: 0.77) and OS (adjusted HR: 0.75) on multivariable analysis
- Results were similar between KRAS-mutant and KRAS-wildtype patients
- Smoking status did not impact ICI treatment efficacy (interaction test aHR: 0.96)
Clinical Takeaway
ICI-based therapy was associated with improved progression-free and overall survival in oncogene-addicted NSCLC, regardless of KRAS mutation status or smoking history. Smoking status alone should not be used to determine ICI candidacy in this population.
Link to Abstract
Molecular Testing and Outcomes in Unresected Stage III NSCLC
Researchers used a large French real-world cohort to assess how often molecular testing was performed in unresected stage III NSCLC and how mutation status and PD-L1 expression correlated with survival outcomes.
Study Snapshot
- Study: Real-world analysis from the ESCAP-2020 study
- Population: Patients with unresected, stage III NSCLC in France
- Sample size: 875 patients
- Focus: Molecular testing patterns and treatment outcomes
Study Background
The aim of this real-world study was to describe molecular testing and treatment outcomes among patients with unresected, stage III NSCLC. Mean age was 68.1 years; 56.8% 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 ≥1% was reported in 60.6% of patients, and 44.1% had squamous histology.
Key Results
- Molecular testing for at least one biomarker was conducted in 51.0% of patients; the most common reason for omission was histology (75.8%)
- KRAS mutations were identified in 32.0% (92/282) of tested patients; KRAS G12C mutations in 16.6% (42/282)
- Other frequent mutations: EGFR mutations (7.7%, 28/360) and BRAF mutations (7.7%, 21/270)
- Chemotherapy was the most common treatment (78.2%), followed by thoracic radiotherapy (52.6%), immunotherapy (35.5%), and chemo-immunotherapy (30.2%)
- 3-year OS: 33.9% for stage IIIA (95% CI: 29.0–39.6%), 32.4% for stage IIIB (95% CI: 28.0–37.4%), and 26.2% for stage IIIC (95% CI: 20.3–33.8%)
- In KRAS-mutant NSCLC, 3-year OS was 41.3% overall (95% CI: 32.4–53.7%), 52.0% in patients with PD-L1 >50% (95% CI: 35.7–75.8%), and 37.5% in patients with PD-L1 <1% (95% CI: 22.4–62.9%)
Clinical Takeaway
Molecular testing was performed in only about half of patients with unresected stage III NSCLC, most often omitted due to histology. Among patients with KRAS-mutant disease, higher PD-L1 expression was associated with improved 3-year survival, underscoring the importance of comprehensive biomarker testing even in stage III disease.