Real-World outcomes of Non-Small cell lung cancer patients harbouring KRAS G12C and KRAS G12D mutations

Adel Shahnam¹, Alexander Davis², Lauren Julia Brown³, Isaac Sullivan⁴, Kevin Lin⁵, Chien Ng⁵, Nicholas Yeo⁶, Benjamin Y Kong⁷, Trisha Khoo⁸, Lydia Warburton⁸, Inês Pires Da Silva⁹, William Mullally¹⁰, Wen Xu¹¹, Ken O'Byrne¹⁰, Victoria Bray⁵, Abhijit Pal⁵, Antony Mersaides¹², Malinda Itchins¹³, Surein Arulananda⁴, Adnan Nagrial³, Steven Kao¹⁴, Marliese Alexander¹⁵, Chee Khoon Lee¹⁶, Benjamin Solomon¹⁷, Thomas John¹⁷

Affiliations

¹ Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria 3000, Australia. Electronic address: adel.shahnam@petermac.org.
² Department of Medical Oncology, Chris O'brien Lifehouse, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal Northshore Hospital, Sydney, New South Wales, Australia.
³ Department of Medical Oncology, Crown Princess Mary Cancer Center, Sydney, New South Wales, Australia; Department of Medical Oncology, Blacktown Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Medical Oncology, Monash Hospital, Melbourne, Victoria, Australia.
⁵ Department of Medical Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.
⁶ Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
⁷ Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia; Clinical Medicine, University of New South Wales, Sydney, New South Australia, Australia.
⁸ Department of Medical Oncology, Fiona Stanley Hospital, Perth, Western Australia, Australia.
⁹ Department of Medical Oncology, Blacktown Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
¹⁰ Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
¹¹ Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Faculty of Medicine and Health, University of Queensland, Brisbane, Queensland, Australia.
¹² Department of Medical Oncology, Northen Beaches Hospital, Sydney, New South Wales, Australia.
¹³ Department of Medical Oncology, Chris O'brien Lifehouse, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal Northshore Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁴ Department of Medical Oncology, Chris O'brien Lifehouse, Sydney, New South Wales, Australia.
¹⁵ Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁶ Department of Medical Oncology, St George Hospital, Sydney, New South Wales, Australia.
¹⁷ Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.

PMID: 39977966
DOI: 10.1016/j.lungcan.2025.108421

Observational Study

Real-World outcomes of Non-Small cell lung cancer patients harbouring KRAS G12C and KRAS G12D mutations

Adel Shahnam et al. Lung Cancer. 2025 Mar.

. 2025 Mar:201:108421.

doi: 10.1016/j.lungcan.2025.108421. Epub 2025 Feb 12.

Authors

Affiliations

¹ Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria 3000, Australia. Electronic address: adel.shahnam@petermac.org.
² Department of Medical Oncology, Chris O'brien Lifehouse, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal Northshore Hospital, Sydney, New South Wales, Australia.
³ Department of Medical Oncology, Crown Princess Mary Cancer Center, Sydney, New South Wales, Australia; Department of Medical Oncology, Blacktown Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Medical Oncology, Monash Hospital, Melbourne, Victoria, Australia.
⁵ Department of Medical Oncology, Liverpool Hospital, Sydney, New South Wales, Australia.
⁶ Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
⁷ Department of Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia; Clinical Medicine, University of New South Wales, Sydney, New South Australia, Australia.
⁸ Department of Medical Oncology, Fiona Stanley Hospital, Perth, Western Australia, Australia.
⁹ Department of Medical Oncology, Blacktown Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, Australia.
¹⁰ Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
¹¹ Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Faculty of Medicine and Health, University of Queensland, Brisbane, Queensland, Australia.
¹² Department of Medical Oncology, Northen Beaches Hospital, Sydney, New South Wales, Australia.
¹³ Department of Medical Oncology, Chris O'brien Lifehouse, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal Northshore Hospital, Sydney, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁴ Department of Medical Oncology, Chris O'brien Lifehouse, Sydney, New South Wales, Australia.
¹⁵ Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁶ Department of Medical Oncology, St George Hospital, Sydney, New South Wales, Australia.
¹⁷ Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.

PMID: 39977966
DOI: 10.1016/j.lungcan.2025.108421

Abstract

Background: KRAS G12D and G12C mutations have distinct biological traits influencing treatment response. This study examines real-world demographics, clinical characteristics, and first-line treatment outcomes in metastatic non-small-cell lung cancer (NSCLC) patients with these mutations.

Methods: This retrospective, multi-institution observational study used data from the AURORA database. Patients aged 18 years or older, diagnosed with metastatic KRAS G12D or G12C NSCLC between January 1, 2010, and April 30, 2024, were included. Descriptive statistics compared patient characteristics, and time-to-event outcomes were assessed using Cox proportional hazards regression.

Results: A total of 298 (216 KRAS G12C and 82 KRAS G12D) patients were included. The KRAS G12D group had a higher proportion of never smokers (15 % vs. 1 %, p < 0.01) and PD-L1 < 1 % (36 % vs. 21 %, p = 0.06). No significant differences were observed in overall survival (OS) (HR 1.09, 95 % CI 0.80-1.48, p = 0.60) or real-world progression-free survival (rwPFS) (HR 1.21, 95 % CI 0.92-1.59, p = 0.18) between mutation groups. In KRAS G12C, monotherapy immunotherapy (HR 0.61, 95 % CI 0.39-0.97, p = 0.04) and chemo-immunotherapy (HR 0.59, 95 % CI 0.37-0.94, p = 0.03) improved OS compared to chemotherapy. For KRAS G12D, neither immunotherapy (HR 0.74, 95 % CI 0.29-1.89, p = 0.53) nor chemo-immunotherapy (HR 0.73, 95 % CI 0.34-1.57, p = 0.42) improved OS compared to chemotherapy alone.

Conclusion: KRAS G12C and G12D mutations demonstrate distinct clinical characteristics and treatment responses, with poorer immunotherapy outcomes in KRAS G12D patients. Prospective studies are needed to validate these findings.

Keywords: KRAS G12C; KRAS G12D; NSCLC.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Real-World outcomes of Non-Small cell lung cancer patients harbouring KRAS G12C and KRAS G12D mutations

Affiliations

Real-World outcomes of Non-Small cell lung cancer patients harbouring KRAS G12C and KRAS G12D mutations

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous