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Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS G12D -mutated non-small-cell lung cancer.
- Source :
-
Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2022 Oct; Vol. 33 (10), pp. 1029-1040. Date of Electronic Publication: 2022 Jul 22. - Publication Year :
- 2022
-
Abstract
- Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRAS <superscript>MUT</superscript> ) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRAS <superscript>G12C</superscript> NSCLC, KRAS <superscript>G12D</superscript> NSCLC is associated with low/never-smoking status and is largely uncharacterized.<br />Patients and Methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype.<br />Results: Of 2327 patients with KRAS-mutated (KRAS <superscript>MUT</superscript> ) NSCLC, 15% (n = 354) harbored KRAS <superscript>G12D</superscript> . Compared to KRAS <superscript>non-G12D</superscript> NSCLC, KRAS <superscript>G12D</superscript> NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRAS <superscript>G12D</superscript> had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRAS <superscript>non-G12D</superscript> (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRAS <superscript>G12D</superscript> had lower intratumoral and total CD8 <superscript>+</superscript> PD1 <superscript>+</superscript> T cells (P < 0.05). Among 850 patients with advanced KRAS <superscript>MUT</superscript> NSCLC who received PD-(L)1-based therapies, KRAS <superscript>G12D</superscript> was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRAS <superscript>non-G12D</superscript> .<br />Conclusions: KRAS <superscript>G12D</superscript> lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRAS <superscript>G12D</superscript> lung cancers will have to take these differences into account.<br /> (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)
- Subjects :
- B7-H1 Antigen
Forkhead Transcription Factors
Genomics
Humans
Mutation
Programmed Cell Death 1 Receptor
Proto-Oncogene Proteins p21(ras) genetics
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Lung Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1569-8041
- Volume :
- 33
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Annals of oncology : official journal of the European Society for Medical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 35872166
- Full Text :
- https://doi.org/10.1016/j.annonc.2022.07.005