A Real-World Experience on the Efficacy of First-Line Treatment with Immune-Checkpoint Inhibitors in Non-Small-Cell
Lucia Motta1, Samantha Epistolio2, Jana Pankovics1
1Oncological Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), 6500 Bellinzona, Switzerland.
Background/Objectives:
Several genetic alterations have been identified as drivers of uncontrolled cell growth in lung cancer, with KRAS mutations representing the most prevalent driver oncogene. Despite advances in targeted treatment, the 5-year survival rate of patients with advanced/metastatic NSCLC is still less than 20%. This study aims to assess the clinical relevance of KRAS mutations in the context of PD-L1 expression, focusing on patients with PD-L1 Tumor Proportion Score (TPS) ≥ 50% and treated with first-line immune checkpoint inhibitors (ICIs).
Methods:
We conducted a retrospective analysis of a real-world cohort comprising all staged NSCLC patients diagnosed and treated between 2018 and 2022 at our Institution with the available Next Generation Sequencing and PD-L1 immunohistochemistry results. Statistical analyses were made using the log-rank test, the two-tailed Fisher's exact test, and Kaplan-Meier survival curves.
Results:
Among 520 NSCLC patients, 288 were adenocarcinoma (AC). Of these, 110/288 (38.2%) were KRAS mutants, and 83/278 (29.8%) presented a PD-L1 TPS ≥ 50%. In this subgroup, KRAS mutants demonstrated longer median overall survival (mOS) and progression-free survival (PFS) compared to the KRAS wild-type (28.7 vs. 10.7 months, p = 0.010; 6.4 vs. 3.5 months, p = 0.005, respectively). While OS did not differ among KRAS mutation subtypes, PFS was significantly shorter in patients with p.G12D (3.5 months, p = 0.03).
Conclusion:
This study is the first to investigate the interplay between KRAS mutations and PD-L1 expression in a real-world stage IV lung AC cohort treated with ICIs. Our findings indicate that the p.G12D mutation is associated with an extremely severe disease upon ICI monotherapy. These preliminary results need further validation in larger, prospective cohorts.
Insights
KRAS mutations in lung adenocarcinoma patients with high PD-L1 expression receiving immune checkpoint inhibitors show improved survival. However, the KRAS p.G12D mutation indicates a poorer prognosis, necessitating further research.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- KRAS mutations are common drivers in lung cancer, yet survival for advanced NSCLC remains poor.
- Immune checkpoint inhibitors (ICIs) targeting PD-L1 are a standard treatment for NSCLC.
- Understanding KRAS mutation impact alongside PD-L1 expression is crucial for optimizing ICI therapy.
Purpose of the Study:
- To evaluate the clinical relevance of KRAS mutations in stage IV lung adenocarcinoma (AC) with PD-L1 Tumor Proportion Score (TPS) ≥ 50%.
- To assess the impact of KRAS mutations on treatment outcomes with first-line immune checkpoint inhibitors (ICIs).
Main Methods:
- Retrospective analysis of a real-world cohort of NSCLC patients (2018-2022).
- Inclusion criteria: available Next Generation Sequencing and PD-L1 IHC results.
- Statistical analysis included log-rank test, Fisher's exact test, and Kaplan-Meier curves.
Main Results:
- Among 288 AC patients, 38.2% had KRAS mutations, and 29.8% had PD-L1 TPS ≥ 50%.
- In the PD-L1 TPS ≥ 50% subgroup, KRAS mutants had significantly longer median overall survival (mOS) and progression-free survival (PFS) than wild-type (mOS: 28.7 vs. 10.7 months; PFS: 6.4 vs. 3.5 months).
- The KRAS p.G12D mutation was associated with significantly shorter PFS (3.5 months).
Conclusions:
- This is the first study to examine KRAS mutations and PD-L1 expression in stage IV lung AC treated with ICIs.
- The KRAS p.G12D mutation may predict a severe disease course with ICI monotherapy.
- Larger, prospective studies are needed to validate these findings.
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