Clinical and Molecular Features of KRAS-Mutated Lung Cancer Patients Treated with Immune Checkpoint Inhibitors
Open accessAbstract
Background: The molecular and clinical features of KRAS-mutated lung cancer patients treated with immunotherapy have yet to be characterized, which could guide the development of therapeutics targeting KRAS with potential immuno-oncology treatment combinations. Research Question: Do KRAS-mutated patients with different subtypes and comutations have different clinical responses and overall survival (OS) to checkpoint inhibitors? Study Design and Methods: 87 patients with NSCLC at the City of Hope who received immune checkpoint inhibitors were identified and analyzed retrospectively. Tumor genomic alterations were extracted from the clinical data with next-generation sequencing using various platforms. Demographic, clinical, molecular, and pathological information was collected with the approval of the institutional review board of the City of Hope. OS was calculated if it was available at the study time point, and responses were determined according to the RECIST v1.1. Results: Among 87 patients, 32 had a KRAS G12C mutation (36.8%), 19 had G12V (21.9%), 18 had G12D (20.7%), 6 had G12A (6.9%), 3 had G12R (3.45%), and 10 had amplification (11.49%) and other uncommon mutations. G12D had a statistically significant Odds Ratio (OR) between patients who had responses and progression of the disease (OR (95% CI) = 0.31 (0.09–0.95), p < 0.05), with 5 G12D-mutated patients having responses and 11 G12D-mutated patients having progression of the disease. In the univariate analysis with OS, there was a trend of better OS in the G12D-mutated patients, with no statistically significant difference in terms of OS between the patients who had G12D mutation and the patients who had other KRAS mutations (HR (95% CI) = 0.53 (0.21–1.36), p = 0.185). The median OS was significantly worse with KRAS comutation CDKN2A/B loss (4.2 vs. 16.9 months, HR = 3.07 (1.09–8.69), p < 0.05) and MET (3.4 vs. 17 months, HR = 3.80 (1.44–10.05), p < 0.01), which were included for the multivariate analysis. The OS with other KRAS comutations was not statistically significant, including STK11 and KEAP1. Conclusion: KRAS mutation subtypes such as G12D and comutations such as CDKN2/A and MET may modulate the immunotherapy responses and outcomes in lung cancer.
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In KRAS-mutated lung cancer, CDKN2A mutation was associated with worse survival on immunotherapy.
“In KRAS-mutated lung cancer, CDKN2A mutation was associated with worse survival on imunotherapy53.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [53]
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Marković, F., Milin-Lazovic, J. S., Nikolić, N., Golubovic, A., Stjepanović, M., & Kontić, M. (2025) · Current Oncology · doi:10.3390/curroncol32060365 · Cited by 8 · see citing works
Knetki‐Wróblewska, M., Tabor, S., Płużański, A., Lewandowska, Z., Tysarowski, A., Pawlik, H., Kowalski, D. M., & Krzakowski, M. J. (2022) · Current Oncology · doi:10.3390/curroncol30010037 · Cited by 7 · see citing works
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Spatial iTME analysis of KRAS mutant NSCLC and immunotherapy outcome
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Mechanisms and current advances in treating KRAS-mutated lung cancer
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- Authors
- Zhao, D., Li, H., Mambetsariev, I., Mirzapoiazova, T., Chen, C., Fricke, J., Kulkarni, P., Villaflor, V., Arvanitis, L., Hamilton, S., Afkhami, M., Pillai, R., Armstrong, B., Erhunmwunsee, L., Massarelli, E., Sattler, M., Amini, A., & Salgia, R.
- Affiliations
- City Of Hope National Medical Center (US)
- Harvard University (US)
- Corresponding author
- Salgia, Ravi
- ORCID
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2022-10-08
- Volume
- 14
- Issue
- 19
- Pages
- 4933
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC9562655
- OpenAlex
- W4303685359
- Cited by
- 24
- References
- 61
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 7 · 2023: 1 · 2022: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Cancer Institute, National Institutes of Health (P30CA033572)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- KRAS mutation, non-small cell lung cancer, immune checkpoint inhibitors, immunotherapy response, KRAS G12D, KRAS G12C, KRAS amplification, CDKN2A/B loss, MET amplification, overall survival, tumor genomic alterations, predictive biomarkers, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4
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