Dataset Information

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

ABSTRACT:

Background

KRAS is the most frequently mutated gene in non-small cell lung cancer (NSCLC), however conflicting data are available on its role as a biomarker.

Objective

The aim of our work was to investigate the impact of KRAS mutations on response and survival outcomes in advanced non-squamous NSCLC patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy.

Patients and methods

We retrospectively identified 119 patients, most of whom (58%) were KRAS wild type. For each patient we evaluated overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). An exploratory analysis was performed among KRAS mutated patients to investigate the impact of specific KRAS mutations on response and survival outcomes.

Results

After a median follow-up of 10.3 months, the median OS was 14.9 months (95% confidence interval [CI] 7.6-22.7) in wild-type KRAS patients versus 14.7 months (95% CI 8.0-19.5) in mutated KRAS patients (p = 0.529). No differences were detected between the two groups in terms of PFS and DCR. Patients with a KRAS G12C mutation reported survival and response outcomes that were not statistically different from those of patients with other KRAS mutations.

Conclusion

Our data confirmed that KRAS mutational status is not associated with survival and response outcomes in advanced non-squamous NSCLC patients treated with immunotherapy alone or combined with chemotherapy.

SUBMITTER: Veccia A

PROVIDER: S-EPMC9928930 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

Veccia Antonello A Dipasquale Mariachiara M Kinspergher Stefania S Monteverdi Sara S Girlando Salvatore S Barbareschi Mattia M Caffo Orazio O

Targeted oncology 20221208 1

<h4>Background</h4>KRAS is the most frequently mutated gene in non-small cell lung cancer (NSCLC), however conflicting data are available on its role as a biomarker.<h4>Objective</h4>The aim of our work was to investigate the impact of KRAS mutations on response and survival outcomes in advanced non-squamous NSCLC patients treated with immune checkpoint inhibitors alone or in combination with chemotherapy.<h4>Patients and methods</h4>We retrospectively identified 119 patients, most of whom (58%) ...[more]

PMID: 36482151

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Project description:BackgroundThe present study aimed to investigate the determinant factors of survival in patients with pretreated advanced stage non-small cell lung cancer (NSCLC) who received anti-PD-1/PD-L1 therapy.MethodsIn this observational retrospective study, the clinical profiles and laboratory parameters of patients with NSCLC treated with anti-PD-1/PD-L1 therapy were consecutively collected. Lung Immune Prognostic Index (LIPI) was calculated based on the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase level (LDH). Modified Glasgow Prognostic Score (mGPS) was calculated based on serum C reactive protein and albumin, and tumor mutation burden (TMB) was calculated using a targeted next-generation sequencing panel based on 422 cancer-relevant genes. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. The Cox regression model was used to identify the potential determinant factors of survival benefit. Trained oncologists at Sun Yat-sen University Cancer Center followed all of the participants through visits to doctors' offices or via telephone calls to determine their clinical status.ResultsSeventy-three patients were included in our study. With a median follow up time of 637 days, there was a significant difference in PFS between patients with high TMB compared to those with low TMB (3.7 vs. 2.1 months; P=0.004), while no significant difference was found in OS (14.0 vs. 16.4 months; P=0.972). Patients with a good LIPI score had a significantly longer OS compared to patients with a poor LIPI score (19.2 vs. 12.6 months; P=0.010). The median OS in patients with a good and a poor mGPS was 16.8 and 4.3 months, respectively (P=0.029). In multivariate analysis, TMB was found to be significantly associated with PFS (HR, 0.38; 95% CI: 0.21-0.69; P=0.002), while LIPI score was found to be significantly associated with OS (HR, 0.50; 95% CI: 0.28-0.89; P=0.012).ConclusionsIn the present study, LIPI score was a significant determinant of OS in patients with advanced NSCLC who received ICIs; however, TMB was only associated with PFS and not associated with OS.

Project description:BackgroundAlthough immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD-1) and its ligand PD-L1 have demonstrated potency towards treating patients with non-small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism.MethodsThe association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort (n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS-mutant NSCLC, such as CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs.ResultsWe observed the inferior efficacy of ICIs in KRAS-G12D-mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS-mutant NSCLC, KRAS-G12D point mutation negatively correlated with PD-L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+ TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS-G12D mutation suppressed PD-L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down-regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD-L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD-L1 inhibitor monotherapy in a mouse model with KRAS-G12D-mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+ TILs via the up-regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo-immunotherapy in patients with KRAS-G12D-mutant NSCLC compared with ICI monotherapy.ConclusionsOur study elucidated the molecular mechanism by which KRAS-G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS-G12D-mutant NSCLC.

Dataset Information

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

Background

Objective

Patients and methods

Results

Conclusion

Publications

Impact of KRAS Mutations on Clinical Outcomes of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer Receiving Anti-PD-1/PD-L1 Therapy.

Similar Datasets

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